Systemic amyloid A (AA) amyloidosis with amyloid deposition in the choroid plexus and pituitary gland.
In correlation with the clinical history and systemic post mortem findings of amyloid in the heart, kidneys, ovaries, thyroid, and spleen, the diagnosis of amyloidosis was considered and an appropriate battery of studies was performed. The vessel walls stained red with Congo red (Fig. 4) and showed light green birefringence under polarized light (Fig. 5). Immunohistochemistry for amyloid A was positive (Fig. 6) while the deposit was negative for kappa and lambda light chains, prealbumin (transthyretin), and amyloid β (Aβ).
While other neurologic complications of FMF have been reported in the literature, to our knowledge this is the first FMF case with CNS amyloidosis confirmed histologically.
Systemic amyloidosis is a heterogeneous group of diseases that is characterized by extracellular deposition of amyloid, a fibrillar material with a β pleated sheet configuration, derived from a variety of precursor proteins. The classification of amyloidosis is based on the specific precursor protein, which can be abnormal such as in immunoglobulin light chain related (AL) amyloidosis in plasma cell dyscrasias, and hereditary amyloidosis with abnormal transthyretin (ATTR) (4). The protein can also be normal but in excess such as serum amyloid A (AA) in reactive amyloidosis in inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease, and familial Mediterranean fever (FMF). Amyloidosis can also be seen with aging (4). FMF is an autosomal recessive inflammatory disease characterized by recurrent episodes of fever and serositis, with the most serious complication of amyloidosis leading to end stage renal disease, which can be effectively prevented by colchicine therapy. FMF may also be associated with increased vascular morbidity such as stroke (1).
The most common type of amyloidosis in industrialized countries is AL amyloidosis followed by AA amyloidosis. Histologic demonstration of Congo red positive material exhibiting "apple green" birefringence under polarized light is the gold standard for confirming amyloid deposition. Fibril typing is important in determining the underlying disorder to guide treatment, and immunohistochemistry (IHC) has been classically and widely used for this purpose. Although IHC is useful in typing AA and ATTR amyloidosis, it is less so in AL amyloidosis due to the nonspecific adsorption of light chains to the amyloid fibril (2,4). Thus, mass spectrometry is currently the preferred method for fibril typing (4).
Neurologic complications of FMF are very rare. These include demyelination, infarcts, aseptic meningitis and rarely posterior reversible leukoencephalopathy syndrome, none of which are known to be related to amyloid deposition (1). It had previously been thought that systemic amyloidosis rarely involved the brain, based on routine examination of the leptomeningeal, cortical, and basal vasculature. However, later investigators have demonstrated that in systemic amyloidosis, amyloid is commonly seen in areas that lack an intact blood-brain barrier, including the choroid plexus, infundibulum, and area postrema, though not in the meningocortical vasculature (2).
This is in contrast to the distribution of amyloid deposition in cerebral amyloid angiopathy (CAA) which preferentially involves the meningocortical vessels and rarely involves the subcortical white matter vessels, deep gray matter, or brainstem (3). A notable exception is systemic ATTR amyloidosis in which the abnormal protein is synthesized by both the liver and choroid plexus, with diffuse involvement of the vessels of the leptomeninges, cortex, and choroid plexus (2).
In CAA, amyloid is deposited in the walls of cerebral arteries/arterioles, veins, and capillaries, and replaces the smooth muscle cells in the case of arteries/arterioles, weakening the vessel walls and increasing the risk of micro- and lobar hemorrhages. CAA can be sporadic, commonly seen in the elderly and closely associated with Alzheimer's disease, or hereditary. The protein deposited in sporadic and some hereditary CAAs, such as the Dutch type, is Aβ (3). A variety of other proteins compose the amyloid in other hereditary CAAs such as mutant cystatin C in hereditary cystatin C amyloid angiopathy and mutant precursor protein encoded by mutations in the BRI2 gene in familial British dementia and familial Danish dementia, the latter two which show CAA widely distributed in the white matter, gray matter, and brainstem (3).
The subclinical nature of the CNS amyloidosis in our case underlines the importance of awareness of potential neurologic manifestations and early CNS evaluation in these patients.
Contributed by Shino Magaki, MD, PhD, Robyn Parks, MD, Harry V. Vinters, Negar Khanlou, MD