Internal watershed infarcts (WI) involve white matter between deep and superficial arterial systems of middle cerebral artery. These infarcts are considered to be either from low blood flow or microembolism. Anemia is an extremely rare cause of watershed infarcts. Very few cases of hemolytic anemia causing watershed cerebral infarcts have been reported. Chronic lymphocytic leukemia (CLL) is frequently complicated with secondary autoimmune cytopenia such as autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and pure red cell aplasia. AIHA is present in about 7–10% of patients with CLL. AIHA from CLL presenting as WI is an extremely rare phenomenon with no previously published case reports to the best of our knowledge.
Chronic lymphocytic lymphoma (CLL) is a chronic lymphoproliferative disorder characterized by progressive monoclonal accumulation of functionally incompetent lymphocytes. It is the most common leukemia in the Western world and accounts for about 25–30% of all leukemia cases in the Unites States [
A 72-year-old man with a history of hypertension and cerebrovascular accident (CVA) 20 years ago without significant residual weakness presented to the emergency department with a 3-day history of right-sided facial droop, slurred speech, and clumsiness of the right hand. He had a 20 pack-year smoking history. His family history revealed a father who died suddenly at the age of 47 from an unknown cause, a brother with acute leukemia, and a sister with myocardial infarction at the age of 37 years.
On examination, he had mild right facial droop, mild dysarthria, right pronator drift, and 4/5 motor strength in the right upper and lower extremity. The remainder of the neurological examination was unremarkable. Other significant findings in physical examination were mild hepatosplenomegaly with axillary and cervical lymphadenopathy. Hematological investigations on admission showed severe anemia with a hemoglobin (Hb) level of 44 g/L, leukocytes 42.8 × 109/L, lymphocytes 35.95 × 109/L, neutrophils 4.28 × 109/L, and a platelet count of 120 × 109/L. Further investigations were most consistent with AIHA with an unconjugated hyperbilirubinemia (2.7 mg/dL), elevated LDH (444 IU/L), low haptoglobulin (<15 mg/dL), an elevated reticulocyte count 83.62 × 109/L (7.4%), and a positive direct antiglobulin test (DAT) with both IgG and anti-C3d.
Peripheral blood flow cytometry showed a monoclonal B-cell population with surface lambda-positive population and positive for CD 45, CD 19, CD 20 (weak), CD 22, CD 23, CD 5, and CD 38 (partial). This immunophenotype pattern was consistent with diagnosis of CLL. The clinical picture was consistent with modified Rai stage III CLL. The patient had multiple autoantibodies on cross match.
Computed tomography (CT) of the head was negative for acute bleed or mass effect but was suspicious for evolving stroke. It also showed an area of encephalomalacia in the left basal ganglia related to an old infarct or hemorrhage. The patient could not receive thrombolytic therapy due to severe anemia. Brain magnetic resonance imaging (MRI) showed multiple small areas of diffusion restriction with corresponding mild T2 hypersensitivity in the bilateral corona radiata and centrum semiovale. These findings were consistent with subcortical WI in a characteristic “string of pearls” pattern (Figure
Brain MRI showing small areas of diffusion restriction with T2 hyperintensity over (a) anterior horn of right lateral ventricle and (b) posterior horn of left lateral ventricle and left corona radiata, consistent with acute infarcts.
The patient was transfused to a goal Hb of 8 g/dL with least incompatible packed red cell (PRBC) transfusions. A total of 7 units of PRBC were transfused during the hospital stay, which the patient tolerated without any significant reactions. AIHA was treated with intravenous immunoglobulin (IVIG) 1 g/kg body weight daily for five days followed by 1 mg/kg of prednisone daily. At the time of discharge, the patient’s Hb was 8.8 g/dL and LDH had normalized. There was no significant change in the platelet count with steroids. At discharge, oral prednisone was continued for four months and gradually tapered off over the next two months.
His blood counts stabilized with steroids and IVIG. About 1 year after initial presentation, he was found to have worsening diffuse adenopathy in the posterior cervical and axillary areas. PET/CT done to evaluate the possibility of Richter’s transformation showed extensive bulky hypermetabolic lymphadenopathy in the head and neck region, bilateral axilla, bilateral hila, mediastinum, and throughout the mesentery and retroperitoneal distribution of the abdomen and pelvis. Maximum standardized uptake value (SUV) of 4.64 was noted in the right posterior cervical region. At this time, the patient’s LDH was 538 IU/L. Repeat flow cytometry showed a monoclonal surface lambda population which was positive for CD 20 (weak), CD 19, CD 5, CD 23, CD45, and CD 22. This pattern was again consistent with CLL.
