Unusual complication of intrathecal methotrexate via ommaya reservoir in diffuse large B-cell lymphoma with central nervous system involvement

Dear Editor, Diffuse large B-cell lymphoma (DLBCL) demand broaden awareness as the most common type of non-Hodgkin lymphoma.[1,2] Malignant B-cell proliferation involving the brain, spine, leptomeninges, or eyes represent rare subtype of this disease arising as primary central nervous system lymphoma (PCNSL) or as secondary CNS lymphoma (SCNSL) from systemic DLBCL. Both forms of CNS lymphoma are uncommon; approximately 5% of all DLBCL cases present with SCNSL at the time of diagnosis. However, CNS progression is known to occur shortly after initiating or completing treatment for systemic disease.[2] PCNSL accounts for approximately 4%–6% of primary CNS neoplasms with an incidence of 1500 cases annually.[2,3] Both PCNSL and SCNSL are associated with significant morbidity and a poor prognosis; however, conventional therapies are aimed at preserving neurological function and prolonging survival. Intrathecal (IT) therapy or high-dose methotrexate (HD-MTX) has been incorporated into induction regimens for patients deemed high-risk.[2] Despite their widespread use, these strategies provide only modest benefit, and their overall efficacy remains controversial due to inconsistent clinical outcomes and a lack of prospective data.[4,5] For patients with leptomeningeal disease, IT chemotherapy is preferably administered through an Ommaya reservoir rather than repeated lumbar punctures (LPs) to provide a less invasive and more reliable method for consistent CNS drug delivery.[6] Nevertheless, concerns regarding treatment-related neurotoxicity have raised caution among clinicians when considering IT-MTX administration, especially via Ommaya reservoir, where case illustrations have been more common.[7–9] A rare complication of IT chemotherapy can involve the development of subdural hygromas, with only a few cases reported in the literature following an LP for chemotherapy administration.[10–13] Herein, we describe what is, to our knowledge, the first reported case of clinically significant bilateral subdural hygromas associated with IT MTX administration via an Ommaya reservoir, including the use of subdural evacuation ports and endovascular embolization. A 68-year-old male with hypertension and diabetes mellitus and no notable family history of oncologic disease presented for evaluation of a lymphoproliferative disorder identified during the workup for abdominal pain and dysphagia. An abdominal lymph node biopsy was performed, demonstrating diffuse infiltrate of intermediate-sized atypical lymphoid cells effacing the nodal architecture, concerning for a [DLBCL; Figure 1a]. Immunohistochemical staining revealed CD20/PAX5 positive B cells coexpressing CD10, BCL6, BCL2 and c-myc [Figure 1b-g], with a high proliferative index (Ki67 95%). A pleural effusion and ascites were also identified, drained, and sent for cytologic analysis which returned positive for abnormal B-cells. Systemic treatment was initiated with the first cycle of R-CHOP treatment. The molecular panel demonstrated double hit c-myc/Bcl2 t (8;14) t (14;18) mutation, and the patient was subsequently planned for 6 cycles of DA-EPOCH-R, including IT CNS prophylaxis with HD-MTX. Cerebrospinal fluid (CSF) was collected during the first administration of IT chemotherapy. This cytology showed an abnormal B-cell population comprising 49% of viable events, with dim CD19 and CD20 expression and bright CD10 and CD38 expression. A brain magnetic resonance imaging (MRI) with gadolinium was completed to rule out intracranial involvement, with no clear anatomical areas of abnormal enhancement identified.Figure 1: Histopathology and immunohistochemistry of the abdominal lymph node. (a) H and E (×200) shows intermediate-sized atypical lymphoid cells effacing the nodal architecture. Immunohistochemical staining at ×20 magnification showing CD20 (b) and PAX5 (c) positive B cells with co-expression of CD10 (d), BCL2 (e), BCL6 (f), and c-MYC (g)Given the lack of clear parenchymal disease, the patient was considered a candidate for placement of an Ommaya reservoir for IT MTX delivery to help achieve disease remission. This procedure was successfully completed using electromagnetic tracking frameless navigation, achieving precise postoperative placement of the catheter with all fenestrations located within the lateral ventricle, and the tip terminating in the third ventricle [Figure 2a]. The patient tolerated the procedure well without complication and was closely followed in the neurointensive care unit (ICU), where he remained neurologically intact. He was then transferred to the hematology/oncology floor on his postoperative day 1 to resume his systemic oncologic treatment. He received the first dose of IT MTX (6 mg) and cytarabine (50 mg; 5 cc of CSF were withdrawn and replaced with a solution diluted in 5 mL of 0.9% sodium chloride) on his postoperative day 2 via the Ommaya reservoir. He tolerated this session well with no acute events and no major changes in his complete blood count.Figure 2: Immediate postoperative head CT showing a right frontal Ommaya reservoir with the catheter