Learning Objectives. Pre test #1. Pre test #3. Pre test #2. From a Parent s Eyes: A Journey into the World of Pseudotumor Cerebri Syndrome

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38 th National Conference on Pediatric Health Care March 16-19, 2017 From a Parent s Eyes: A Journey into the World of Pseudotumor Cerebri Syndrome Liz Rende DNP, RN, CPNP PC Duke Pediatric Neurology

1 38 th National Conference on Pediatric Health Care March 16-19, 2017 From a Parent s Eyes: A Journey into the World of Pseudotumor Cerebri Syndrome Liz Rende DNP, RN, CPNP PC Duke Pediatric Neurology & Duke Pediatric Headache Clinic Duke University Medical Center Durham, NC DISCLOSURES Liz Rende has no personal financial relationships with commercial interests relevant to this educational activity within the past 12 months. Learning Objectives Pre test #1 After attending this presentation, participants will be able to Explain the diagnostic dilemmas of PTCS in children Define three common presenting symptoms reported by caregivers and/or child Describe two diagnostic tests to aid in the confirmation of the PTCS diagnosis Describe two common forms of pharmacological treatment for this condition PTCS is a condition that is universally characterized by: A. Visual complaints B. Increased opening pressure with LP C. Difficulty with cognitive function D. vomiting Pre test #2 The team of providers caring for a child with PTCS should include the: A. Podiatrist B. Cardiologist C. Ophthalmologist D. Nutritionist Pre test #3 Children who meet the diagnostic criteria for Idiopathic Intracranial Hypertension have increased ICP with or without papilledema. A. True B. False 1

Pre test #4 Anatomy 101 The medication acetazolamide used to treat PTCS is: A. Well tolerated B. Very effective C. Also used for treating venous sinus thrombosis D.

choroid plexus; Total CSF volume 150ml (more in adults); volume in ventricles is about 25ml Children 4 13yr: 65 150ml/day Replenished every 4 6 hours Circulation aided by pulsations in choroid plexus

2 Pre test #4 Anatomy 101 The medication acetazolamide used to treat PTCS is: A. Well tolerated B. Very effective C. Also used for treating venous sinus thrombosis D. An old medication initially used for adjunct treatment of seizures CSF 101 Clear, colorless fluid Produced in choroid plexus (80%); parenchyma (20%) Plasma ultrafiltrate, transformed into CSF by choroid plexus; Total CSF volume 150ml (more in adults); volume in ventricles is about 25ml Children 4 13yr: ml/day Replenished every 4 6 hours Circulation aided by pulsations in choroid plexus & motion of cilia of ependymal cells Absorbed across arachnoid villi into venous circulation large amount into lymphatic vessels around cranial cavities/spinal canal Retrieved from: Youauttoknow.wordpress.com What are we talking about? Pseudotumor Cerebri AND Idiopathic Intracranial Hypertension Diagnostic Criteria Nomenclature 1897 Heinrich Quincke serous meningitis Late 1800 s Max Nonne pseudotumor cerebri 1937 Dandy Criteria 1955 (Foley) Benign intracranial hypertension 1985 (Smith) Modified Dandy Criteria 1993= Idiopathic Intracranial Hypertension 2013 Pseudotumor Cerebri Syndrome (proposed) Classification And Nomenclature Depends On Presence Or Absence Of Underlying Cause 2

IIH Definition Condition with increased intracranial pressure (ICP) in the absence of a space occupying lesion or hydrocephalus and with a normal cerebrospinal (CSF) composition without clinical,

