Arthroprosthetic Cobaltism is Common A screening study of 241 patients with joint replacements with Urine-Cobalt and Cobaltism- Symptom-Inventory (CSI)

Utility of FDG-PET Brain Scanning in the Diagnosis of Arthroplasty Cobalt Neuro-Q analysis of 69 FDG-PET Brain Scans in neurologically symptomatic cobalturic patients shows brain hypometabolism c/w Chronic Toxic Encephalopathy

8.5 minute public testimony 11/13/19 FDA Expert Panel

Stephen S. Tower, M.D. Affiliated Professor UAA/ WWAMI Robert Bridges, M.D. Diagnostic Radiology and Nuclear Medicine Christina Cho, BA Research Assistant TOJRC Bradford Gessner, MD, MPH Epidemiology and Vaccines www.tjrclinic.com Disclosures

Index Case of Arthroprosthetic Cobaltism from modern MoM Hip replacement 2006-2009

Author of Index Case Reports: AK State Epi, Alaska Medicine, JBJS 2010. Now about 10 other peer-reviewed publications on various aspects Arthroprosthetic Cobaltism

As surgeon has implanted about 2000 “AT RISK” Joint Replacements

No commercial Conflict-of-Interest

Son-in-Law is an Arthroplasty Design Engineer

Settled Litigation with J&J concerning own ASR MoM Hip Suit filed 11/2011, settled 11/2019 Structured Settlement net $186,873

Compensated Legal Expert in one case concerning cobalt-chrome hip metallosis complications. I was primary and revision surgeon. Gross compensation to date for this work $28,500 for 57 hours. > 20 hours spent complying with Subpoena Duces Tecum Primary Immune Presentation: Monoclonal Gammopathy (IGA), Oat Allergy, , Peripheral Neuropathy, Cognitive Decline, Irritability

46 y/o Executive at 1* THA, 2009 Zimmer Kinnectiv MoP Hip, Severe Immune GI Syndrome, Oat Allergy, Mast Cell Activation Syndrome, Later Onset of hip pain, , Cognitive Decline, B[Co] = 2.4 ppb, U[Co]=8.0, Monoclonal IGA, FDG PET (-97, 9 clusters), MS MRI Hip pseudotumor, Hips Revised to Ceramic- 510K MoP Hip on-Plastic, 3 months post revision B[Co] Not recalled = 0.7, U[Co]=1.5, Improved Cognitive Function, Bone Marrow Pending Arthroprosthetic Cobaltism Clinical Syndrome (REVERSABLE!) • Fatigue • Cognitive decline • Disordered mood • Motor and Sensory Dysfunction • Immune Syndrome • Cardiomyopathy • Periprosthetic Adverse Reactions to Metallic Debris Pathophysiology • Suppression of cellular metabolism • Immune reaction to cobalt (periprosthetic and systemic) Imaging • 18-F-FDG PET Brain scan • Cross-sectional Imaging of prosthetic Joint “at-risk-joint”

A hip, knee, or shoulder replacement with any Chrome-Cobalt (CrCo) part Regardless of bearing couple • Metal-on-Metal (MoM) resurfacing and stemmed, CrCo Head and Socket • Metal-on-Plastic (MoP) Modular CrCo Head • Some Ceramic-on-Plastic hip designs with modular CrCo necks, stems, or sockets Alaskan 241/139/102/69 Series Screened with Urine-Cobalt and 13 symptom inventory

• 241 patients with an “at-risk-joint” screened over 48 months • 139 Cobalt-Positive (U[Co] ≥1 ppb or B[Co] ≥ 0.4 ppb) 102 Cobalt-Negative • 69 of 139 Co+ patients with confirmed Arthroplasty- Cobalt-Encephalopathy (ACE) by FDG-PET-Brain-Scan 13 symptom inventory (incidence in Co+ patients, p value)

• Tremor (77%, p<0.0001) • Audiovestibular dysfunction (33%, p=0.0028) • Forgetfulness (59%, p<0.0001) • Peripheral Neuropathy (18%, • Fatigue (55%,p<>0.0001) p=0.0003) • Imbalance or Weakness (47%, • Non-refractive Blindness (15%, p<0.0001) p=0.0005)

• Disordered Mood (53%, • New non-ischemic CV problem p<0.0001) (27%, p=0.0002)

• Disordered Sleep (35%, • New Immune problem (15%, p<0.001) p=0.012)

• Chronic Pain (26%, p<0.001) • Symptoms at replaced joint (60%, p=0.006) MoM Articulation N=37, Mean U[Co]=54.0 Not-MoM Articulation N=194, Mean U[Co]=5.4 p<0.001

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• 16 followed greater than 6 months post-revision • 16 of 16 improved cobaltemia and cobalturia • 12 of 16 notably improved ACE symptoms • 1 of 16 notably worse one year post-revision 37 Patients with FDG/PET Brain Scan

• Analysis with NeuroStat and Neuro Q software • All brains significantly hypometabolic compared to age and gender matched normal • A brains show pattern of hypometabolism consistent with Chronic Toxic Encephalopathy (CTE) described in solvent exposure, heavy metal exposure, carbon monoxide poisoning, and “chemo brain” • CTE pattern of hypometabolism is distinct from than described for Alzheimer's, Lewy Body, and Frontal-Temporal and that noted for Parkinson’s disease. 37 Patients with FDG/PET Brain Scan Sort into 3 groups relating to sensitivity of the patient to Arthroprosthetically Generated, Systemically Circulated COBALT

