Cerebral Localization of Chronic Lymphocytic Leukemia Simulating Progressive Multifocal Leukoencephalopathy: The Lessons from a Case

Background: Central neurological involvement is the most frequent extra hematological manifestation of chronic lymphocytic leukemia; it is multifactorial and rarely due to a cerebral localization of the disease. We report a case of cerebral localization of chronic lymphoid leukemia whose clinical and radiological aspects were very suggestive of progressive multifocal leukoencephalopathy. Case Presentation: A 65-year-old patient who was HIV-negative (human immu-nodeficiency virus), had consulted for bilateral axillary, cervical and inguinal lymphadenopathy associated with major asthenia and hyper lymphocytosis (lymphocyte count was 11 giga/l). Chronic lymphocyticleukemia with TP53 mutation was diagnosed and treatment with Ibrutinib 420 mg/day was initiat-ed. After 2 months of treatment, the evolution was marked by the onset of neurological multifocal leukoencephalopathy in this context should lead to the histological study of brain lesions.


Background
Chronic Lymphocytic Leukemia (CLL) is the most common malignant hemopathy after the age of 60. It is characterized by a monoclonal proliferation of mature B lymphocytes infiltrating the bone marrow and the lymphoid organs, responsible for hyper lymphocytosis in the blood with or without tumor syndrome (lymphadenopathy, hepatosplenomegaly) [1]. Outside of these classical sanctuaries, extra-hematological tumor infiltration is a rare situation.
Although central neurological involvement is one of the most common extrahematological manifestations in CLL, it is rarely an expression of a cerebral localization of the disease, as a variety of etiologies may be responsible for central neurological manifestation in CLL [2].
Progressive multifocal leukoencephalopathy (PML) is a central nervous system infection caused by the John Cunningham Virus (JCV) and promoted by immunosuppression. A classic complication of HIV, PML is also found in lymphoproliferative syndromes where it can be responsible for non-specific neurological manifestations with a radiological expression that is most often quite evocative [3].
Because of the highly variable therapeutic implications depending on the etiology, certainty diagnosis of neurological manifestations in CLL is of highly critical importance.
We report a case of cerebral localization of CLL whose clinical-radiological and evolutionary aspects were very suggestive of progressive multifocal leukoencephalopathy.

Case Presentation
A 65-year-old diabetic patient, HIV negative, in good general condition (WHO 0), consulted in January 2018 for permanent, bilateral and symmetrical cervical, axillary and inguinal supra-centimetric adenopathies which had appeared 1 month earlier and were evolving in a context generalized asthenia without weight loss.
On clinical examination, the lymphadenopathies were isolated without hepatosplenomegaly. Blood cell count showed isolated hyper lymphocytosis at 11 giga/l.
The blood smear identified small mature lymphocytes with Gumprecht shadows and lymphocyte immunophenotyping gave a Matutes score of 4/5 (CD5+/ CD23+/FMC7-/CHL weak/CD79b+). The diagnosis of Chronic Lymphocytic Ibrutinib was started at a dose of 420 mg/day. Two months later the patient was hospitalized for seizures with sudden tetraparesis. Spinal magnetic resonance imaging (MRI) was normal, but subcortical white matter abnormalities were seen on brain MRI on T1, Fluid Attenuation Inversion Recovery (FLAIR) and DIFFUSION sequences ( Figure 1); the hepatic, renal and metabolic workup was free of abnormalities. The topography and appearance of the brain lesions, particularly the lack of contrast enhancement, associated with the clinical and  Figure 2). Again, both the CSF analysis and the PCR of JCV in the CSF were negative. Hematologically, the lymphocyte count was normal, but lymph node activity was noted. The worsening of the clinical picture, the extension and the contrast enhancement of the cerebral lesions following the discontinuation of ibrutinib, led to the hypothesis of an immune reconstitution inflammatory syndrome (IRIS). Systemic corticosteroid therapy was started immediately at a dose of 1 mg/kg/day but was discontinued after 4 weeks due to the glycemic imbalance

