Case Study 63

1. Case Study 63 Kenneth Clark, MD

2. Question 1 • This is a 79-year-old woman with a past medical history significant for hypothyroidism who presented to an outside hospital following sudden onset of severe headache and left sided weakness. A CT scan of the head was performed. • Describe the CT scan findings.

4. Answer • A large heterogeneous intraparenchymal hematoma in right frontotemporal lobe with vasogenic edema, mass effect and right to left midline shift.

5. Question 2 • What is the differential diagnosis of a spontaneous intracranial hemorrhage?

6. Answer • Metastatic tumor • Primary CNS tumor • Hemorrhagic Infarct • Vascular Malformation • Amyloid Angiopathy • Coagulopathy • Infection

7. Question 3 • The blood was evacuated and the tissue sent for pathologic examination. Describe the findings. • Click here to review the slide

8. Answer • Sections show fresh blood clot with small islands of entrapped micro-vacuolated, devitalized brain parenchyma and leptomeninges. The medium caliber arteries have markedly thickened, multilaminar sclerotic walls. One vessel shows penetrating hemorrhage into and through the vascular wall.

9. Question 4 • What immunohistochemical stains would you order to help better characterize the etiology of this hemorrhage?

10. Answer • A-beta amyloid • Smooth muscle actin • Pankeratin (to rule out carcinoma not readily apparent on the slide) • PAS (to rule out CADASIL – see question XX) • Click to see A-beta amyloid, Actin, PAS

11. Question 5 • Based on the clinical history, H&E impression and immunohistochemical findings (see below), what is your diagnosis? • A-beta Amyloid – intense concentric staining of arterial walls; highlights numerous diffuse and neuritic plaques in residual parenchyma • Actin – reveals near-complete loss of the smooth muscle from vascular media • PAS – negative for positive granules

12. Answer • A. Cerebral Amyloid Angiopathy • B. Alzheimer’s Disease Pathology

13. Question 6 • What causes cerebral amyloid angiopathy and how is it related to other forms of amyloidosis?

14. Answer • Cerebral amyloid angiopathy is not related to other forms of systemic amyloidosis. • It occurs in both sporadic and familial forms and is caused mainly by the deposition of a specific type of amyloid (Ab-amyloid) in the vessels walls. • This is the same amyloid protein that is found in Alzheimer’s disease, encoded on chromosome 21. • Rare forms of CAA amyloid occur through mutations in cystatin C, transthyretin, gelsolin, ABri-precursor protein, ADan-precursor protein and prion protein (these are very rare)

15. Question 7 • What is amyloid?

16. Answer • Amyloid is a pathologic protein aggregate that forms from the abnormal cleavage and subsequent abnormal folding of ab-amyloid peptide that results in extensive b-pleated sheet secondary structure. In this secondary structure, proteins form insoluble fibrils that deposit in the walls of vessels, leading to medial destruction and loss of vascular integrity and function.

17. Question 8 • What is the most common cause of spontaneous intracranial hemorrhage and how is the clinical presentation of cerebral amyloid angiopathy different?

18. Answer • Hypertensive vasculopathy (HV) is the most common cause of spontaneous intracranial hemorrhage (70-90%). • CAA most prominently involves the leptomeningeal and cortical vessels (resulting in hemorrhages in these regions), usually sparing the deep white matter and brainstem vessels. Commonly found in demented individuals with Alzheimer’s like pathology. • HV typically causes hemorrhages in the basal ganglia (40-50%), lobar regions (20-50%), thalamus (10-15%), pons (5-12%), cerebellum (5-10%), and other brainstem sites (1-5%). More commonly fatal (rapid).

19. Question 9 • What is CADASIL?

20. Answer • CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary cerebrovascular disorder that results in markedly thickened cerebral vessels and can result in migraines, strokes (with and without hemorrhage) and dementia.

21. Question 10 • How does CADASIL differ from CAA both clinically and histologically?

22. Answer • CADASIL affects patients at a younger age than CAA (45 year vs 65 years) • CADASIL usually associated with multiple ischemic events (transient or stroke) • CADASIL has a progressive course, whereas CAA can present abruptly • Histologically, CAA shows strong Ab-amyloid staining of the vessel walls while CADASIL vessels show marked deposition of PAS-positive granular material in the walls

23. Question 11 • This patient also had amyloid plaques deposited in the surrounding cortex. How closely associated is CAA with Alzheimer’s disease?

24. Answer • Alzheimer’s disease pathology is clearly associated with CAA. Recent studies have shown that more than 90% of patients with clinical AD have some degree of CAA. However, it has also been shown that 30% of all people with CAA have no additional Alzheimer’s pathology (usually younger patients).

25. References • Mandybur TI. The incidence of cerebral amyloid angiopathy in Alzheimer's disease (1975). Neurology. 25:120-126. • Prayson RA. Neuropathology (A Volume in the Foundations of Diagnostic Pathology Series). 2005. Elsevier, Inc. • Attems J, Jellinger KA. Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology - a pilot study (2004). Acta Neuropathol. 107:83-90. • Arvanitakis Z, et al. Cerebral amyloid angiopathy pathology and cognitive domains in older persons (2011). Annals of Neurology. 69(2):320-327 • Dietmar R, et al. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease (2008). Acta Neuropathol. 115:599-609.