Final Diagnosis -- Inflammatory Amyloid Angiopathy and Leptomeningeal Amyloidosis with Inflammation


FINAL DIAGNOSIS

Inflammatory Amyloid Angiopathy and leptomeningeal amyloidosis with inflammation.

DISCUSSION

We report an unusual case of vasculitic/inflammatory cerebral amyloid angiopathy associated with zonal leptomeningeal β-amyloid deposits and inflammation, in a young (36 years of age), cognitively intact subject without AD changes in the neuropil.

Aside from the better-known histological characteristics of Alzheimer's Disease (AD) such as presence of diffuse and neuritic plaques due to presence of ß-amyloid (Aβ) deposition, and neurofibrillary changes resulting from hyperphosphorylation of tau protein; Aß deposits can also be found within leptomeningeal and intraparenchymal blood-vessel walls (of any size, i.e. large, medium or small blood vessels), a condition known as Cerebral Amyloid Angiopathy (CAA) (1). In fact, this is a common finding at autopsy, both in subjects presenting sporadic AD, as well as in familial AD cases (3).

CAA is characterized by β-amyloid deposits in small, medium or large size leptomeningeal and intracerebral blood vessel walls (1). Degenerative changes secondary to Aβ deposits in blood vessel walls may predispose to rupture, leading to spontaneous cerebral hemorrhage. Less frequently, CAA may be asymptomatic or contribute to cognitive impairment, as a result of cerebral ischemia and microhemorrhages (2, 3). Most CAA cases are sporadic, affecting elderly individuals, with or without additional morphologic evidence of Alzheimer´s disease (AD) pathology (3). Although a common feature in transthyretin amyloidosis, leptomeningeal ?-amyloid deposits could also be considered characteristic of CAA.

Inflammatory cerebral amyloid angiopathy (CAA-I) is a less frequent form of CAA, most commonly presenting with cognitive decline, acute or subacute onset of headaches, behavioral changes, focal neurological deficits, and more rarely, fever (1). Mean patient age is 69 years (range 42-84) (1) and clinical course is usually aggressive. Characteristic MRI findings show patchy or confluent T2, or fluid attenuation inversion recovery (FLAIR) hyperintensity (1). Brain samples from CAA-I patients show vascular amyloid deposition in addition to perivascular and/or parietal inflammatory infiltrates, with or without giant-cell formation (1, 2, 5). Although CAA-I patients are significantly younger than patients with CAA alone, diagnostic criteria suggest they will generally be 40 years or older (only 10 % of reported patients are under 50 years of age) (1, 5).

The majority of cases respond, at least partially, to immunosuppressive therapy, rendering CAA-I a form of CAA amenable to treatment; however, recurrences have occasionally been reported (1). Therefore, prompt diagnosis is key for adequate management.

Finally, it has been observed that from a clinical standpoint, CAA-I often resembles primary CNS vasculitis (PCNSV) more than CAA (4). In our case, the aggressive clinical course, imaging characteristics, response observed to immunosuppressive therapy and the patient's young age (36 years), in the absence of cognitive impairment, would all be in line with this concept. In fact, a cut-off of 40 years of age has been suggested as diagnostic of CAA-I (1); whereas mean age at diagnosis for PCNSV is 42 years (4). It has also been speculated that the similarities between CAA-I and PCNSV stem from the driving role of vascular inflammation in determining disease manifestations (4). In this case however, histological and immunohistochemical analysis confirmed CAA-I as the diagnosis, underscoring the need to consider CAA-I among the differentials even in younger patients. ?-amyloid deposits could be acting as immune response triggers in this condition, which in turn may play a direct role in the aggressive clinical course observed in patients (2).

In summary, our report illustrates a case of zonal CAA-I with leptomeningeal amyloidosis, in an unusually young patient with intact cognition and aggressive clinical course.

REFERENCES

  1. Chung KK, Anderson NE, Hutchinson D, Synek B, Barber PA (2011) Cerebral amyloid angiopathy related inflammation: three case reports and a review. J Neurol Neurosurg Psychiatry.82(1):20-6.
  2. Eng JA, Frosch MP, Choi K, Rebeck GW, Greenberg SM (2004) Clinical manifestations of cerebral amyloid angiopath2. y-related inflammation. Ann Neurol.55(2):250-6.
  3. Revesz T, Holton JL, Lashley T, Plant G, Frangione B, Rostagno A, Ghiso J (2009) Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathol.118(1):115-30.
  4. Salvarani C, Brown RD, Jr., Calamia KT, Christianson TJ, Huston J, 3rd, Meschia JF, Giannini C, Miller DV, Hunder GG (2008) Primary central nervous system vasculitis: comparison of patients with and without cerebral amyloid angiopathy. Rheumatology (Oxford).47(11):1671-7.
  5. Scolding NJ, Joseph F, Kirby PA, Mazanti I, Gray F, Mikol J, Ellison D, Hilton DA, Williams TL, MacKenzie JM, Xuereb JH, Love S (2005) Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain.128(Pt 3):500-15.

Contributed by Miguel A. Riudavets, MD, PhD; Ana Lía Taratuto, MD, PhD; Facundo Pelorosso, MD, PhD; Gustavo Sevlever, MD, PhD




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