tip terminating in the third ventricle, associated with bifrontal pneumocephalus and a small amount of air in the right lateral ventricle (a). Head CT on postoperative day 3 demonstrating bilateral hemispheric subdural hypodense collections, with a maximal thickness of 8 mm bilaterally and partial effacement of the underlying hemispheric sulci (b). Repeat imaging on postoperative day 4 showing stable hypodense subdural collections (c). Head CT on postoperative day 12, following the second intrathecal methotrexate session, showing interval enlargement of the subdural collections, now measuring approximately 12 mm on the right and 10 mm on the left with associated crowding of the basilar cisterns (d)However, one day after receiving the first dose of IT chemotherapy via Ommaya reservoir, the patient developed a new onset altered mental status, becoming increasingly lethargic and difficult to arouse. As a result, the EPOCH session with doxorubicin/etoposide/vincristine was subsequently delayed, and a hematopoietic cell transplant (HCT) was subsequently completed, demonstrating new bilateral subdural hygromas measuring up to 8 mm in thickness [Figure 2b]. On the following day, his mental status had spontaneously improved without intervention, and he returned to his neurological baseline: awake, alert, oriented, briskly conversant, and following commands in all extremities. An interval HCT was obtained which demonstrated stable subdural collections [Figure 2c]. However, systemic treatment was delayed for 3 days as his mental status continued to wax and wane over time with intermittent periods of somnolence. An electroencephalogram (EEG) was performed which ruled out seizures as a contributing factor towards his altered mental status. His systemic treatment was then resumed, and after completing the second session of IT chemotherapy, the patient’s neurological status was noted to quickly decline once again. He became increasingly more lethargic and difficult to arouse, requiring prolonged verbal and noxious stimuli. He also exhibited a new symptom of frequent hiccups. Given this significant change in his mental status, he was transferred back to the neurocritical care unit and completed an emergent HCT, which demonstrated slightly enlarged bilateral subdural hygromas, slit ventricles, and crowding of the posterior fossa [Figure 2d]. The Ommaya reservoir was tapped for CSF analysis and to assess intracranial pressure. These studies were not indicative of an infectious process, and the pressure was noted to be low with a minimal amount of CSF retrieved without aspiration. A stability HCT completed on the same day demonstrated no further expansion of the subdural hygromas. Surgical intervention via burr hole drainage was discussed and offered with the patient’s sister. However, given the high risk for this patient to undergo an open surgical procedure, placement of a subdural evacuation port system (SEPS) at the bedside under local anesthesia was offered as well. The patient’s family was hopeful for spontaneous improvement given his previous waxing-and-waning mental status, therefore further intervention was deferred by the patient’s next of kin at that time. The patient’s condition continued to deteriorate into the following day until he was noted to no longer open his eyes to verbal or noxious stimuli and began to show new motor signs of extensor posturing in the upper extremities. With clinical concern for impending herniation, urgent surgical evacuation was re-discussed with the patient’s next of kin, who ultimately elected to proceed with a bilateral twist drill craniostomy with bilateral SEPS placement. After durotomy, the burr holes were noted to egress fluid at high pressure; interestingly, the right-sided port drained chronic-appearing, hemosiderin-stained blood contents; and the left-sided port drained more thin serous liquid [Figure 3a].Figure 3: Emergent placement of a subdural evacuation port system (SEPS) bilaterally, resulting in evacuation of chronic blood products on the right and serous fluid on the left (a). Immediate postoperative CT after SEPS placement demonstrating decreased bilateral subdural hygromas and improved effacement of the basal cisterns (b). Lateral view of a plain radiograph following liquid embolic injection (Onyx®), demonstrating radiopacity along the expected course of both embolized middle meningeal arteries (c)Approximately 20 min following this procedure, the patient acutely developed forced left gaze deviation, lip smacking, and tonic posturing of the upper extremities for approximately 20 s. This was associated with a brief oxygen desaturation down to 56%, which later required intubation, given his loss of motor exam in the postictal state and inability to protect his airway. He was given 4 mg of Lorazepam, loaded with 3 g of Keppra, and started on standing Keppra 750 mg twice daily. An emergent HCT was obtained which demonstrated a significant decrease in the size of the subdural hygromas with interval brain expansion [Figure 3b]. EEG demonstrated generalized slowing without evidence of ongoing seizure activity. The SEPS were then clamped approximately 48 h after they were initially placed in preparation for removal. Despite