Chronic Lymphocytic Leukemia With Leptomeningeal Involvement Presenting as an Acute Encephalopathy

Abstract

Introduction

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. Extramedullary involvement in the central nervous system (CNS) is a rare complication of the disease, and less than 200 cases have been reported. We report a case of leptomeningeal involvement of CLL that presented as an acute encephalopathy.

Case presentation

A 76-year-old man with treatment-naïve, Rai stage 0 CLL presented with altered mental status. Cerebrospinal-fluid studies, including flow cytometry, confirmed the leptomeningeal involvement of the previously diagnosed CLL. Surveillance imaging and lab studies showed no evidence of disease progression or Richter’s transformation. One-time intrathecal methotrexate resulted in transient improvement of his mental status.

Conclusion

CLL patients with new-onset neurologic manifestations should be evaluated for the CNS involvement of the neoplasm via brain imaging and cerebrospinal-fluid flow cytometry. This CNS involvement of CLL is associated with poor clinical outcomes. Intrathecal treatment with methotrexate, cytarabine, and steroid may improve neurologic symptoms.

Introduction

Chronic lymphocytic leukemia (CLL) is a mature, B-cell neoplasm characterized by a progressive accumulation of monoclonal-B lymphocytes. This disease is the most common adult leukemia in the United States, accounting for 35% of new cases in 2021.¹ Clinical presentations vary widely from no clinical symptoms to lymphadenopathy, splenomegaly, fever, fatigue, weight loss, or night sweats. Systemic treatment is indicated only for active disease with anemia, thrombocytopenia, symptomatic splenomegaly or lymphadenopathy, symptomatic extranodal involvements, or other systemic symptoms.²

Central nervous system (CNS) involvement is a rare complication of CLL.^3,4 The pathophysiology, risk factors, treatment options, and prognosis are not well understood. Because the prognosis of CLL with CNS involvement is poor, it is generally recommended to promptly initiate systemic or intrathecal treatment.^5,6 In our literature search, we identified fewer than 200 cases reported to date. We contribute a case of leptomeningeal involvement of otherwise stable CLL disease presenting with acute encephalopathy. This patient showed transient clinical improvement to treatment with intrathecal methotrexate.

Case Narrative

A 76-year-old man presented to the Kaiser Permanente Moanalua Medical Center (Honolulu, HI) emergency department for confusion and generalized weakness. Emergency medical services was called after a neighbor found the patient on the floor and confused. According to emergency medical services, the patient reported falling on the floor the night prior and not being able to get up because of bilateral leg weakness. We were unable to confirm this history because of the patient’s confusion.

Collateral information was obtained from the patient’s durable power of attorney and family members. At baseline, he was functional and independent with all activities of daily living and some instrumental activities of daily living. His neighbors provided transportation and helped with grocery shopping. He lived alone. His son and stepdaughter lived in other states. His son last saw the patient a few months prior when his mental activity was at baseline.

The patient had a history of treatment-naïve, Rai stage 0, Binet stage A CLL on active surveillance, and cutaneous B-cell follicular lymphoma in remission after radiation therapy. Both cutaneous lymphoma and CLL were diagnosed in 2014 when the patient developed multiple areas of alopecia (Table 1). Skin biopsy of an alopecic lesion confirmed the diagnosis of cutaneous B-cell follicular lymphoma. Subsequent flow cytometry of bone marrow revealed an aberrant, monoclonal, CD45-bright, B-lymphoid population that co-expressed CD5, CD43, CD19, CD20 (dim), CD22 (dim), and CD23 with kappa clonal excess. These cells were phenotypically distinct from the cutaneous follicular B-cell lymphoma because the latter did not express T-cell antigens CD5 and CD43. Other past medical history includes prostate cancer in remission, prior radical prostatectomy, hyperlipidemia, gastroesophageal reflux disease, history of saddle pulmonary embolus, and deep vein thrombosis.

