Intravascular Lymphoma-Associated Stroke: A Systematic Review of Case Studies

Intravascular lymphoma (IVL) is an aggressive systemic large B-cell lymphoma that is a rare cause of stroke. The clinical characteristics of stroke associated with IVL remain underexplored, contributing to diagnostic complexities and a high mortality rate. This study endeavors to elucidate the salient clinical and investigative features of stroke linked to this condition. A systematic review was performed using the PubMed database from the incident to August 2023 including search categories for IVL and stroke. All studies, excluding review articles, were included in this study. There were 58 cases with a confirmed diagnosis of IVL associated with stroke, with a mean age of 62.9 ± 9.6 years (female 50%). Classical lateralizing stroke symptoms were noted in only 69% of cases. Other clinical syndromes included altered sensorium (31%), rapidly progressive cognitive impairment (23%), seizures (22%), and gait disturbances (19%). Common hematological abnormalities included elevated lactate dehydrogenase (LDH, 97%), erythrocyte sedimentation rate (ESR, 79%), C-reactive protein (CRP, 61%), interleukin-2, microglobulins, and cerebrospinal fluid (CSF) protein. CSF flow cytometry was not diagnostic, and cytology was mostly negative. The dynamic pattern for DWI/T2 lesions was predominant and primarily located in the subcortical regions. Diffuse background slowing (64%) was a major finding in the electroencephalogram. Seventy-one percent of cases died (n=45) mostly due to delayed diagnosis. Only 31% were treated with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisone) chemotherapy, among whom 25% died. This study suggests that IVL-associated strokes carry a high mortality rate, largely due to challenges in timely diagnosis and therapy. Unlike classical stroke syndrome, key indicators to aid in early diagnosis include a clinical syndrome of multiple non-lateralizing neurological symptoms, dynamic MRI DWI/T2-lesions primarily located in subcortical regions, elevated serum LDH, ESR, CRP, interleukins, microglobulin, CSF protein, and CSF polymerase chain reaction analysis, apart from tissue examination. Larger studies should be performed to establish diagnostic and predictive scores.


Introduction And Background
Intravascular lymphoma (IVL) is a rare, aggressive systemic diffuse large B-cell lymphoma (DLBCL) in which lymphoma cells selectively involve lumina of vessels, particularly small and medium-sized, and rarely involve parenchyma [1,2].It was first described as "angiotropic lymphoma" by Pfleger and Tappeiner in 1959 [3].IVL is distinct from primary central nervous system lymphoma as it lacks the expression of adhesion molecules and matrix metalloproteinases, which are needed for the invasion of tumor cells from blood vessels into the brain parenchyma.Thereby, IVL is usually contained in the blood vessel lumen [4].The lumen of blood vessels not only serves as a vehicle for dissemination but also as an active site for replication [5].Based on clinical features, IVL is classified as a "classical" or Western variant, which mainly involves the central nervous system and skin, and an "Asian" variant, which predominantly presents as hemophagocytic syndrome [6].Tumor cells can aggressively proliferate within the lumen, leading to its occlusion and ischemic stroke.Nevertheless, IVL is associated with a myriad of clinical syndromes, with cognitive impairment being a notable manifestation, while stroke symptoms make up only 8% of its symptomatic profile [7].Detection of specific cell surface glycoproteins aids in the diagnosis; however, tissue biopsy with demonstration of lymphoid cells within the blood vessel lumen is essential for a definitive diagnosis [1,5].The first line treatment for IVL is R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisone) combination chemotherapy with a remission rate of 43-53% [8,9].Due to the atypical presentations of IVL-associated strokes leading to diagnostic challenges, we aim to investigate the demographics, clinical features, investigative findings, and management of strokes associated with IVL.We hypothesized that strokes associated with IVL have specific clinical, laboratory, and radiological markers that can aid in early diagnosis.
We performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.The PubMed database was searched using the Medical Subject Headings (MeSH) terms and keywords from the incident to August 2023 to find the relevant studies in English literature.The search strategy used is shown in Table 1.Relevant references included in the articles searched were added for review.PubMed

Inclusion and Exclusion Criteria
All human studies associated with IVL and stroke, including case reports, case series, observational studies, clinical trials, editorials, and opinion articles, were included.All non-human studies, IVL not associated with stroke, and review articles were excluded.

Outcome of Interest
Data regarding demographics, clinical features, neuro-imaging features, laboratory findings, management, and prognosis were extracted.Primary outcomes were the frequency of the above-outlined variables.

Statistical Analysis
Descriptive analysis was performed using the SAS software (StataCorp 18.0, USA).Kempen et al. reporting guidelines were followed for reporting the systematic review of case reports [10].

