3. Discussion and conclusions
We describe a case of acute cerebellar hemorrhage secondary to CLIPPERS, with PET/CT suggesting increased metabolism in both cerebellar. In a recent review of the published cases, Buttmann et al(Buttmann, et al.,2013) have reported a case of subacute bleeding in the right cerebellar. Blaabjerg et al(Blaabjerg, et al.,2016) presented a patient that responded to steroid treatment but then had a fatal brainstem hemorrhage. Additionally, In the case report presented by Vivek Sudhakar, susceptibility-weighted angiography (SWAN) imaging demonstrated a hemorrhagic component of the right occipital lobe lesion in the patient(Sudhakar, et al.,2021). Since cerebrovascular events in CLIPPERS patients are rare, the mechanism by which CLIPPERS leads to cerebrovascular manifestations has not been established yet.
There are usually a large number of lymphocytes or lymphoid tissue infiltration around the blood vessels of CLIPPERS lesions, and the affected lymphocytes are mainly CD3+ and CD4+(Axelerad, et al.,2021). Different from previous case reports showing CD4+T cell infiltration around CLIPPERS related intracerebral hemorrhage lesions, our patient’s cerebellar biopsy showed diffuse CD3+T cell infiltration around blood vessels, which indicated significant inflammation around blood vessels(Buttmann, et al.,2013; Blaabjerg, et al.,2016; Sudhakar, et al.,2021). Similar to most CLIPPERS, there is perivascular infiltration of inflammatory cells pathologically in our case, but no characteristic histological features of vasculitis such as fibrinoid necrosis(Axelerad, et al.,2021). However, transmural lymphocytic infiltrates and inflammatory vessel occlusion have been shown to be present in biopsy samples in patients with CLIPPERS(Taieb, et al.,2016; Axelerad, et al.,2021), suggesting the direct destruction of immune cells around the blood vessel wall may be the main cause of bleeding. Interestingly, most CLIPPERS secondary to cerebral hemorrhage are characterized by a long course or recurrent disease. The patients reported in our report had cerebral hemorrhage during hormone therapy due to multiple relapses of the disease. We can speculate that the long course of disease and repeated intensive treatment may easily cause cerebral hemorrhage.
It is worth mentioning that Primary central nervous system lymphomas (PCNSL) is easily confused with CLIPPERS clinically. In addition to similar clinical symptoms, PCNSL can also show CLIPPERS like image appearance, and lesions can show high metabolism on PET/CT(Lin, et al.,2014). The pathology of PCNSL is not specific and therefore cannot be completely distinguished from CLIPPERS(Axelerad, et al.,2021). However, PCNSL is not sensitive to hormone therapy, and the condition cannot be effectively improved(Schaff and Grommes,2021). Recently, one case reported that patients with intracerebral hemorrhage secondary to CLIPPERS showed hypermetabolism at the focal site on PET/CT(Sudhakar, et al.,2021), and our patient also showed hypermetabolism at the focal site, which was confined to the brain. In addition, our patient was responding to glucocorticoid therapy and were more radiologically and pathologically prone to CLIPPERS. Although there is no more evidence, this led us to wonder if hypermetabolic lesions were associated with bleeding.
Intracranial hemorrhage is an unfamiliar complication of CLIPPERS, and physicians should be reminded to pay attention to the possibility of intracranial hemorrhage, especially in patients with acute neurological deterioration. In addition, intracranial hemorrhage may be associated with a long course of disease and repeated treatment. To our knowledge, this is the first report of cerebellar hemorrhage and PET shows hypermetabolism in a Chinese CLIPPERS patient. The possibility of this complication should also be considered when finding hypermetabolic lesions in CLIPPERS patients.