FIP1L1-PDGFRA-Associated Hypereosinophilic Syndrome as a Treatable Cause of Watershed Infarction

Abstract

Background and Purpose: Ischemic stroke has been reported in various conditions associated with eosinophilia. FIP1L1-PDGFRA fusion ([Fip1-like 1-platelet-derived growth factor receptor alpha]; F/P ) leads to the proliferation of the eosinophilic lineage and thus to a clonal hypereosinophilic syndrome that is highly responsive to imatinib. Methods: We previously reported on a nationwide retrospective study of 151 patients with F/P -associated clonal hypereosinophilic syndrome. Patients from this cohort with a clinical history of ischemic stroke (as well as 2 additional cases) were further analyzed to better define their clinical picture and outcomes. Results: Sixteen male patients (median age, 51 [43–59] years) with low-to-intermediate cardiovascular risk were included. Median National Institutes of Health Stroke Scale was 4 (range, 1–6). Most cerebral imaging disclosed multiple bilateral infarctions of watershed distribution (69%). Despite frequent cardiac involvement (50%), cardiac thrombus was evidenced in a single patient and, according to the TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment), 62.5% of strokes were presumably of undetermined etiology. Among the 15 patients treated with imatinib, and after a median follow-up of 4.5 years, stroke recurred in only 3 patients (consisting of either cardio embolic or hemorrhagic events, unrelated to the first episode). Conclusions: F/P + clonal hypereosinophilic syndrome is a diagnosis to consider in patients with unexplained ischemic stroke and hypereosinophilia (especially in the setting of multiple cortical borderzone distribution) and warrants prompt initiation of imatinib.

Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis

“…The workup should include testing for ANCA (positive in 10–40% of EGPA patients), serological testing for toxocariasis (which has a broad geographic distribution), ova and parasite tests (while further serologies for parasitic infections are generally guided by the patient's country of origin, travel history and dietary habits), serum vitamin B12 and tryptase levels (which are sensitive for the diagnosis of myeloid variant HES), total IgE levels (which are suggestive of reactive polyclonal eosinophilia mediated by IL-5, when elevated), lactate dehydrogenase (suggestive of lymphoma), thoraco-abdominopelvic CT scan (seeking for extra-cardiac eosinophil-related organ involvements as well as underlying solid or hematological malignancies). Furthermore, brain CT or brain MRI should be performed when embolic stroke is suspected in patients with eosinophilic myocarditis or Loeffler cardiomyopathy ( 144 ). Additionally, testing for FIP1L1-PDGFRA fusion gene should be performed in selected cases when clinical (e.g., male sex, splenomegaly), biologic (e.g., high B12 vitamin and/or tryptase levels) features and/or primary resistance to steroids are observed ( 145 ).…”

Literature reviews of stroke with hypereosinophilic syndrome

“…In fact, five cases of FIP1L1-PDGFRA positive HES with stroke (5%) were reported in our review. Previous review reported 9.3% of FIP1L1-PDGFRA positive HES had at least one ischemic stroke [83] . Among secondary (reactive HES), lymphocytic variant HES is defined by the presence of a Th2 T-cell subset overproducing interleukin-5 (IL-5).…”

“…HES is classified into three groups: (A) idiopathic HES, in which no underlying disease or syndrome is apparent; (B) primary (clonal/neoplastic), which includes acute leukemia, chronic myeloid disorders, and myeloproliferative syndromes; (C) secondary (reactive), which is caused by infections, allergic disorders, medications, autoimmune disorders, endocrinopathies, and metastatic malignancies [82] . FIP1-like-1-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFRA) results in a constitutively active tyrosine kinase which induces uncontrolled cell proliferation and primary HES, and FIP1L1-PDGFRA positive myeloid neoplasm with eosinophilia is reported to be accounting for up to 10% of all patients with HES [83] . In fact, five cases of FIP1L1-PDGFRA positive HES with stroke (5%) were reported in our review.…”

“…In previous studies, consecutive patients with cardioembolic stroke were examined, but border zone strokes were rarely reported [37] . Although cardioembolic stroke often present as multiple bilateral lesions, watershed distribution is not frequently associated with this condition, accounting for less than 10% of cases in a large series of strokes with such distribution [83] , [90] . Watershed areas refer to hypoperfused vascular territories; thus, low perfusion pressure and related changes in the dynamics of blood flow in the cerebral arteries affect the clearance and destination of embolic particles.…”

“…Interferon alpha activates CD8 T and NK cells leading to suppression of Th2 activity and a decrease in IL-4 and IL-5. In the case of primary (clonal/neoplastic) HES such as FIP1L1/PDGFRA-associated HES, imatinib mesylate can be effective for treatment [51] , [53] , [83] . Imatinib mesylate is a specific tyrosine kinase inhibitor with potent inhibiting activity against the Abl and Bcr–Abl protein kinase activity as well as c-kit and PDGFR.…”