Lawrence B. Schonberger, M.D., M.P.H US-Diagnosed Variant Creutzfeldt-Jakob Disease in Two Patients Born and Raised in Saudi Arabia Lawrence B. Schonberger, M.D., M.P.H Prion and Public Health Office, Division of High-Consequence Pathogens & Pathology, National Center for Emerging & Zoonotic Diseases National Center for Emerging and Zoonotic Infectious Diseases Division of High-Consequence Pathogens & Pathology

Characteristics of the Two vCJD Patients Birth Country (yr) Saudi Arabia (1970) Saudi Arabia (1983) Citizenship Saudi Arabia Egypt Social Class “Professional” Country of vCJD onset (yr) Saudi Arabia (2003) United States (2006) Age at Onset 32.5 yrs. 22.8 yrs

Early Symptoms of the Two vCJD Patients Increased irritability Numbness & “heat” sensation in Withdrawn shoulders, legs, & thigh Agitated Paranoia Insomnia Altered sleep/wake cycle Increased anxiety (diagnosed by psychiatrist) Unsteady gait, scissor steps Unsteady gait, ataxia Slurring of speech Emotionally labile, frequent crying “Sensory symptoms”

Subsequent Dementia and Duration of the Two vCJD Illnesses Patient 1 Patient 2 Within 10 months of onset: Within 6 months of onset: “Global cognitive impairment” Severe dementia Decreased verbal output Non-ambulatory Making incomprehensible sounds Increased deep tendon reflexes, ankle and jaw clonus Illness duration: 6.9 years, mostly in akinetic mute state; died in 2010. Illness duration: 8.5 months; died in 2006

Diagnostic Test Results on the Two vCJD Patients EEG Non-specific slow wave activity; no periodic complexes Diffuse slowing; no periodic complexes MRI Positive pulvinar sign Positive pulvinar sign PRNP Genetics Genotype 129MM, no mutations Adenoid Biopsy Lymphoid follicles positive for PrPsc; vCJD staining pattern Brain Biopsy Immunopositive for PrPsc; “Florid plaques” Intense immunopositive deposits of PrPsc; Pericellular “encrustations” of stellate-shaped cells with PrPsc

Intervals before Onset (yrs) Countries of Residence of 1st US-Diagnosed vCJD Patient by Calendar Years, Age, and Time Intervals Before vCJD Onset Country* Calendar Years Age (yrs) Intervals before Onset (yrs) Saudi Arabia 1970- late 1997 0 - 27.25 32.5 - 5.25 United States late 1997 – late 1998 27.25 - 28.3 5.25 – 4.2 late 1998 – early 2003 (onset) 28.3 - 32.5 4.2 - 0 *Visited United Kingdom for 4 days in late 1997 and France for 1 and/or 2 weeks in 1995 and/or 1996 (Maximum interval before vCJD onset, 8.1 years)

Intervals before Onset (yrs) Countries of Residence of 2nd US-Diagnosed vCJD Patient by Calendar Years, Age, and Time Intervals Before vCJD Onset Country* Calendar Years Age (yrs) Intervals before Onset (yrs) Saudi Arabia 1983 - 1999 0 - 16 23 - 7 Egypt 1999 – late 2005 16 – 22.5 7 – 0.3 United States late 2005 – early 2006 (onset) 22.5 – 22.8 0.3 - 0 *Visited the United States for 1½ months in 1989 and since 2001, occasionally during vacations each year for up to about 3 months at a time.

Acknowledgments Pathologist Pierluigi Gambetti and his staff at the National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio, USA Professors Robert Will and Richard Knight and their staff at the UK CJD Surveillance Unit, Edinburgh, Scotland, UK Neurologist Michael Geschwind and Pathologist Stephen DeArmond and their staff at the University of California, San Francisco, USA State Epidemiologists and their staff at the Arizona, California, North Carolina and Virginia State Departments of Health, USA Neurologists Shireen A. Qureshi, Saudi Arabia and Alireza Atri, USA Pathologist Caterina Giannini, Mayo Clinic, Minnesota, USA Dr. Imad A. Al Jahdall, Chief Preventive Medicine Services Division, Saudi Aramco Medical Services Organization, Dhahran, Saudi Arabia Colleagues at the Centers for Disease Control and Prevention, Atlanta, Georgia, USA, particularly members of the Prion and Public Health Office, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases.

MRI on Saudi vCJD Patient T2 & Fluid-Attenuated Inversion-Recovery, FLAIR “Pulvinar Sign”

Histopathological and Immunohistochemical Findings on Brain Biopsy of First Saudi vCJD Case compared to sCJD, 2004 A C B H&E of a florid plaque in the present case. Immunostaining showing florid plaques. Immunostaining of sCJDMM1 (B and C Mab 3F4).

B: magnification 40X – US Patient PrP IHC Plaque-like and spider-like formations; HE of the location of the plaque-like formations is unremarkable (mAb 3F4)

Thank You! For more information please contact Centers for Disease Control and Prevention 1600 Clifton Road NE, Atlanta, GA 30333 Telephone: 1-800-CDC-INFO (232-4636)/TTY: 1-888-232-6348 E-mail: cdcinfo@cdc.gov Web: http://www.cdc.gov The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. National Center for Emerging and Zoonotic Infectious Diseases Division of High-Consequence Pathogens & Pathology

National Prion Disease Pathology Surveillance Center - Referrals, By Year of Death Prion disease (total) vCJD 1996 & earlier 51 33 1997 114 68 1998 87 1999 122 74 2000 146 103 2001 209 119 2002 248 149 2003 274 176 2004 325 186 1* 2005 344 194 2006 382 196 2* 2007 376 213 2008 396 232 2009 423 256 2010 403 251 Total 3900 2301 (59.5%) 3* * Disease almost certainly acquired outside the US (UK or Saudi Arabia).