3 IIH Definition Condition with increased intracranial pressure (ICP) in the absence of a space occupying lesion or hydrocephalus and with a normal cerebrospinal (CSF) composition without clinical, radiological, laboratory evidence of secondary cause Should have papilledema Diagnosis of exclusion What is Pseudotumor Cerebri Syndrome? AKA Idiopathic Intracranial hypertension? NO Secondary Idiopathic Intracranial Hypertension? 1:100,000 general population 15 19:100,000 women 20 44year, who are 20% over ideal body weight Now all ages, gender, obese and non obese More recognized in pediatric population Before puberty M=F; after puberty, female 9:1 male What is so Important about PTCS? Unpredictable & disabling symptoms and pain Missed school days & decline in academic function Parental frustration, missed days of work Main Goal is Preservation of Vision PTCS Criteria required for Diagnosis (proposed) A. Papilledema B. Nl exam X cranial nerve abnormalities C. Neuroimaging MRI/MRV nl brain parenchyma; if contraindicated contrasted CT ok D. Normal CSF composition E. Elevated LP opening pressure: 28cm H20 pressure in children (sedated) or > 25cm H20 pressure if child not sedated N=472 children, >90% ; unknown effects of age, BMI, sedation Friedman, Liu, & Digre. (2013). Neurology, Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children Avery et al, (2010). NEJM, Reference range for CSF opening pressure in children. PTCS w/o Papilledema (proposed) In the ABSENCE of papilledema: B E satisfied AND Unilateral/bilateral 6 th nerve palsy In the Absence of papilledema AND 6 th nerve palsy: Diagnosis of PTCS can be suggested, but not made unless: At least 3 of the following neuroimaging criteria are satisfied *Empty sella *Transverse venous sinus stenosis *Flattening of posterior aspect of the globe *Distention of the perioptic subarachnoid space w/wo tortuous optic nerve Revised Diagnostic Criteria Pseudotumor Cerebri Syndrome? IIH from a secondary cause oxymoron? Primary Pseudotumor Cerebri IIH Secondary Pseudotumor Cerebri Cerebral Venous Abnormalities Medications and Exposures Medical Conditions Friedman, Liu, & Digre. (2013). Neurology, Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children 3

Call from mom of SF 8 yo female SF sees pink and blue colors covering everything.

Case #1 8 year old Caucasian female, nl G&D, previous history of OCD/CBT, complains of frequent headaches and visual complaints, seeing

caused weight gain and significant anxiety, behavioral changes www.blissplan.

Acetazolamide appetite suppression; weight loss Topamax weight loss, not eating, Visual complaints lessened but still present Headaches

opinion at Johns Hopkins Avoid shunting, try furosemide (Lasix) Parents choose another trial of medicine Case #1 Findings Elevated OP

4 Call from mom of SF 8 yo female SF sees pink and blue colors covering everything. She is seeing double all the time, she even drew a picture of two toothpaste tubes. She is quitting gymnastics it hurts too much! Case #1 8 year old Caucasian female, nl G&D, previous history of OCD/CBT, complains of frequent headaches and visual complaints, seeing 2 toothpastes next to each other and clouds of blue and pink Neurophthalmology nl exam MRI of Brain normal Trial of cyproheptadine caused weight gain and significant anxiety, behavioral changes Case #1 Case #1 LP OP= 28 Repeat LP under CT guidance OP= 32 (diazepam sedation) Treatment: Neuro ophthalmology regular follow up Acetazolamide appetite suppression; weight loss Topamax weight loss, not eating, Visual complaints lessened but still present Headaches not resolved school, home, gymnastics Duke Neurosurgical consult Shunting to lower OP pressure and resolve visual complaints 2 nd opinion at Johns Hopkins Avoid shunting, try furosemide (Lasix) Parents choose another trial of medicine Case #1 Findings Elevated OP Normal MRI/MRV of brain No cranial nerve abnormalities No papilledema TOTAL relief of HA and visual complaints with Lasix Diagnosis? A. Idiopathic Intracranial hypertension without papilledema B. Brain tumor C. Malingering D. PTCS E. Primary headache disorder 4

Demographics of IIH/PTCS in Children & Teens Limited info in children and adolescents Prepubertal more likely to be secondary vs idiopathic Obese & female? IIH infrequent < 10yo; rare <3yo Genetics?