Study Selection
A total of 83 studies were identified through a database search, as shown in Figure 1.Forty-seven articles were excluded, among which five were review articles and 42 were not associated with stroke.A total of 36 studies met the inclusion criteria and were included in the review.All of the 36 studies were either case reports or series.

Study Characteristics
From 36 studies, there was a cohort of 58 cases with a confirmed diagnosis of IVL associated with stroke.The mean age was 62.9 ± 9.6 years, of which 50% were female.The diagnosis of the IVL was confirmed mostly from the tissue biopsy, except in two cases, which were confirmed from cerebrospinal fluid (CSF) polymerase chain reaction (PCR) analysis [11].The characteristics of the cases are presented in Table 2.     and 2 globulin or gamma-globulin were elevated among its four cases [13].Serum beta-2 microglobulin was elevated in one case [16], while CSF beta-2 microglobulin was elevated in another case [40].Thrombocytopenia was noted in 17.9% of cases (n=56) and anemia in 18.2% of cases (n=55).None of the cases had leukopenia.[42].CSF cytology was tested in five cases, among whom only one case cytology showed several malignant lymphoblastic cells [28], while others were negative for malignant cells [16,21,29,36,45].CSF clonal immunoglobulin heavy chain (IgH) gene rearrangement was noted in two cases that are diagnostic of CNS Bcell lymphoma [11].Frequencies of significant serum and CSF findings are shown in Figure 3.
Forty-five cases had follow-up reports, among whom 71.1% died.Only 30.8% of patients were treated with R-CHOP chemotherapy, of whom 25% died.Other therapies included steroids (39.7%) and other chemotherapy (27.6%), along with anti-platelet therapies that proved to be ineffective, leading to death.

Discussion
Our review of 58 cases of IVL with associated stroke first suggests an atypical clinical presentation, unlike classical stroke syndromes.Only 69% of cases had classical lateralizing symptoms to suggest a clinical marker for acute stroke, while the majority had admixed non-specific, non-lateralizing symptoms including altered sensorium, rapidly progressive cognitive impairment, and seizures.There was a high mortality rate among these patients (71%), mainly due to diagnostic challenges and a lack of timely, proper treatment.We summarized frequently occurring laboratory abnormalities and typical radiological characteristics that can aid in the early diagnosis of this fatal disease.[48].A retrospective study reported that 96% of cases of IVL had elevated CRP levels [9].In our study, limited data were available for inflammatory markers; however, among reported cases, 79% and 61% cases had elevated ESR and CRP, respectively.Though these are highly non-specific markers for IVL, their persistently elevated levels can serve as an adjunctive to suspect IVL.
sIL-2R is the serum-detectable form of IL-2R, which is found on the lymphocyte membranes, contributing to their activation and proliferation.Its levels elevate in patients with DLBCL, including IVL.With the cutoff of 1104 U/ml, the specificity is 80%, and with a higher cut-off value of 1500-2000 U/ml, the specificity increases to 87-93%, with a positive likelihood ratio of 4.97 [49].Its sensitivity lies around 35%, even with a higher cut-off value in diagnosing DLBCL since it is detected in most hematolymphoid neoplasms [49].Since IVL is more associated with stroke-like lesions, sIL-2R levels are of higher yield in the diagnosis.There was a limited sample size for sIL-2R testing in our study; however, in all cases, its level was elevated.It emphasizes that elevated sIL-2R levels can be of high diagnostic utility.
Elevated levels of LDH are a sign of rapid cell turnover, which occurs with lymphoma.The sensitivity and specificity of elevated LDH are 47.4% and 86.5%, respectively, for detecting relapse of DLBCL [50].Brunet et al. reported that 97% of cases of IVL had elevated LDH levels [9].Similarly, in our study, almost 97% of cases had elevated LDH levels, which thereby can serve as a key marker for the diagnosis of IVL.
Like LDH, beta-2 microglobulin levels can increase in blood, urine, and CSF in lymphoma due to rapid cell turnover and can serve as a powerful diagnostic and prognostic marker for IVL [51].Concurrent with the findings, in our study, serum and CSF microglobulin levels were elevated in almost all cases among whom it was tested.
Other hematological abnormalities, like thrombocytopenia and anemia, were noted less frequently in our study, similar to the previous study [48].However, a study by Brunet et al. suggested a high frequency of anemia and leukopenia among IVL cases [9].
Lymphoma with false-positive perinuclear anti-neutrophil cytoplasmic antibodies (MPO-ANCA) is frequently reported as well.There might be a co-occurrence of vasculitis (biopsy-proven) and lymphoma [26].Muto et al. reported a case of false-positive MPO-ANCA and IVL, which was thought to be associated with immune dysregulation [26].