the reassuring HCT findings and weaning off all sedative agents, the patient’s neurological status remained relatively unchanged with no significant improvement. A repeat HCT was obtained 1 day into the SEPS clamp trial which demonstrated a slight interval increase in the size of the hygromas. The SEPS were subsequently reopened to promote further drainage. The patient’s mental status gradually improved by postprocedure day 3, when he passed a spontaneous breathing trial and was successfully extubated. The following day after extubation, he experienced a gradual return to consciousness, being alert, awake, oriented, and briskly following commands. The SEPS were then clamped once again in preparation for removal, and an interval HCT was obtained 1 day later which demonstrated stability of his intracranial findings. The SEPS were then subsequently removed. Two days after SEPS removal, a minimal increase in the size of the bilateral collections was noted on a planned delayed interval follow-up HCT. However, his neurological exam remained stable, and he was eventually transferred out of the ICU to the step-down unit. Middle meningeal artery (MMA) embolization was then discussed with and offered to the patient’s next of kin as an off-label use to theoretically reduce the risk of hygroma re-accumulation, since the patient was anticipated to continue with further sessions of IT chemotherapy. The MMA embolization was successfully performed with Onyx® [Figure 3c]. The patient tolerated this procedure well without complication. A follow-up HCT was obtained, which demonstrated stability in the size of the left subdural collection and a slight interval decrease in the size of the right subdural collection. To further investigate the etiology of the collections, intracranial hypotension due to occult CSF leak was considered. An MRI of the entire spine was completed which was not indicative of an occult CSF leak. Intermittent and minor fluctuations were noted in his mental status over the next several days which were attributed to hospital-acquired delirium from a prolonged hospitalization and repeated ICU stay. He otherwise remained hemodynamically and neurologically stable enough to resume his systemic oncologic treatment and was ultimately discharged from the hospital to home with visiting nursing services in stable condition. Such an unusual complication provides an opportunity to reexamine current CNS-directed strategies for DLBCL. Standard systemic regimens include six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), or alternatively, dose-adjusted EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone), both of which have shown promise in patients with relapsed or refractory disease.[14,15] However, due to their inherent pharmacokinetic properties, these standard regimens have limited penetration into the CSF. IT chemotherapy has been proposed as a potential solution to help enhance CNS drug delivery in populations at high-risk for SCNL and potentially improve survival outcomes. MTX exerts its cytotoxic effects by inhibiting dihydrofolate reductase and blocking the conversion of folic acid to tetrahydrofolate, which is an essential cofactor for nucleotide biosynthesis and DNA replication. MTX plays a central role in both the treatment and CNS prophylaxis of acute lymphoblastic leukemia and aggressive lymphomas due to its ability to cross the blood–brain barrier.[16] However, MTX may also induce unwanted side effects, including adenosine-mediated vasodilation, impair neurotransmission, disruption of astroglial folate metabolism, and cytotoxic edema.[17,18] Each of these side effects can predispose patients to neurotoxicity, as a more frequent phenomenon in patients receiving IT-MTX through Ommaya reservoirs.[9] In our case, the patient developed bilateral subdural hygromas following the administration of IT-MTX via an Ommaya reservoir. Although the precise etiology remains unclear, several mechanisms are hypothesized to have contributed to this result. Passing the Ommaya catheter from the skull to the lateral ventricle inherently violates both the subdural space and the subarachnoid space, creating a pathway for them to communicate in continuity. Moreover, the hemorrhagic nature of the right-sided collection may have resulted from inadvertent injury to a bridging vein during reservoir placement, further promoting its formation. Postoperative pneumocephalus, as identified on tomographic images following placement, could have also introduced a third space in which air was gradually replaced by CSF, which then redistributed to form the bilateral subdural collections. In addition, the brief osmotic gradients created after delivery of MTX into the ventricular system, and subsequently into the subarachnoid space, may have facilitated fluid shifts, resulting in accumulation of subdural collections. However, the authors noted that MTX solutions have osmolarity values close to the physiologic CSF range (281–306 mOsm/kg) which is intended to prevent fluid shifts and neurotoxicity.[19] Rather than an osmotic process, the authors propose a chemical-related phenomenon. IT-MTX is recognized to induce meningitis or arachnoiditis, during which CSF frequently demonstrates elevated protein and pleocytosis, and MRI may reveal leptomeningeal enhancement.