Table 1:

Timeline with emphasis on oncologic events

Date	Event
6/19/2014	Patient seen by a dermatologist for multiple areas of alopecia on posterior scalp with indurated erythema. Punch biopsy of the scalp lesion showed diffuse infiltrate of bcl-6(+), bcl-2(−) lymphocytic infiltrate consistent with cutaneous follicular lymphoma.
7/16/2014	Bone marrow biopsy showed 25% involvement of B-cell chronic lymphocytic leukemia (CLL) with normal cytogenetics. Bone marrow flow cytometry result was compared with the scalp biopsy result. The CLL B-cells from the bone marrows were immunophenotypically distinct from the cutaneous follicular lymphoma. CLL B-cells from the bone marrow showed aberrant expression of CD5 and CD43, whereas follicular lymphoma were negative for CD5 and CD43.
7/24/2014	Staging computed tomography (CT) chest/abdomen/pelvis were unremarkable.
8/17—9/12/2014	Radiotherapy to the scalp cutaneous follicular lymphoma to 2400 cGY.
6/26/2015	Had a near syncopal event due to deep vein thrombosis of left lower extremity and saddle embolus of bilateral pulmonary arteries.
3/2/2018	Development of new left frontal scalp lesions. Skin punch biopsy results in cutaneous involvement of mature B-cell CLL.
3/16/2018	Surveillance CT chest/abdomen/pelvis were unremarkable with stable pelvic, inguinal lymph nodes since 7/2014. No indication for treatment.
2/17/2021-3/8/2021	New development of encephalopathy. Admitted to the Moanalua Medical Center for workup for encephalopathy.
2/22/2021	Lumbar puncture performed due to new fever and encephalopathy. Flow cytometry of the cerebrospinal fluid revealed 70% of all cells were consistent with CLL lymphocytes.
2/26/2021	Intrathecal infusion with 12 mg methotrexate and 100 mg hydrocortisone.
2/26/2021	Repeat cerebrospinal-fluid flow cytometry again revealed 60% CLL lymphocytes.
3/5/2021	Obinutuzumab/venetoclax started with obinutuzumab 100 mg on day one of first chemotherapy treatment. But patient developed severe reaction to the obinutuzumab with fever, rigor, hypoxemia, and tachycardia. Treatment was aborted.
3/5/2021	Family meeting including durable power of attorney. Family decided not to pursue systemic therapy.
3/8/2021	Discharged to nearby care home.
3/13—3/19/2021	Readmitted for encephalopathy, fever, and generalized weakness. Empiric treatment with broad-spectrum antibiotics without improvement. Infectious workups remained negative, but patient transitioned to hospice at family request.

In the emergency department, the patient’s vital signs were normal and stable. He spoke slowly in 2- and 3-word sentences, mostly inappropriate and incoherent. He was alert and oriented only to himself. He appeared comfortable but had only minimal facial expressions. His bilateral, proximal lower extremities were weak with the motor grade 3/5. Upper extremity strength was normal. No neck stiffness, muscle rigidity, cogwheeling, tremor, apraxia, or micrographia were observed. The abdomen was soft and non-tender, without palpable splenomegaly. He had no cervical, submandibular, supraclavicular, axillary, or femoral lymphadenopathy.

Laboratory studies revealed white blood cell (WBC) counts of 51.3 × 103/µL with 83% lymphocytes, hemoglobin of 12.3 g/dL, and platelets of 176 × 103/µL. Leukocytosis had worsened from 2 months prior when WBC was 32.8 × 103/µL with 68% lymphocytes. Electrolytes, calcium, blood urea nitrogen, creatinine, liver function tests, lactate, glucose, and troponin levels were normal. Creatine kinase was mildly elevated at 250 U/L. Lactate dehydrogenase was 247 U/L, which was increased from 214 U/L 2 months prior. Beta-2 microglobulin was elevated to 3.88 mg/L (no prior lab for comparison). Urinalysis showed no abnormalities. Electrocardiogram showed sinus rhythm and normal rate without evidence of acute ischemia. Chest radiograph showed no acute cardiopulmonary abnormalities. The brain computed tomography (CT) showed no intracranial abnormality. The patient was admitted to the general medicine floor for his acute encephalopathy.

In collaboration with neurology and infectious disease, the hospitalist team initiated an extensive workup for acute encephalopathy. Magnetic resonance imaging (MRI) of the brain showed no acute or recent infarct, hemorrhage, or mass, though there was mild volume loss in the frontotemporal area with diffuse cerebral white matter changes consistent with chronic ischemia. Carotid duplex ultrasound revealed no stenosis. Electroencephalogram showed mild, diffuse slowing but no epileptiform discharges. Initial blood cultures grew coagulase-negative staphylococcus in one of two blood culture bottles. However, repeat blood cultures collected prior to any antibiotic treatment did not grow any organism.