The patient’s clinical status declined rapidly. Plan for excision lymph node biopsy to rule out Richter’s phenomenon had to be deferred due to severe debilitation and refractory AIHA. He was started on obinutuzumab with chlorambucil but had an anaphylactic reaction to obinutuzumab which led to discontinuation after 2 doses. His diffuse adenopathy did respond to the two doses of obinutuzumab with near-complete resolution over the next several days. The patient however remained very debilitated and confined to bed and further consideration of therapy was not appropriate and further staging of his lymphoma was deferred until his condition improved. His hospital course was complicated with recurrence of autoimmune hemolytic anemia, which was managed with blood product transfusions, steroids, and IVIG as before. He was eventually started on rituximab for refractory AIHA. He was in the middle of his second course of rituximab before his counts began to improve.
CLL is the most common leukemia in the Western countries. In the United States, CLL accounts for approximately 25 to 30% of all leukemia cases [
WI or border zone infarcts are ischemic lesions in the brain parenchyma located at the junction of territories supplied by 2 different non-anastomosing arterial systems. Two main types of WI described in literature are the cortical WI and the internal WI. The cortical WI occurs between cortical territories of anterior cerebral artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery (PCA). The internal WI affects corona radiata between territories supplied by superficial and deep perforators of MCA and/or centrum semiovale between territories of superficial perforators of ACA and MCA [
WI represents about 10% of all brain infarcts in autopsy studies [
Radiologically, internal WI can be either confluent or partial. Confluent infarcts are larger cigar shaped along the lateral ventricle. Partial internal WI can be either in the form of isolated single lesions or a chain-like “rosary” pattern. This rosary-like pattern in the centrum semiovale strongly supports the hemodynamic mechanism theory of causing WI [
Atrial fibrillation and atheromatous plaques are major offenders in causing microembolic diseases. Hemodynamic compromise leading to WI can arise from severe stenosis or occlusion of craniocervical arteries and/or systemic hypoperfusion in the setting of cardiac arrest or systemic hypotension. Hypoperfusion can further potentiate effects by affecting the clearance of microemboli [
AIHA occurs in about 7% of patients with CLL and an additional 7–14% of patients may have a positive DAT without clinical evidence of hemolysis. [
Various theories have been postulated to explain the pathophysiology behind these secondary cytopenias. Nonmalignant B cells in CLL can produce high affinity immunoglobulin G (IgG) directed against the antigens on erythrocytes and platelets, leading to AIHA and ITP [
Although DAT is the most important diagnostic test, AIHA is also known to occur with a negative DAT. DAT-negative AIHA can arise from either lower affinity antibodies, antibodies in concentrations below threshold for the test, or autoantibodies of IgA class which are not detected with the current testing methods [
Warm AIHA is caused by warm agglutinins which are predominantly IgG antibodies that react with protein antigens on the red blood cell (RBC) surface at body temperature and cause extravascular hemolysis. Cold agglutinins cause cold AIHA and are predominantly IgM antibodies that generally react with polysaccharide antigens on the RBC surface only at temperatures below that of the core temperature of the body and commonly cause intravascular hemolysis. Differentiating between these two forms is important in terms of diagnosis and treatment.
Initial management of patients presenting with acute anemia consists of supportive care and may require transfusion of blood products based on local protocols that consider the blood count and patient symptoms. When treatment of CLL is not indicated, immunosuppression can be used alone. Immunosuppression with systemic glucocorticoids is used as a first-line treatment for AIHA from warm agglutinins. Prednisone 1 mg/kg is given for 4 weeks, which can be tapered over 1-2 months. Use of intravenous immunoglobulin (1 g/kg body weight daily for 5 days) in the beginning can also be considered. Chemotherapeutic agents are not to be used as first-line agents for CLL associated with AIHA or ITP [
If underlying CLL also needs to be treated, steroids can be used to manage AIHA while chemotherapeutic agents are being used. Rituximab also has some activity against CLL, so it can be used in monotherapy or in combination with other chemotherapy agents [
For patients who fail to respond to first-line therapy, cyclophosphamide, azathioprine, cyclosporine, and mycophenolate mofetil have been used as second-line agents in the treatment of DAT-positive AIHA [
Patients not responding to first- or second-line treatment within 4–6 weeks must be considered for alternate treatment options such as cyclophosphamide, mycophenolate mofetil, cyclosporine, or azathioprine [
Rituximab has also been used in combination with other cytotoxic agents to provide more “CLL-directed treatment.” Combination therapies with rituximab for autoimmune cytopenias include rituximab–cyclophosphamide–dexamethasone (RCD) [
Recently, newer monoclonal antibodies have been studied for their role in the treatment of refractory cases of AIHA with CLL. Nader et al. reported a case of rituximab-refractory AIHA associated with CLL which was successfully treated with ofatumumab [
In a randomized controlled trial from a German CLL study group, obinituzumab combined with chlorambucil was found to be superior to rituximab–chlorambucil combination or chlorambucil monotherapy in previously untreated patients [
Our patient was given a trial of obinituzumab–chlorambucil based on its superiority over the rituximab–chlorambucil combination. Despite favorable response in his lymph nodes after two treatments, it was not reinitiated due to severe reaction and near-complete remission of his adenopathy.
The authors declare that they have no conflicts of interest.