Blood [Co] " (UrineB Ratio),, (Age/lOOr(Years EXl)OS ed /100) v Number Hypomet abolic Clusters

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• 5 • -0- • •• D V=OOl 5'iV+J,7;;1 --t-- - __ ___!...1.-..U--- _____.;..· -.. ) = o.c,60Y9 u • • • D D D )1 C•.l }.!) 10.0 100.0 A•c:i s Title SEVERE HYPOMETABOLISM GENERALIZED and FOCAL • MEDIAL TEMPORAL LOBES • ANTERIOR CINGULATE GYRUS • • DESCRETE AREAS OF • FRONTAL • PARIENTAL • OCCIPITAL CORTICES

• SHORT TERM MEMORY • PROCESSING SPEED • WORD FINDING DIFFICULTIES • MOTOR SPEED • FINE MOTOR COORDINATION • DISORDERED MOOD • FATIGUE AND DISORDERED SLEEP 10 Patients with Repeat FDG/PET Brain Scan

• 8 patients 6-12 months post revision surgery with improved cobaltemia • 4 clinically improved patients had significantly improved scans at 6-12 months • 1 clinically stable patient’s scan was notably improved at 18 months post-revision. • 2 clinically worse patients’ scans were worse at 6 months post revision. • 2 patients not revised had repeat scans at 18 months after first scan • 1 with decreased cobaltemia had an improved scan. • 1 with increased cobaltemia had a worse scan Cobaltism Awareness: Cobaltism may precede Hip Symptoms

46 y/o Pilot F/H PD 2009 Biomet “Magnum” MoM Hips 42 months max DBS & Drugs Onset of hip pain B[Co] = 116 PPB Hips Revised to Ceramic-on-Plastic 2 months post revision B[Co] = 0.7 12 months post-op off DBS & Drugs 2 years post-op off Drugs, lowest 510K MoM Hip DBS setting Not recalled Cobaltism Awareness: Systematic Monitoring of Patients with Most Hip Replacements Indicated

40 y/o nurse, missed 2 Weight Bea~n annual follow-ups but L <5 saw surgeon vocationally 1-2 times a week [BCo] = 63 ppb Reversible 510K MoM Hip Neurocobaltism with 48 Not recalled months of surplus morbidity Cobaltism Awareness: Systematic Monitoring of Patients at Risk for Taper Corrosion Indicated

Rejuvenate Implanted 8/2010 70 YO GENERALLY WELL WOMAN 20 months later: progressive fatigue, poor sleep, nausea, weight loss from 140 to120 pounds, deafness, myalgia, cognitive decline, arrhythmia and diastolic dysfunction B[Co] = 11 PPB 510K Recalled 7/2012 (at 23 months) MoP Hip Explanted after 33 months RECALLED Cobaltism Awareness: Systematic Monitoring of Most Patients with Replaced Hips or Shoulders is Indicated

Stryker Accolade “fitted” 2006 for a 68 year-old Professor 8 years later onset of progressive cognitive decline, tremor, fatigue, incoordination, and B[Co] = 5.8 PPB U[Co] = 35 PPB Joint Fluid [Co] = 1100 PPB Neurocognitive testing unfit to drive due to incoordination, reaction time, and judgment 510K issues. Revised 8/2016 patient now 78 YO. MoP Hip Not Recalled “Silent Recall” V40 Taper CrCo heads 10/2016 Acetabular Side MACC MDM and MoM

Lc.n~ ZOO:X6 Periprosthetic Consequences of Chrome- Cobalt Metallosis

Pseudotumors and Necrosis of Capsule, Tendons and Bone leading to Hip Instability Weakness Prosthetic loosening can be Painful or Painless Systemic Consequences of Chrome-Cobalt Related Cytotoxicity Toxic Progeria Oxidative Stress and Mitochondrial Toxicity leading to Death or Dysfunction of Highly Metabolic Cells resulting in Mood and Sleep Disorders Constitutional and Cognitive Decline Motor-Sensory Neuropathy CNS & PNS Audio-vestibular and Optic Dysfunction Movement Disorders Cardiomyopathy Immune Dysfunction Monitoring Hip Patients at Risk Blood or Urine Cobalt (PBB)

• 0.1 NORMAL • 1 BIOLOGIC EXPOSURE THRESHOLD (BET) • > 0.4 Nearly all MoM, MOST MODULAR CrCo Modular Neck • > 0.4 Many (10-50%) MODULAR CrCo Modular Head MoP Hips • 0.4-10 Pseudotumors, subclinical and mild COBALTISM • 11-100 subclinical, mild, and moderate COBALTISM • 101-300 moderate to severe COBALTISM • 301-1000 extreme COBALTISM (30 CR), DEATH (5 cases) Cobalt debris from corrosion a order of magnitude more toxic than that produced by abrasive wear. Urine levels generally 2.5 X Blood Levels Dose Response of U[Co]Years to CSI Score

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