Brunet et al. studied 38% of cases of IVL with elevated CSF protein levels [9].In our study, approximately 46% of cases had elevated CSF protein, which serves as a marker of inflammation.CSF flow cytometry was noted to be unremarkable in our study, while only one case had positive cytology findings among the five tested cases.There is no dedicated study performed yet analyzing the sensitivity and specificity of CSF flow cytometry and cytology in IVL cases, yet Brunet et al. found no cases with cytology suggesting malignant cells among 29 cases of IVL [9].This suggests a high likelihood of false negative results from CSF flow cytometry or cytology in diagnosing IVL.Therefore, IVL should not be excluded from the differential solely based on these negative findings.However, the sample size of tested cases is smaller in our study, and further studies must be conducted on this topic.
CSF clonal IgH gene rearrangement through PCR analysis has a high specificity of 97% and sensitivity of 54% in the case of CNS lymphomas, with positive and negative predictive values of 93% and 74%, respectively.This test can serve as a significant marker in the diagnosis of CNS lymphoma as well as monitor the therapeutic efficacy given the likelihood of a high false-negative rate of cytology [52].In our case, only one case was tested and diagnosed with IVL based on clonal IgH gene rearrangement.
Our study further suggests a significant number of cases of EEG diffuse background slowing, which is an indicator of encephalopathy.This is a unique finding, unlike typical stroke cases where focal slowing is usually noted [53].
Among brain MRI markers, the topography of the DWI/T2 lesions was typical in IVL cases, mostly located in the subcortical regions.There is a dynamic pattern in the appearance and resolution of DWI/T2 lesions, with new ones emerging over time.As per Baehring et al., during the acute phase, DWI is highly sensitive, capturing both infarcts and possible tumor cell infiltration.In chronic stages, T2-weighted sequences are more informative, showing subacute infarcts or lymphoid collections, primarily subcortical.Contrast enhancement may appear around DWI/T2 lesions over time due to infarct sequela and blood-brain barrier disruption [15].Symmetrical confluent white matter lesions that can be seen in IVL can be differentiated from ischemic leukoraiosis or Binswanger's disease from associated DWI hyperintensity in IVL, which is absent in the case of ischemic leukoraiosis [54].Due to the involvement of small vessels and non-eloquent areas, initial scans might show T2 changes with or without DWI changes as per the age of the infarcts, where all the lesions might not localize to the presenting symptoms.
Further blood flow dynamics may be unaffected due to the prime involvement of small vessels, and therefore perfusion studies tend to be unremarkable [14].Other neuroimaging modalities that can be useful in early diagnosis include an 18-fluorodeoxyglucose (FDG-PET) scan [23].Yamada et al. noted high FDG uptake at the lesion site secondary to IVL [23].
Finally, first-line chemotherapy for IVL includes R-CHOP therapy.In our study, the lowest number of cases received R-CHOP therapy, mostly due to post-mortem diagnosis, concurring with a high mortality rate.A quarter of patients on R-CHOP therapy died, which can be due to delayed diagnosis, high disease burden, or late initiation of treatment.Other chemotherapy and anti-platelet therapies were ineffective, leading to the death.Therefore, early initiation of R-CHOP therapy should be the cornerstone of treatment in patients with IVL-associated strokes.

Limitations
The limitations of our study include a retrospective study design and being able to include only case reports, limiting the sample size and control group.We acknowledge the selection and publication bias associated with this study design.There was limited, complete data on the variables that we intended to study.This further limited our sample size, which might have skewed the values of certain variables.Further large-scale ("Intravascular"[All Fields] AND ("large"[All Fields] OR "largely"[All Fields] OR "larges"[All Fields]) AND ("lymphoma, b cell" [MeSH Terms] OR ("lymphoma"[All Fields] AND "b cell"[All Fields]) OR "b-cell lymphoma"[All Fields] OR "b cell lymphoma"[All Fields])) OR ("Intravascular"[All Fields] AND ("lymphoma"[MeSH Terms] OR "lymphoma"[All Fields] OR "lymphomas"[All Fields] OR "lymphoma s"[All Fields]))) AND ("stroke"[MeSH Terms] OR "stroke"[All Fields] OR "strokes"[All Fields] OR "stroke s"[All Fields] OR ("hemorrhagic stroke"[MeSH Terms] OR ("hemorrhagic"[All Fields] AND "stroke"[All Fields]) OR "hemorrhagic stroke"[All Fields]) OR ("ischemic stroke"[MeSH Terms] OR ("ischemic"[All Fields] AND "stroke"[All Fields]) OR "ischemic stroke"[All Fields]))