5 Demographics of IIH/PTCS in Children & Teens Limited info in children and adolescents Prepubertal more likely to be secondary vs idiopathic Obese & female? IIH infrequent < 10yo; rare <3yo Genetics? Familial history? Challenges in Diagnosis Papilledema may be only sign identified by dilated eye exam Headaches pediatric population may not be able to articulate symptoms Spectrum insidious vs sudden; mild vs severe Lack of awareness that young, thin children can have this diagnosis IIH more common in older population In younger children; the diagnosis of pseudotumor more likely with a secondary, unrecognized cause Secondary Causes & Conditions Medical & Systemic Conditions Infectious Diseases Drugs Head trauma Infectious Diseases Tetracycline Subarachnoid hemorrhage Bacterial and viral meningitis Minocycline Cerebral venous abnormalities Lyme disease Doxycycline Increased R heart pressure HIV Nalidixic acid AV fistulas Poliomyelitis Sulfa Drugs Lupus Coxsackie B viral encephalitis Vitamin A Sarcoidosis Guillain Barre syndrome Isotretinoin Hypoparathyroidism Infectious mononucleosis All trans retinoic acid Addison disease Syphilis Amiodarone Superior vena cava syndrome Malaria Nitofurantoin Hypercoagulable states Lithium Renal failure Levonorgestrel Liver failure Growth hormone Sleep apnea Thyroxine Behcet disease Leuprorelin acetate Middle ear or mastoid infection Steroid withdrawal Hypercapnia Testosterone? Pickwickian syndrome Anemia Turner Syndrome Down Syndrome Adapted from Rogers, D. (2014). A Review of Pediatric Intracranial Hypertension, Pediatric Clinics of North America, 61: Multidisciplinary Team EMR message from Mom of OG 15yr old female OG needs to be seen right away; the pressure is unbearable, I just know it is skyrocketing. She needs another spinal tap! Case #2 Camp waterfront game gone wrong NDPH began August 2015 Multiple evaluations at major medical centers across US Headache and pressure complaints are separate & different Positional excruciating pain when upright Missed > ½ of 8 th grade r/t ongoing complaints, evaluations All headache prophylactic medication trials, + Botox no HA relief (Mooseheadcoabins.com) 5

Case #2 Evaluation: Normal neurological and physical exam Neuro ophthalmology eval normal Cardiology orthostatic hypotension allergic to mineralcorticoid; Rx for midodrine, push fluids,

heart pounding, worsening pressure sensations Acute eval volume depletion, SE of paresthesias, appetite suppression Diamox stopped Furosemide (Lasix) started (Mooseheadcoabins.

Normal MRI/MRV of brain No cranial nerve abnormalities No papilledema No definitive relief from any therapies Neck abnormalities? A. Idiopathic Intracranial hypertension without papilledema B.

com) Presenting Symptoms Headaches migrainous 90% Exacerbated by Valsalva & postural changes Pulsatile tinnitus, rushing water sounds Dizziness, disequilibrium Blurry vision, double vision

6 Case #2 Evaluation: Normal neurological and physical exam Neuro ophthalmology eval normal Cardiology orthostatic hypotension allergic to mineralcorticoid; Rx for midodrine, push fluids, exercise MRI/MRV/MRA normal C spine xray C5 & C6 facet injection LP OP=22, 20, 18cm H20 pressure ( most recent) Started on Diamox Case #2 Acute side effects of Diamox body aches; weight loss; heart pounding, worsening pressure sensations Acute eval volume depletion, SE of paresthesias, appetite suppression Diamox stopped Furosemide (Lasix) started (Mooseheadcoabins.com) (Mooseheadcoabins.com) Case #2 Findings Diagnosis? Elevated or normal OP? hypothesis of sweet spot? Normal MRI/MRV of brain No cranial nerve abnormalities No papilledema No definitive relief from any therapies Neck abnormalities? A. Idiopathic Intracranial hypertension without papilledema B. Brain tumor C. Malingering D. PTCS probable E. Primary headache disorder (Mooseheadcoabins.com) (Mooseheadcoabins.com) Presenting Symptoms Headaches migrainous 90% Exacerbated by Valsalva & postural changes Pulsatile tinnitus, rushing water sounds Dizziness, disequilibrium Blurry vision, double vision (Abducens N.), blind spots, wavy lines Light and sound sensitivity Nausea / Vomiting Wakes patient in the middle of the night Clinical Evaluation Physical Exam History recent weight gain, recent illness, medications, stage of puberty, N/V, neck/back pain Dilated ophthalmologic exam evaluate for papilledema psuedopapilledema/drusen Retrieved from: IIH #awareness #raredisease; pinterest.com 6

Papilledema Diagnostic Evaluation Retrieved from webeye.ophth.