[12,20] Such inflammatory changes could plausibly alter arachnoid permeability or promote membrane formation that traps proteinaceous CSF.[21] However, no studies to date have directly measured MTX concentrations, osmolarity gradients, or other biochemical differences between CSF and subdural hygroma fluid, leaving definitive evidence for a primary chemical or osmotic driver lacking. Nevertheless, the progressive enlargement of the collections with repeated IT-MTX, leading to mass effect and neurological decline in our case, supports the plausibility of a non-hydrostatic chemical mechanism. A similar case was described by Shenouda et al., in which a patient with B-cell acute lymphoblastic leukemia developed progressively enlarging bilateral subdural hygromas following IT-MTX. Intracranial findings demonstrated significant mass effect and sulcal effacement upon the surrounding brain parenchyma which required bilateral burr hole evacuation.[13] Assad et al. and Lewis et al. both reported similar case studies and complications following the administration of IT-MTX, ultimately requiring surgical evacuation for definitive management.[10,11] A summary of the available cases of subdural hygromas following IT-MTX is presented below in Table 1.Table 1: Summary of cases reported in the literature about patients that presented with symptomatic subdural hygromas after administration of intrathecal chemotherapyIn each of the illustrated cases above, the proposed mechanism of hygroma formation was attributed to intracranial hypotension secondary to an LP and subsequent CSF leak, causing downward displacement of the brain. Indeed, in patients with hematopoietic stem cell transplants, reports indicate that symptomatic subdural hygromas can develop in 1%–2% of patients post-LP cases.[22] This directly contrasts with the mechanism of hygroma formation in our case, in which there was no clear evidence of CSF leakage, which suggests a chemical rather than hydrostatic or physical process involved in the subdural collection formation. Moreover, our case was distinct not only in its etiology but also in its management, as SEPS was used to evacuate the hygromas with adjuvant MMA embolization, rather than surgical evacuation alone. Bedside craniostomy with SEPS is increasingly recognized as a minimally invasive alternative to burr-hole drainage or craniotomy. Large retrospective cohorts have specifically demonstrated that SEPS offers comparable efficacy in subdural hematoma evacuation with lower rates of morbidity and reduced costs.[23] In this same cohort, SEPS was associated with significantly shorter hospitalizations and fewer postoperative seizures, though reoperation rates have reported to be higher with on chronic subdural a a delayed and low rates of acute and seizures In patients over the of SEPS with has shown a of approximately a complication of and under Although most SEPS literature on the underlying drainage to subdural hygromas. overall low complication and efficacy its role as a or minimally invasive alternative in refractory subdural This is especially for or patients that may be deemed to have high surgical after SEPS placement in our case, the patient developed clinical are a known complication following evacuation of subdural collections and can in significant postoperative morbidity and However, their incidence is relatively low in the reported in approximately of patients following and is in SEPS of seizures after subdural drainage that brain could to altered or on the brain ultimately the seizure In our case, the patient to and was subsequently started on therapy with no further clinical or seizures our case incorporated MMA embolization to reduce the risk of subdural hygroma MMA embolization has been increasingly in the of and its efficacy is well by and These studies decreased rates of and the for surgical The its use in in the embolization of the MMA that the further and promoting fluid In a similar chemical meningitis by IT-MTX can alter arachnoid permeability and promote hygroma formation through a process to that of This supports the use of adjuvant MMA embolization to prevent hygroma the same of to these inflammatory Although our case suggests a potential role for MMA embolization in patients with subdural hygromas who are expected to continue receiving IT chemotherapy and therefore at risk of over time. hygromas a rare but potentially clinically significant complication of MTX we the first case after MTX administration through an Ommaya reservoir, requiring bedside twist drill drainage and off-label adjuvant bilateral MMA embolization to IT chemotherapy remains an for CNS in patients with clinicians to the potential for neurotoxicity and subdural hygroma formation. and and and and and and The following case followed the of the of of the was obtained from the patient’s next of kin for of this case and of patient The authors that they have obtained all patient In the the patient has given his for his images and other clinical to be reported in the The patient that and not be and due be to but be is not to this as no were or during the current and of are no of