FIGURE 1 :
FIGURE 1: PRISMA flowchart Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 flowchart showing study selection

5 lymphocytes/mm 3 CT
head: hypodense lesion in septum pellucidum and corpus callosum; CT head after 2 months: periventricular hypodensities and ventriculomegaly; brain biopsy: bland infarction with lymphoma cells in blood vessels lumen, perivascular space, and extravascular foci in corpus callosum Treated with dexamethasone and whole brain radiation.Died after 2 months 2023 Bhagat et al.Cureus 15(12): e50896.DOI 10.7759/cureus.hypodenselesion in right motor strip; CT head after 2 months: multiple while matter hypodensities; conventional angiogram: left MCA distal occlusion; brain biopsy: ischemic damage, with lymphoma cells within small hr, LDH 5843 U/I MRI brain: multiple T2 hyperintense lesions of centrum semiovale in the occipital region, enhancing lesions in occipital lobe white matter, lacune in right periventricular region, ventriculomegaly; vessel imaging: normal; SPECT: normal; EEG: normal; bone marrow biopsy: myelofibrosis; splenic aspirate: negative; left quadriceps biopsy: IVL cells; brain biopsy: multiple infarcts with occlusion of small vessels by neoplastic cells mixed with fibrin Treated with steroids.Died after 8 months M Initially presented with seizure, confusion, left leftsided hemiparesis. 1 month later developed status epilepticus Serum: ESR 29/hr, LDH 942 U/I, alfa-2-globulin 11% CT head: right pons hypodense lesion; EEG: diffuse slowing brain biopsy: multiple hemorrhages and necrosis in right pons with occlusion of small vessels by neoplastic cells Died after CT head: hypodense lesion in right parietal and bilateral occipital lobes; cerebral angiography: negative; EEG: diffuse slowing; brain biopsy: multiple recent and older infarcts and small vessel occlusion by neoplastic cells Died after hypodense lesion in the right parieto-occipital region; MRI brain: multiple ischemic strokes in the subcortical region; EEG: diffuse slowing; brain biopsy: positive for infarcts with intravascular tumor cells Died after CT head: unremarkable; EEG: diffuse slowing; bone marrow biopsy: lymphoid neoplasia; brain biopsy: microinfarcts with intravascular tumor cells Died microgm/L MRI brain: DWI hyperintense along with T2 hyperintense small periventricular, cortical-subcortical lesions; vessel imaging: no significant stenosis; brain biopsy: lymphoma cells in the vascular wall of small and medium-sized leptomeningeal and intracerebral blood vessels Died on the 10 th day of admission F Progressive cognitive decline, headache, ataxia, and left homonymous hemianopia NA MRI brain: acute infarction along with enhancing cortical and sub-cortical lesions; brain biopsy: IVL NA 2023 Bhagat et al.Cureus 15(12): e50896.DOI 10.7759/cureus.resolvingDWI and T2 hyperintense lesions in bilateral subcortical regions and few contrast-enhancing lesions, left optic nerve T2 hyperintensity; skin biopsy-

1 Initially 5 months
DWI hyperintensity in right insular cortex; repeat MRI brain: continued new infarction; vessel imaging: multiple stenosis of right MCA; FDG-PET on 10 th day: high uptake in right temporal lobe; bone marrow and scalp biopsy: negative Treated with R-CHOP and whole brain radiationbrain: disseminated subcortical T2 hyperintense lesions; repeat MRI brain: acute and subacute infarction in multiple vascular territories; repeat MRI brain: new multiple arterial territory stroke; conventional angiogram: negative; brain biopsy: : perfusion defect in left hemisphere; MRI brain: large wedge-shaped T2 hyperintense lesion in right parietal lobe and pons; abdominal skin biopsy: negative; spleen biopsy: IVL Initial with suspicion of acute stroke and symptomatic seizure, treated with thrombolytics and anti-epileptics.With suspicion of autoimmune encephalitis, treated with steroids, with improvement of symptoms.left hemiparesis, altered mental status, and fever of unknown origin Serum: elevated ESR 89 mm/hr, CRP 64 mg/L, and LDH 873 U/L CT head: Multiple hypodensities in the bilateral cerebrum and in the cerebellum; MRI head: diffuse bilateral multistage infarction and hemorrhages; MRA head: negative; bone marrow biopsy: negative; random skin biopsy from thigh: IVL Initially treated with antiplatelet for stroke.For suspicion of vasculitis, treated with pulse steroids k with mild improvement of symptoms.Died on the 10 th day from septic subacute bilateral scattered infarcts; EMG: multiple mononeuropathies; repeat MRI brain: new stroke in the corpus callosum, bilateral cerebellar and cerebral hemisphere; CT abdomen: hypodensity in bilateral kidney and spleen; FDG-PET/CT: increased uptake in the spleen, liver, sternum, right thyroid, para-aortic lymph node, bone