(2014) Secondary intracranial hypertension from testosterone

Seminars of Ophthalmology, doi: 10.3109/08820538.2013.788678.

Morbidity: Risk of visual loss, acuity and field defects

domain optical coherence tomography) measures structural

Committee for the NORDIC Idiopathic Intracranial Hypertension

4, 2014. Part I, doi:10.1167/iovs.14 14960; Part II, doi:10.

Close surveillance by neuropthalmology is a MUST!

7 Papilledema Diagnostic Evaluation Retrieved from webeye.ophth.uiowa.edu Park, Cheng, Lim, Gerber. (2014) Secondary intracranial hypertension from testosterone therapy in the transgender patient. Seminars of Ophthalmology, doi: / Epub. Optometrist OR Ophthalmologist? Morbidity: Risk of visual loss, acuity and field defects Visual Acuity Visual Fields Papilledema SD OCT (spectral domain optical coherence tomography) measures structural changes in the optic nerve Kupersmith MK; OCT Sub Study Committee for the NORDIC Idiopathic Intracranial Hypertension Study Group. Invest Ophthalmol Vis Sci. Published online Nov. 4, Part I, doi: /iovs ; Part II, doi: /iovs Close surveillance by neuropthalmology is a MUST! Ophthalmologic Findings Optic disc edema causing Impaired visual acuity Visual field defects enlargement of blind spot Mimic of Optic nerve edema: Optic nerve head drusen (pseudopapilledema) Increased Intracranial Pressure 7

Imaging Imaging Findings CT evaluate ventricle symmetry and size Bony abnormalities

MRV venous sinus thrombosis Venous stenosis Opening Pressure 34cm H2O pressure

atrium Avoid sedation (Ketamine, Precedex (dexmedetomidine), Valium, Versed,

breath holding) CSF pressure Record OP; abnormal pressure reading is < 25; <28 if

Provocative Maneuvers Diagnostic LP with pressure check Provocative maneuvers:

of CSF Interpretation of provocative maneuvers Improvement of SX: headache, vision,

8 Imaging Imaging Findings CT evaluate ventricle symmetry and size Bony abnormalities MRI flattening of globes Swollen optic nerve sheath Empty sella Chiari malformation MRV venous sinus thrombosis Venous stenosis Opening Pressure 34cm H2O pressure Lumber Puncture Proper positioning Lateral decubitus Base of manometer level with R atrium Avoid sedation (Ketamine, Precedex (dexmedetomidine), Valium, Versed, Fentanyl, Chloral Hydrate) Hypercapnia CSF pressure Valsalva maneuver (crying, breath holding) CSF pressure Record OP; abnormal pressure reading is < 25; <28 if sedated Sweet spot? Retrieved from: pediatrics.aappublications.org; sb.scientific; Avery, Shah, & Licht Reference range for CSP opening pressure in children, N Engl J Med LP with Provocative Maneuvers Diagnostic LP with pressure check Provocative maneuvers: 1)Addition of 5 10ccs Elliot B s solution ( artificial CSF) 2) Removal of 10 20ccs of CSF Interpretation of provocative maneuvers Improvement of SX: headache, vision, hearing, pressure intensity, tinnitus, dizziness Interpretation of HA relief what does this tell us, placebo effect? Flowchart/Algorithm based on recent diagnostic criteria for PTCS 8

Call from mom about HK 7yo female She loves to jump rope! She was jumping rope and smiling and all of a sudden she stopped, and started screaming at the top of her lungs, Make it stop!

