1. Case Study 32 Henry Armah, M.D., M.Phil.

2. Question 1 Clinical history: 78-year-old white female with history of morbid obesity, hypertension, hypercholesterolemia, hypothyroidism, left knee replacement surgery, and partial colectomy for a 6.2 cm villous adenoma. She had a 35 pack-year history of smoking ending approximately 15 years prior. She occasionally used alcohol socially and did not use illicit drugs. She also had a recent history of bilateral pulmonary embolism following a motor vehicle accident and she was then started on Coumadin. The findings of a subsequent cranial MRI performed for complaints of vertigo and bilateral tinnitus resulted in the discontinuation of Coumadin. Describe the abnormal MRI findings?

3. T1

4. T1+C

5. T2

7. Answer  Multifocal decreased T2 signal throughout the cerebral hemispheres bilaterally.  No abnormal contrast enhancement other than some vague enhancement surrounding some of the foci of abnormal T2 signal.  Extensive multifocal white matter signal seen with aging.  Moderately extensive microvascular disease changes and age-appropriate symmetrical brain volume loss.

8. Question 2 What are your differential diagnoses from these radiographs?

9. Answer  Multiple cavernous angiomata.  Extensive amyloid angiopathic changes. T2

10. Question 3 Ultimately she died from a combination of pulmonary thromboembolism due to presumptive deep venous thrombosis; morbid obesity which is a predisposing factor in the development of deep venous thrombosis; severe atherosclerotic coronary artery disease due to hypertension and hypercholesterolemia; and mild cardiac amyloidosis. An autopsy was performed. Describe the abnormal gross brain findings?

15. Answer Multiple bilateral coalescent hemorrhagic foci in cerebral white matter especially centrum semiovale and corpus callosum, cerebellar white matter, pons, and medulla.

16. Question 4 Sections of the brain lesions were processed for histology. Describe the microscopic findings on this slide? Click here to view slide.here

17. Answer Multiple foci of coalescent cavernous angiomas with minimal intervening perivascular gliosis, foamy and hemosiderin-laden macrophages, and mineralization.

18. Question 5 What additional stain would you need to rule out an important differential diagnosis in this case?

19. Answer Beta-A4 amyloid immunostain to rule out amyloid angiopathy.

20. Question 6 Describe the microscopic findings on this additional stain? Click here to view slide.here

21. Answer Beta-A4 amyloid immunostain is negative in wall of vessels.

22. Question 7 What is your final diagnosis in this case?

23. Answer Multiple Cerebral Cavernous Angiomas.

24. Question 8 Is the likely pathogenesis of lesion sporadic or familial/congenital in this case? Give reason for your choice.

25. Answer Familial/Congenital on account of multiple lesions.

26. Question 9 Based on cranial MRI and necropsy studies of large cohorts of patients, the estimated population prevalence of this lesion is? A. 0.1% B. 0.5% C. 5% D. 10% E. 25%

27. Answer B. 0.5%

28. Question 10 In what percentage of individuals is lesion clinically symptomatic? A. 2-4% B. 5-10% C. 20-30% D. 40-50% E. None of the above

29. Answer C. 20-30%

30. Question 11 What is the mode of inheritance of the familial/congenital form of this lesion?

31. Answer Autosomal Dominant

32. Question 12 Familial/congenital forms of this lesion have been associated with loss of function gene mutations at all the following chromosomal loci, except? A. KRIT1/CCM1 (7q21-22) B. NF2 (22q12) C. MGC4607/CCM2 (7p13-15) D. PDCD10/CCM3 (3q25.2-27)

33. Answer B. NF2 (22q12)

34. Question 13 What follow-up studies may be warranted in symptomatic and/or at-risk relatives of this patient?

35. Answer  Cerebral magnetic resonance imaging.  DNA-based genetic screening for CCM1, CCM2, and CCM3 mutations.