Respiratory virus panels including COVID-19, influenza, and respiratory syncytial virus yielded negative results. Peripheral-blood viral polymerase chain reaction (PCR) studies for varicella-zoster virus, Epstein-Barr virus, and enterovirus also returned negative. Peripheral-blood HIV antigen, HIV 1/2 antibody, and syphilis IgG antibody were not detected. Tuberculosis screening with a sputum acid-fast bacillus stain and interferon-gamma assay returned negative. No growth resulted from sputum fungal culture. Thiamine, cobalamin, folate, thyroid-stimulating hormone, and ammonia levels were within normal limits. A 10-panel urine drug screen and paraneoplastic antibody panel were negative. There was no pathologically enlarged lymphadenopathy on the CT of chest, abdomen, and pelvis. The size of the patient’s spleen grew to 15.4 cm from 13.4 cm on the CT scan 3 years prior.

On the fourth day of hospitalization, the patient developed a fever of 102 °F. He underwent a fluoroscopy-guided lumbar puncture. The cerebrospinal fluid (CSF) was colorless with an elevated WBC of 26/mcL with 89% lymphocytes, 10% mononuclear cells, and 1% polymorphonuclear leukocytes. CSF cytology returned positive for malignant cells. Flow cytometry showed a 70% monoclonal CD45 bright B-cell population which co-expressed CD5, CD19, and CD23 with a kappa clonal excess. These cells were immunophenotypically similar to his CLL B-lymphocyte population from the 2014 bone marrow biopsy, except for the loss of CD20 and CD22. CD43 was not part of the 16 markers evaluated. CSF bacterial, fungal, and acid-fast bacillus cultures did not grow any organisms. Virus PCRs and cryptococcus antigen test were also negative. The neurology team concluded that the patient’s encephalopathy was primarily related to the CSF involvement of his CLL.

After discussion with the patient’s durable power of attorney, son, and daughter, a decision was made to treat with an intrathecal infusion of methotrexate 12 mg and hydrocortisone 100 mg. A mild improvement in his mental status was noted 2 days after treatment. He was able to recall the reason for hospitalization, location, and time. Based on the clinical improvement, the patient was initiated on systemic therapy with obinutuzumab and venetoclax, which is known to have a good CNS penetration.⁷ Unfortunately, his first dose of obinutuzumab caused severe allergic reactions involving hypotension, fever, rigor, and hypoxemia. The durable power of attorney decided not to pursue further systemic treatment.

While awaiting placement to a care facility, the patient’s mental status improved to his baseline level. On day 10 from the intrathecal treatment, the patient recognized his primary oncologist and continued a conversation from 2 months ago during his prior outpatient visit. His speech, cognition, and affect all returned to normal. The patient was discharged with a plan to follow up outpatient.

One week later the patient was admitted to the hospital for recurrent confusion, fever, and generalized weakness. Chest CT showed mild peribronchial thickening with mildly increased mediastinal and hilar lymphadenopathy. The patient was treated for possible pneumonia with empiric cefepime, vancomycin, and azithromycin without resolving his encephalopathy. The family decided to pursue hospice care during this hospitalization.

Discussion

We report a case of leptomeningeal involvement of CLL that presented as an acute encephalopathy. The patient’s CLL had been asymptomatic and indolent for over 6 years until the development of acute confusion. Interestingly, surveillance imaging and lab tests did not suggest other signs of significant disease progression or Richter’s transformation, consistent with a prior autopsy report suggesting that meningeal involvement may occur at any stages of the disease.⁶ This clinical case highlights that clinicians should consider CNS involvement of CLL as part of their differentials when evaluating patients with new neurologic symptoms.

CNS involvement of CLL is still a poorly understood phenomenon due to its scarcity. Previous literature suggests that the CNS involvement of CLL can present with a broad spectrum of nonspecific clinical manifestations ranging from asymptomatic to headaches, cranial nerve palsies, vision changes, hearing loss, altered mental status, ataxia, weakness, or paresthesia.^4,8 It is not fully understood how the CNS involvement could lead to the development of neurologic symptoms. Previously, it was postulated that the leptomeningeal cells can obstruct the CSF outlet, leading to increased intracranial pressure and encephalopathy.⁵ Unfortunately, the opening pressure during lumbar puncture was not measured in our case. Parenchymal irritation by CLL cells and subsequent inflammation can also cause encephalopathy, seizure, or ataxia.^9,10 The clumping of the leptomeningeal cells in the nerve root may cause bilateral lower-extremity weakness, as noted in our patient.⁵