Case #3 Debilitating headaches began at 5yo MRI chiari malformation w/ 8mm tonsillar descent Chiari decompression temp relief of HA Multiple trials of HA prophylactic medications Dilated eye exam

9 Call from mom about HK 7yo female She loves to jump rope! She was jumping rope and smiling and all of a sudden she stopped, and started screaming at the top of her lungs, Make it stop! Make it stop! Case #3 Debilitating headaches began at 5yo MRI chiari malformation w/ 8mm tonsillar descent Chiari decompression temp relief of HA Multiple trials of HA prophylactic medications Dilated eye exam papilledema LP(sedated)=OP 30 Diamox dose limited by tolerance; Papilledema persisted HK can t play with the other kids she loves to run, but her head hurts so bad, the teachers are always calling me to come get her! Case #3 Visual complaints Neurosurgical Consult VP shunt Papilledema resolved Visual acuity 20/20; no visual field deficits Headaches persist Case #3 Findings Elevated OP Chiari Malformation & decompression No cranial nerve abnormalities VP shunting & papilledema resolved Diagnosis? A. Idiopathic Intracranial hypertension without papilledema B. Brain tumor C. Malingering D. PTCS E. Primary headache disorder Treatment Options 9

Pharmacological Treatment Decrease CSF formation by: Interfering with: Entire cellular metabolic process Acetazolamide decreases CSF production by interfering with the function of carbonic anhydrase.

Common Medications used for PTCS (off label) acetazolamide (Diamox) carbonic anhydrase inhibitor 10 20mg/kg/day divided into 2/3 doses Metallic taste to Soda Fatigue Paresthesias Decreased K+

6mg/kg/dose potential for cross reactivity for Sulfasensitive Fluid loss, electrolyte imbalances; Decreased K+ Constipation, diarrhea, N/V spironalactone diuretic; K sparing 1 3.

10 Pharmacological Treatment Decrease CSF formation by: Interfering with: Entire cellular metabolic process Acetazolamide decreases CSF production by interfering with the function of carbonic anhydrase. Specific transport mechanisms Furosemide interfering with chloride transport? Do glucocorticoids alter CSF formation? Common Medications used for PTCS (off label) acetazolamide (Diamox) carbonic anhydrase inhibitor 10 20mg/kg/day divided into 2/3 doses Metallic taste to Soda Fatigue Paresthesias Decreased K+ topiramate (Topamax) AED; weak carbonic anhydrase inhibitor 1 3mg/kg/day Paresthesias Acute angle glaucoma reversible Weight loss 30% furosimide (Lasix) loop diuretic 2mg/kg/ day; do not exceed 6mg/kg/dose potential for cross reactivity for Sulfasensitive Fluid loss, electrolyte imbalances; Decreased K+ Constipation, diarrhea, N/V spironalactone diuretic; K sparing mg/kg/day in divided doses every 6 12 hours; not to exceed 100 mg/day N/V, abd pain, ethacrynic acid (Edecrin); loop diuretic 1 mg/kg/dose once daily, increase at intervals of 2 3 days to a maximum of 3 mg/kg/day Primary Purpose-PRESERVE VISION Surgical Management & Complications Venous sinus Stenting SE: Subdural hematoma, transient hearing loss, venous sinus dissection, syncope, retro orbital pain; stroke Bariatric Surgery SE: Infection, incisional hernia, ulcer, intra abdominal hemorrhage, nutritional deficiency, metabolic disturbances Optic Nerve Sheath Fenestration (ONSF) SE: Conjunctival bleb, globe perforation, corneal ulcers, glaucoma, tonic pupil, branch retinal artery occlusion diplopia CSF Diversion LPS & VPS) SE: Shunt obstruction, infection, CSF leak, low ICP, catheter migration leading to bower perforation, subdural or subarachnoid hemorrhage Treatment Weight Loss It works! ~10 lbs Mechanism unknown Preservation of visual function is primary goal? Physical habitus thick neck Increased intrathoracic pressure Hormonal interplay Retrieved from:clipartfest Call from dad of HK 16yo male We went out for a bike ride going up a hill was excruciating he just sat down and cried, Someone has to do something! This is no way to live! You have got to figure this out for him! Case #4 Headaches prior to gender identity Bilateral mastectomy Testosterone injections in Fall 2016 Worsening headaches & diplopia MRI/MRV normal +papilledema LP OP=55cm H2O pressure Diamox initiated 20mg/kg/day Transgender Male + Testosterone Image retrieved from stock illustration teen riding a bicycle.jpg 10

