Crizanlizumab Use in Recurrent Neurologic Symptoms Attributed to Sickle Cell Disease Induced Moyamoya Syndrome

Sickle cell disease (SCD) is a genetic disorder that affects about 100,000 Americans and carries the risk of significant complications including ischemic stroke. Moyamoya syndrome (MMS), a complication of SCD, is characterized by progressive stenosis of carotid arteries leading to ischemic stroke (Dobson, et al). To reduce these complications, the mainstay of treatment of SCD, until recently, has been transfusion and hydroxyurea. In 2019, the FDA approved the monoclonal antibody crizanlizumab. Crizanlizumab binds and blocks p-selectin to prevent downstream cell to cell interactions, including platelet aggregation, thereby improving blood flow and preventing vaso-occlusion (Ataga, et al). We report a case of a sickle cell patient with recurrent neurological symptoms and MRI findings of MMS that unexpectedly resolved with crizanlizumab treatment.

A 26 year old woman with history of vitamin B12 deficiency, HbSS disease complicated by silent cerebral infarct in childhood treated with hydroxyurea and red blood cell (RBC) exchange presented to the hospital with left lower extremity weakness. She reported that her sickle cell crisis typically manifested with left sided weakness rather than pain. Her most recent RBC exchange six days prior had revealed a hemoglobin S level of 11.8%. Her initial workup including MRI brain demonstrated right parietal encephalomalacia and evidence of chronic ischemic change of the right frontal and parietal lobes consistent with previously known silent ischemia of the right middle cerebral artery (MCA). There was no evidence of acute stroke. The patient continued monthly RBC exchange, maintaining a hemoglobin S level less than 36% and continued to experience symptoms of intermittent weakness, typically of the left lower extremity, but also at times involving the bilateral lower extremities and left upper extremity. Repeat MRI brain did not demonstrate any additional acute infarctions. However brain MRA did reveal bilateral stenosis of the MCA arteries and high-grade stenosis of the M1 segment and considered stable from previous MRI, consistent with MMS. Her symptoms continued intermittently and additional evaluation including MRI cervical, thoracic, and lumbar spine was unrevealing. Of note, at one point laboratory evaluation demonstrated a vitamin B12 level of 248 pg/mL, however her symptoms continued in spite of adequate repletion.

Approximately 21 months following her initial presentation, the SARS-CoV-2 pandemic began, resulting in limited access to hospital facilities including RBC exchange. Consequently the patient was started on crizanlizumab with intermittent simple transfusion for hemoglobin less than 8 g/dL in an effort to see if this therapeutic measure would alleviate her symptoms. Interestingly, after initiating crizanlizumab, even without continued RBC exchange and a hemoglobin S level of 83%, she had no further episodes of weakness until, due to insurance issues, her crizanlizmab was delayed. Subsequently her symptoms of weakness returned requiring hospital admission. Repeat workup including both MRI and MRA brain were negative for acute ischemia and again consistent with MMS. Resumption of crizanlizumab again alleviated symptoms until infusion was delayed again for insurance reasons. She was readmitted and repeat MRI and MRA of the brain again did not show acute ischemia. Given recurrent issues with insurance and easing of the SARS-CoV-2 pandemic restrictions she was resumed on both red-cell exchange followed by crizanlizumab and continues to do well to this day.

SCD carries significant potential neurological morbidity and mortality. SCD patients experience a significantly higher risk of stroke due to repeated vaso-occlusive events leading to cerebral ischemia and the development of MMS. This is the first case we are aware of in which a patient with sickle cell disease and MMS and worsening neurologic symptoms but without acute stroke was successfully was treated with crizanlizumab after failure of RBC exchange. Crizanlizumab targets P-selectin which is implicated in increased platelet aggregation in sickle cell disease. It is possible that crizanlizumab improved the patient's symptoms by reducing the risk of transient cerebral ischemia associated with her underlying abnormal vasculature, which was suspected due to acute cerebral vaso-occlusion secondary to sickle cell disease induced moyamoya syndrome.

No relevant conflicts of interest to declare.