marrow; random skin biopsy from lower abdomen and thigh: IVL; bone marrow biopsy: a diagnosis of IVL on the 14 th day of re-admission started on CHOP-R every 21 days.After the 5 th cycle, the patient died of aspiration pneumonia Presents with gait unsteadiness.6 months later, left leg weakness and MRI brain: left inferior cerebellar infarct; MRI brain after 6 months: new infarcts in bilateral cerebellum; multiple MRI brain thereafter: new numerous Initially treated with antiplatelets.After the second stroke antiplatelet was switched.After the third stroke, dual antiplatelet therapy was used.Later verapamil 2023 Bhagat et al.Cureus 15(12): e50896.DOI 10.7759/cureus..A few weeks later came with a fall NA new punctuate infarcts of both acute and subacute onset in the cerebellar hemispheres, pons, internal capsule, splenium of the corpus callosum, and centrum semiovale bilaterally; conventional angiogram: negative; CSF: normal; bone marrow biopsy: normal; brain biopsy of right occipital cortex with stroke: IVL and cilostazol were added for possible vaso-spasm which caused orthostatic hypotension.After diagnosis of IVL-High dose methotrexate and CHOP-R After 3 cycles, attention span and MRI brain: unremarkable; EEG: left temporal theta waves during hyperpnea; repeat MRI brain: acute ischemic lesion in the left pons; repeat MRI brain after new symptoms: diffuse tumefactive hemorrhagic leukoencephalopathy with patchy restricted diffusion and enhancement; CT abdomen: lumbo-aortic lymph node of 2 cm in diameter with benign features; brain autopsy: multiple localizations of intravascular large B-cell lymphoma (CD20+, CD3−, CD5−, MUM1+, CD10−) in the brain, adrenal glands, kidneys, stomach and lungs, brain microhemorrhages The patient developed a rapid progressive impairment of consciousness until coma.left-sided hemiparesis Serum: elevated LDH at 256U/L, elevated sIL-2R at 5896U/mL; CSF: cytology negative for malignancy MRI brain: multiple ischemic lesions; repeat MRI brain: progressive new lesions; MRA: negative; FDG-PET: negative; bone marrow: negative; needle brain biopsy: within vessels accumulation of tumor cells positive staining for CD31 & 20, MUM-1.Negative for CD5,10 and BCL-6 Treated with steroid administration (betamethasone 4-8 mg/body) with minimal improvement then with 3 cycles of high-dose methotrexate chemotherapy followed by whole-brain radiation therapy.Despite improvement noted on MRI, the patient's general condition declined.Died 6 months post-disease onset Cruto et al. (2013) [30] 57 F Acute onset left leg numbness and weakness.Three months later left arm weakness and left visual field blurry vision Serum: elevated LDH 290 U/L, normal ESR/CRP; CSF: negative MRI brain: subcortical multifocal T2 and DWI hyperintense lesions, ADC hypo intensity and contrast enhancement in some lesions suggesting watershed infraction; MRA: normal; TTE: PFO without ASA; brain biopsy: proliferation of large atypical lymphoid cells in the vessels producing luminal obstruction surrounded by necrotic lesions consistent with cerebral infarction; Immunohistochemistry: + CD20 3 days of 1 gm IV steroids Vit K antagonist.After diagnosis of IVL, R-CHOP plus MTX followed by cranial radiotherapy.Eight months after the diagnosis neurological state remains stable, without recovery (hemorrhagic infarct in left frontal lobe with focal bilateral parietal lobe infarct; EEG: potential epileptogenic activity in left frontal region; MRI/CT head after 2 weeks: new infarcts, mass effect in right ventricles and MLS to left; brain biopsy: diffuse proliferation of malignant lymphocytes within the lumina of both large and small vessels with luminal obstruction; immunophenotyping: +CD20, -CD5, +BCL-2, +MUM-1, -CD10, -BCL-6 The patient died after 4 weeks of initial symptoms Hung et al. (2014) [32] 70 F Mild aphasia, right visual field defect, acalculia, and memory impairment.8 weeks later developed acute onset dressing apraxia and left-sided neglect.Five weeks later, acute global aphasia, drowsiness, right hemiparesis, and left gaze deviation Serum: elevated ESR 88 mm/hr, ANA 1:160; CSF: elevated protein 152 mg/dl and IgG level 25 mg/dl; CSF immunofixation electrophoresis: monoclonal gammopathy of IgG with lambda light chains MRI brain: Left parietal-occipital DWI hyperintense and ADC hypointense lesion; MRI brain after 8 weeks: multiple bilateral ischemic infarcts with mild hemorrhagic conversion; MRA: mild stenosis of bilateral ICA, MCA, ACA, and left VA; MRI brain after 13 weeks: new multistage bilateral infarcts with unchanged MRA; conventional angiogram: multiple focal segmental narrowing suggesting vasculitis; brain biopsy: discohesive cells with high nucleus to cytoplasm ration in the vascular spaces which were immunoreactive to CD45 and CD20 