11 Case #4 Headaches and diplopia continue Papilledema decreased Testosterone dose decreased by ½ LP OP=24 Diamox continued side effects of weight loss, fatigue, cognitive fog increasingly concerning Diamox tapering New HA prophylactic medication prescribed Transgender Male + Testosterone Case #4 Findings Elevated OP Normal MRI/MRV of brain No cranial nerve abnormalities Normalized OP r/t decreased T or Diamox? Persistent HA Transgender Male + Testosterone Diagnosis? Transgender Male + Testosterone Call from mom of DS 17yo female A. Idiopathic Intracranial hypertension without papilledema B. Brain tumor C. Malingering D. PTCS E. Primary headache disorder The tingling is unbearable and she is having trouble in school for the 1 st time in her life. She can t concentrate and everything hurts! CC daily headache+ Weight= 335# 4+papilledema OP=30cm H20 pressure Non compliant with visits & treatment? Barriers???? The End of the Story? Prognosis.. Post test #1 85% resolve without treatment If able, treatment focused on secondary causes Most children respond well to medical management Surgical intervention reserved for cases that do not improve Papilledema most important clinical finding associated with visual loss, most feared consequence of IIH/PTCS PTSC is a condition that is universally characterized by: A. Visual complaints B. Increased opening pressure with LP C. Difficulty with cognitive function D. vomiting 11

False Post test #4 The medication acetazolamide used to treat PTCS is: A. Well tolerated B. Very effective C. Also used for treating venous sinus thrombosis D.

12 Post test #2 The team of providers caring for a child with PTSC should include the: A. Podiatrist B. Cardiologist C. Ophthalmologist D. Nutritionist Post test #3 Children who meet the diagnostic criteria for IIH have increased ICP with or without papilledema. A. True B. False Post test #4 The medication acetazolamide used to treat PTCS is: A. Well tolerated B. Very effective C. Also used for treating venous sinus thrombosis D. An old medication initially used for adjunct treatment of seizures Summary Benign Intracranial Hypertension is NOT benign PTCS and IIH can overlap Without papilledema, you must meet other criteria for these diagnoses Can be difficult to treat medications are not always effective or tolerated Symptoms vary; can sound like a migraine headache; imaging and LP are needed to differentiate Young children cannot articulate what they are feeling Remember new normals! References Avery, RA., Licht, DJ., Shah, SS., Huh, JW., Seiden, JA., Boswinkel, J., Ruppe, MD., Mistry, RD., & Liu, G. (2011). CSF opening pressure in children with optic nerve head edema. Neurology, 76, Babiker, M., Prasad, M., MacLeod, S., Chow, G., & Whitehouse, W. (2014). Fifteen minute consultation: the child with idiopathic intracranial hypertension. Archives of Disease in Childhood: Education and Practice Edition, 0, 1 7. doi: /archdischild Friedman, D., Liu, G., & Digre, K., (2013). Revised diagnostic criteria for the psuedotumor cerebri syndrome in adults and children. Neurology, 81, Paley, G., Sheldon, CA., Burrows, EK., Chilutti, M., Liu, G., & McCormack, S. ( Overweight and obesity in pediatric secondary pseudotumor cerebri syndrome. American Journal of Opthalmology, 159: 2, doi: /ajo Rangwala, L. & Liu, G., (2007). Pediatric idiopathic intracranial hypertension. Survey of Opthalmology. 52:6, doi: /j.survopthal Ravid, S., Shahar, E., Schif, A., Yehudian, S. (2015). Visual outcome and recurrence rate in children with idiopathic intracranial hypertension. Journal of Child Neurology, DOI: / jcn.sgepub.com Sheldon, C., Kwon, YJ., & McCormack, S. (2015). An integrated mechanism of pediatric pseutumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics. Pediatric Research, 77:2, doi: /pr Standridge, S. (2010). Idiopathic intracranial hypertension in children: a review and algorithm. Pediatric Neurology. 43:6, doi: /pediatneurol rende001@mc.duke.edu 12

13 THE END 13

Intracranial hypertension and headache. Daniel Tibussek, MD

Intracranial hypertension and headache. Daniel Tibussek, MD none Disclosures Overview Case Clinical presentation of pediatric PTC Nomenclature, Definition What is intracranial hypertension? Diagnostic