Interestingly, this patient’s CLL extended to the leptomeningeal space when there were no other features of rapid disease progression or transformation into a more aggressive neoplasm. Currently there is no identified risk factor for CNS involvement of CLL. A retrospective literature review of 78 CNS diseases related to CLL revealed no apparent correlation with patient gender, age, presentation, duration of the disease, or Rai stage at the time of diagnosis.^11,12 It is noteworthy that our patient received radiation therapy for cutaneous follicular lymphoma in 2014. Radiation therapy can directly disrupt the integrity of the blood-brain barrier via increased inflammation,¹³ cell apoptosis,^13,14 and tissue necrosis via vascular endothelial damage.¹⁵ It is possible that the neoplastic cells in our patient’s peripheral blood may have gained access to CSF through the weakened blood–CSF barrier in the choroid plexus.¹⁶ Similarly, the CLL cells in the bone marrow of the skull base might have extended along the perforating vessels to the dura mater, then to subarachnoid space through the weakened endothelial wall of the vessel.

Our case demonstrated that imaging studies, including MRI and CT scans of the brain, are insensitive to screen for CNS involvement in CLL. Consistently, a previous comprehensive review study reported that CLL with CNS disease was detected in the CT or MRI scans of only 32 of 80 patients.¹¹ CSF cytology without flow cytometry also lacked sensitivity due to the paucity of the tumor cells in the CSF and the morphological similarity between reactive lymphocyte and CLL cells in other cases.^17–19 As a result, flow cytometry should be ordered as part of CSF analysis to accurately screen for the disease if one suspects CNS involvement. In our case, the slight elevation in CSF WBC count of 26/mcL, compared to a normal WBC of 0 to 5 mcL, was relevant to cause neurologic symptoms.

CNS involvement of CLL portends poor clinical prognosis.^20,21 A retrospective literature review reported the median overall survival of 9 to 10 months in CLL patients with CNS involvement, shorter than the median survival of 6 years in patients without CNS disease.⁵ Current guidelines do not have consensus treatment recommendations.²² Few case reports suggested favorable outcomes with systemic, intrathecal, or combined treatment approaches. Naydenov et al reported an improved median overall survival when CSF clearance was achieved via therapy (10 months vs 2 months).⁵ Further, even if patients did not achieve CSF clearance, more than 70% showed clinical improvement of their CNS symptoms with treatments.

Intrathecal treatment with cytarabine and/or fludarabine-based therapy with or without intrathecal methotrexate resulted in the rapid resolution of neurologic symptoms in leptomeningeal CLL.^16,23,24 Systemic ibrutinib- or rituximab-based treatment alone also improved neurologic symptoms and survival outcomes.⁵ In particular, ibrutinib monotherapy at a standard dose (420 mg/d) was highly effective on both treatment-naïve and refractory-progressive CLL with leptomeningeal diseases,²⁵ achieving a complete response in all 4 patients treated. Further, ibrutinib monotherapy led to the complete disappearance of metastatic brain masses in 2 CLL patients within 4 and 6 months, which is partly attributable to the drug’s excellent permeability to the blood-brain barrier.²⁶ Previously, intrathecal methotrexate and systemic treatment with venetoclax and rituximab also resulted in a rapid resolution of CNS symptoms and stable disease up to 24 weeks.²⁷

This case report has several limitations. Despite the presence of CLL in the CSF and the transient clinical response to the intrathecal methotrexate, we cannot rule out the possibility of other undiagnosed conditions contributing to the clinical presentations, such as Lewy body dementia and delirium. We also did not confirm the clearance of CLL cells in CSF after the treatment, although the patient’s mental status and neurologic symptoms showed improvement. A case series reported improved neurologic symptoms with systemic treatment of CLL despite the persistent identification of disease cells in the CSF.³ In addition, some CLL patients remain asymptomatic despite the involvement of CSF.¹¹ These reports may suggest that the CLL cells, in some cases, may simply be “bystanders” in CLL-related CNS disease. Lastly, because the patient declined further treatment, we could not assess the long-term impacts of CNS disease in CLL.

Conclusion

CLL patients with new-onset neurologic manifestations should be evaluated for the CNS involvement via brain imaging and CSF flow cytometry. Once CNS involvement with CLL disease has been diagnosed, it is recommended to promptly initiate treatment as this condition is associated with poor clinical outcomes. Treatments involving intrathecal methotrexate, cytarabine, and steroids may improve neurologic symptoms and survival outcomes.