antibodies suggesting IVL Initially started on aspirin.Died from septic shock one month after the pathological diagnosis Received IV TPA 85 minutes after 2023 Bhagat et al.Cureus 15(12): e50896.DOI 10.7759/cureus.hoursafter initial symptoms: right frontal acute infarct; MRA head: negative; repeat MRI brain: new bilateral hemisphere infarction; brain biopsy: enlarged discohesive atypical cells with high nucleus-cytoplasm ratio, logged in vascular spaces and positive for CD20, MUM-1, BCL-10 small infarcts in bilateral cerebrum and cerebellum; DSA: suggestive of vasculitis (no further explanation); brain biopsy: proliferation of large, atypical cells in vessel lumen stained positively with CD20 sugar, and hemoglobin A1c, sIL-2R (3300 U/mL), elevated biliary enzymes MRI brain: multiple ischemic lesions including in the left temporal-parietal region and bilateral cerebellum which were T2 hyperintense; serial MRI brain: T2WI showed a new ischemic lesion in the left anterior region and later in the right frontal region; MRA head: mild stenosis of the bilateral internal carotid arteries, middle cerebral arteries, and anterior cerebral arteries; CT CAP: multiple bilateral nodular lesions in the lung and multiple tumor lesions in the liver; autopsy: atypical lymphoid cells within vessels of brain, lung, and liver Aspirin 200 mg and ticlopidine 100 mg for suspected ischemic lacunar stroke.Anticoagulant therapy by argatroban, heparin, and warfarin for suspected recurrent ischemic stroke.Treated with antibiotics for cholecystitis.Died on the 123 rd day in the setting of multi-organ failure small lesions in the bilateral subcortical region of the frontal lobe, which were hyperintense on T2 FLAIR; serial brain MRI (2 nd admission): showed more and larger hyperintense lesions in the bilateral subcortical region on DWI and T2; MRA: unremarkable for stenosis in intracranial and carotid arteries; transesophageal echocardiography: 7-mm complicated lesion in the aortic arch; skin biopsy: negative for lymphoid cells; autopsy/brain biopsy: lymphoid tumor cells confined to the small vessels of brain, sleep, bone marrow, kidney and liver Aspirin was initiated for suspected ischemic stroke.Died on 11: two enhancing lesions in the left frontal operculum and right parietal cortex.A small hyperintense DWI lesion in the right cerebellum indicating possible ischemia; repeat MRI brain 1 month later: near complete resolution of the above lesions; MRI brain 2 yrs later: multiple areas of acute ischemia in the right lateral splenium, left corona radiata, right parietal convexity and left superior vermis, as well as multiple areas of vasogenic edema with contrast enhancement in bilateral hemispheres; conventional cerebral angiography: diffuse but mild distal small vessel irregularities suggestive of atherosclerotic changes in the anterior and posterior circulation; CT chest, abdomen, pelvis and whole body PET: unremarkable for cancer; bone marrow aspirate/biopsy/flow cytometry: unremarkable; brain biopsy: hand and arm numbness, transient left facial droop, and vertigo over 1 month which progressed in 2023 Bhagat et al.Cureus 15(12): e50896.DOI 10.7759/cureus.brain:old left cerebellar lacunar infarction; repeat MRI brain: bilateral multifocal white matter change; MRI spine: negative; conventional angiogram: negative; EEG: bilateral temporal epileptiform discharges; PET/CT was notable for mild diffuse FDG uptake throughout the visualized axial and appendicular skeleton; bone marrow biopsy: normal; T-cell gene rearrangement flow cytometry was normal; random skin biopsy: confirmed the presence of IVL For suspected stroke patient was started on aspirin and a statin.Initial MRI brain: multifocal acute and subacute infarcts; initial MRI spine: noncontributory; repeat MRI brain and spine: new cerebral infarction and new spinal infarction at T6-7; CTAP: splenomegaly; cerebral angiogram: negative; bone marrow biopsy: elevated plasma cells of normal morphology and normal flow cytometry; brain biopsy: consistent with "double expressor" (MYC and BCL2) nongerminal center IVL Started on anticoagulation for a possible embolic stroke.The patient deteriorated and passed away prior to starting IVL treatment new multifocal infarctions; MRA brain: revealed no stenosis; CT chest and AP: was remarkable for cancer; Brain biopsy: IVL; immunohistochemical analysis: revealed positive expression of CD20, Bcl-2, Bcl-6, Ki-67, and MUMfocal hyperintense T2 lesions in the left splenium and right occipital lobe; over the next 2 months.Sequential, acute infarct noted in right MCA, R PCA, and left MCA territories; brain MRI 5 months later: revealed leptomeningeal enhancement with enhanced nodules around the fourth ventricle, which was consistent with meningeal involvement of IVL; MRA: