Case Study 63

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Case Study 63

• Kenneth Clark, MD

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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.

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(No Transcript)
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Answer

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

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Question 2

• What is the differential diagnosis of a
  spontaneous intracranial hemorrhage?

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Answer

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

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Question 3

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

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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.

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Question 4

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

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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

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Question 5

• Based on the clinical history, HE 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

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Answer

• A. Cerebral Amyloid Angiopathy
• B. Alzheimers Disease Pathology

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Question 6

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

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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
  Alzheimers 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)

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Question 7

• What is amyloid?

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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.

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Question 8

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

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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 Alzheimers 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).

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Question 9

• What is CADASIL?

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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.

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Question 10

• How does CADASIL differ from CAA both clinically
  and histologically?

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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

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Question 11

• This patient also had amyloid plaques deposited
  in the surrounding cortex. How closely associated
  is CAA with Alzheimers disease?

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Answer

• Alzheimers 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 Alzheimers pathology (usually
  younger patients).

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References

• Mandybur TI. The incidence of cerebral amyloid
  angiopathy in Alzheimer's disease (1975).
  Neurology. 25120-126.
• 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. 10783-90.
• 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 Alzheimers disease (2008).
  Acta Neuropathol. 115599-609.