no stenosis; CTAP: wedge-shaped infarcts in kidney and spleen; duplex venous legs: DVT in bilateral tibial veins Initially treated with aspirin and warfarin considering embolic stroke.Later after diagnosis of IVL treated with rituximab-based chemotherapy regimen.On a contrast: non-specific (T2FLAIR) hyperintensities in the subcortical white matter; serial MRI brain: progressive new development of restricted diffusion lesion on deep white matter, progressive T2 hyperintense lesions, right hemispheric IPH, cerebral edema with mass effect and enhancing lesions; cerebral angiography/MRA: irregular corrugated and beaded appearance of the cervical carotid arteries, thought to be consistent with chronic fibro-muscular dysplasia; repeat cerebral angiography: new right cervical internal carotid artery dissection in the distal extracranial portion as well as progression of luminal irregularities indicative of progressive vasculopathy; MRA: new bilateral intracranial vertebral artery dissection; highresolution vessel wall MRI: no arterial wall enhancement to suggest vasculitis; FDG-PET scan of the brain: unrevealing; brain biopsy (right temporo-parietal): neoplastic lymphocytes distending small cortical vessels; immunohistochemistry: CD20+ B-cell and labeled widely for MIB-1 Initially treated with a five-day trial of intravenous methylprednisolone followed by a prednisone taper.Then (R-CHOP) therapy along with decompressive craniectomy.Therapy halted the progression of the disease and improved modified Rankin Scale to 1 2023 Bhagat et al.Cureus 15(12): e50896.DOI 10.7759/cureus.multifocalareas of DWI hyperintense signal involving the white matter of both frontal lobes, the left parietal lobe, the splenium of the corpus callosum, the left temporal lobe, and the left cerebellar hemisphere; repeat MRI brain: enlargement of many of the foci of abnormal DWI signal, compared to previous one; MRA: unremarkable for carotid or vertebral stenosis; optical coherence tomography scans: thickening of the choroid; fluorescein angiography: bilateral delayed arteriovenous and choroidal filling with distal pruned capillary bed, leakage, and window defects more prominent in the left eye; computed tomography of the abdomen and pelvis with contrast: 3 distinct lobulated retroperitoneal masses that demonstrated softtissue attenuation with mass effect on the adjacent right kidney; biopsy of perinephric mass: large neoplastic lymphoid cells; immunohistochemistry: CD20+ PAX5+ B cells that coexpress BCL6, MUM1, and BCL2.Negative for CD10, CD21, and CD30.60% + CMYC.The proliferation fraction was approximately 90% based on Ki-67; brain biopsy (right frontal lesion): large atypical lymphoid cells, with occasional mitoses plugging capillaries in the cerebral cortex; immunohistochemical stains: CD20 and Pax-5 positive tumor cells, extremely high positivity with Ki-67.CD3 shows scattered perivascular and parenchymal mature T-cells Treated with aspirin 81 mg daily and atorvastatin 10 mg for multifocal embolic stroke of unknown etiology.Received intercalated high-dose methotrexate and R-T2-hyperintense subcortical lesions in the frontal and temporal regions, with negative DWI, suspected inflammatory-vasculitis appearance; total body CT and cerebral angiography: unremarkable; EEG: mild slowing; postmortem brain biopsy: consistent with IVL Treated with high-dose IV cerebral hemorrhagic changes MRI brain: numerous microbleeds and superficial siderosis with edematous changes around the hematomas; repeat MRI brain: expanding hematoma; PET: diffuse accumulation in the bone marrow of the limbs and pelvis; brain biopsy of microbleed at right temporal tip: showed CD20-positive cells in small vessels confirming IVL; bone marrow biopsy: atypical lymphocytes in blood vessels consistent with IVL R-CHOP X 6 cycles and 4 cytometry MRI brain: abnormal susceptibility was seen in all patients, occurring in both supratentorial and infratentorial gray and white matter, often punctate or gyri form, inconsistently associated with T2 hyperintensity and/or reduced diffusion.All patients demonstrated abnormal white matter T2 or FLAIR hyperintensities.5 patients demonstrated reduced diffusion, predominantly in small vessel patterns.4 patients showed abnormal enhancements, often subtle, parenchymal, and involving gray or white matter.Case1: innumerable subcortical microhemorrhages; case 2: few punctate foci of microhemorrhage on SWI not appreciable on subsequent gradient echo sequences T2*weighted imaging; case 6: lobar microhemorrhages; Biopsy (unremarkable; MRI brain: bilateral embolic infarcts; serial brain MRIs demonstrated evolving multiage infarctions that were atypical of embolic etiology; cerebral angiogram: unremarkable for large vessel vasculitis; EEG: unremarkable; whole-body PET scan: hypermetabolic 4-mm cervical lymph node suspicious for nodal metastasis; brain biopsy: focal dilated vessels containing abnormal lymphoid cells, with Immunostaining positivity of PAX5 and CD20 consistent with IVL Initially treated with apixaban with concern for embolic infarcts.IVIG and methylprednisolone were administered daily with 4 sessions of plasmapheresis, resulting in mild improvement in bilateral plantar flexion.Discharged on prednisone.Referred to oncology for initiation of chemotherapy 6-month history of rapidly progressive dementia along with 3 days of left limb weakness and numbness.Serum: initially normal LDH and routine blood test.On readmission, LDH was elevated (338 U/L); initial CSF: leukocyte count (20106 /L) and protein (0.89 g/L) MRI brain: bilateral multiple hyperintense lesions in periventricular white Treated with IV methylprednisolone (1000 mg/d 2023 Bhagat et al.Cureus 15(12): e50896.DOI 10.7759/cureus.semiovale,corpus callosum, and cerebellum on T2 FLAIR; MRI spine: within normal limits; repeat MRI brain: enlarged and increased lesions on T2/DWI with open ring enhancement; MRA: unremarkable; bone marrow and random incisional skin biopsy: unremarkable; brain biopsy: occlusion of the small vessels by neoplastic cells with prominent nucleoli, CD2+, consistent with IVL for 5 days, 500 mg/d for 3 days, 250 mg/d for 2 days, and 125 mg/d for 1 day), with subsequent oral methylprednisolone (20 mg/d) for 1 month and azathioprine (100 mg/d) for maintenance.Died of brain herniation after 10 abnormal T2/FLAIR signal in the superior vermis, enlarged pituitary gland; bone marrow biopsy: hypercellularity without malignancy; brain biopsy: pituitary and cerebellar vasculature contained lymphoma cell associated with clots; autopsy of the body showed extensive disease with involvement of every major organ system and extensive intravascular involvement Trial of steroids, mental status transiently improved.Died 3.brain: mild periventricular white matter ischemic changes of aging.No sign of acute infarction or enhancing lesions.No intracranial hemorrhage; bone marrow biopsy: small clonal population of B cells; brain biopsy: striking infiltration of lymphoma cells within the lumina of intramuscular blood vessels; immunocytochemical identification of CD20, CD79a, CD5 positive atypical large B-cell population in clumps Responded to R-CHOP therapy X 6 cycles.Relapsed one year after the initial presentation and was treated with MIME and rituximab, MRI brain: dynamic change with recurrent multiple foci restricted diffusion in the bilateral frontal and parietal lobes, and thalamus, confluent white matter hyper-intensities involving multiple cortical and sub-cortical locations; brain biopsy and autopsy: revealed CD20-positive atypical B-cell within the lumina of the vessel in brain tissue Trial of steroids with transient improvement brain: dynamic changes with recurrent multiple foci restricted diffusion involving multiple watershed distributions.Diffuse patchy T2/FLAIR signals involving both white matter and cortical areas, with some enhancement.Different stages of SAH and IPH; brain biopsy and autopsy: extensive lymphoma cells within the lumina of blood vessels with positive pleocytosis MRI brain: patchy cortical and sub-cortical areas of T2/FLAIR signal abnormalities with corresponding patchy enhancement within the frontal lobe and cerebellum; bone marrow biopsy: negative; brain biopsy: IVL with CD20+ cells within the small vessels and capillaries throughout Treated with MTX and rituximab X 8 cycles and monthly maintenance MTX X 12 cycles.Survived for 23 months and still alive till publication

FIGURE 2 :
FIGURE 2: Frequency of serum and CSF analysis findings of all cases CSF: cerebrospinal fluid, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, LDH: lactate dehydrogenase, IL: interleukin
[20,46]CSF analysis findings were elevated protein (45.7%; n=35) and pleocytosis (35.3%; n=34).CSF flow cytometry was done in eight cases, which were all unremarkable.Richie et al.'s study showed at least one negative result on flow cytometry in six cases, and three cases had unremarkable results[43].Also, CSF flow cytometry of a case from Zhong et al. and Sips et al. showed no evidence of malignancy[20,46].Kimura et al. reported monoclonal B-cell lymphocytosis in flow cytometric analysis from cerebral bleeding sites During serum work-up, we noted a high frequency of elevated ESR, CRP, sIL-2R, microglobulins, and LDH levels.Inflammatory markers like ESR and CRP have long served as diagnostic markers of malignancy.CRP had 46.1% sensitivity and 75.4% specificity, and ESR had 43.6% sensitivity and 75.6% specificity to predict various cancers [47].Ponzoni et al. reported 43% of cases with IVL with elevated ESR