Discussion
Central neurologic involvement is one of the most common extra-hematologic manifestations encountered in CLL. It is multifactorial; it can be the direct expression of a cerebral localization of tumor lymphocytes or secondary to various infectious, inflammatory, vascular, neoplastic, metabolic or other etiologies [2].
In a study published in 2016, concerning 172 patients followed for CLL who were investigated for central neurological symptoms, approximately 80% of the cases were due to an etiology other than CLL [2]. Autopsy series revealed that the central nervous system was completely asymptomatically infiltrated in a  the CSF or brain tissue. It should be noted, however, that CSF negativity does not rule out the diagnosis of PML and a histological study is essential to formally conclude [11].
Its management is not codified; no treatment has been proven for this indication, as restoration of immunity remains the only condition capable of controlling viral replication [6]. In addition to the initial clinical and radiological presentation, the occurrence of an immune reconstitution inflammatory syndrome (IRIS), which was sug- The diagnosis of PML was based on highly compatible clinical and radiological data, but we lacked virological or histological evidence of JCV imputability. The lack of diagnostic evidence on the one hand and the rapid progression of adenopathies on the other made each of the hypotheses plausible: tumor infiltration by CLL, PML or other. It is in this context that the stereotaxic biopsy of an occipital lesion was performed; Histology revealed tumor infiltration of the white matter and the cortex by cells of known CLL with high expression of CD20, CD5, CD23 and Bcl2. However, it must be stressed that this discovery does not resolve one question: is it an extension of the disease complicating its evolution or rather an initially asymptomatic localization revealed by the therapeutic effect of Ibrutinib, when we know the capacity of this drug to cross the blood-brain barrier [13]? On the other hand, this discovery, in conjunction with our patient's CSF analysis, highlights the low sensitivity of CSF in the diagnosis of a cerebral localization of CLL. A previously cited study had shown the discrepancy between CSF cytology and cerebral histology: among 131 patients with negative cytology, 11% had a positive histology; finally among 31 patients with positive cytology, 58% had an alternative diagnosis to histology [2]. In the latter case, the presence of tumor lymphocytes in the CSF could be secondary to contamination with peripheral blood at the time of collection. As a result, CSF analysis is of low positive and negative predictive value for the diagnosis of a cerebral localization of the CLL.
Cases of CNS infiltration in CLL are described in the literature. The analysis of these cases allows us to observe a mean age of 64.5 years with a slight predominance of the male sex, a very heterogeneous clinical symptomatology with a predominance of cranial neuropathy followed by non-specific manifestations such as headache, cognitive disorders, coordination disorders or convulsions.
The time from diagnosis of CLL to the onset of neurologic complications varied widely from patient to patient, ranging from a few weeks to several years; however, neurologic complications are rarely a mode of revelation of CLL [14] [15] [16]. The non-specific nature of the symptoms justifies the diagnostic delay with an average delay of 5 months. The leptomeningeal localization was the most represented, confirmed most often by the cytological study and CSF flow cytometry [14] [15]. No correlation has been established between the stage of CLL and the occurrence of neurological complications; indeed neurological localization has been diagnosed in patients in the early stage of the disease or in completely asymptomatic patients with no systemic CLL activity [17]. To date, no study has been able to identify a risk factor for neurological progression of CLL, although soluble CD27 and the study of CD49d/CD82 expression have been proposed as biomarkers of risk [16] [18]. Overall, a favourable therapeutic response was obtained [14] [15].
In addition to the common characteristics it shares with the cases described in the literature, our case has the following particularities: • The occurrence of neurological complications during the treatment phase • A relatively infrequent mode of disclosure compared to previously published cases.
• The hematological response under targeted therapy (normal blood count, disappearance of lymphadenopathy) coupled with the absence of tumor cells in the CSF made a neurological localization of the disease very unlikely. • Ibrutinib, the targeted therapy used, has pharmacological properties that allow it to cross the blood-brain barrier and therefore exert its anti-tumor effect [13]; this, in view of the hematological response obtained, would make a neurological localization of CLL highly unlikely.
• The therapeutic implications are radically opposed in this context: while the diagnosis of CLL with neurological invasion requires, local or systemic chemotherapy, PML contraindicates all chemotherapy and requires immune restoration as the only therapeutic weapon recognized to date. In our case, the PML hypothesis would have been very detrimental for our patient who, let us recall, had CLL with a 17p deletion.
Furthermore, this case raises some questions: how can we explain the neurological impairment in CLL-patients in hematological response to ibrutinib, which is also an effective molecule in the CNS? How to explain the clinical picture and the morphological aspects observed on MRI?
Given the high frequency of asymptomatic CLL cerebral localizations, we believe that in our case the central nervous system was probably already silently infiltrated before the start of ibrutinib treatment. The efficacy of ibrutinib on peripheral tumor mass makes the opposite hypothesis unlikely. This invasive capacity of CLL cells is thought to be due to the dysregulation of certain integrins involved in cell migration [16].
At first glance, the morphological aspects observed on MRI would seem to correspond to a local inflammatory phenomenon as shown by MRI contrast enhancement reflecting the rupture of the blood-meningeal barrier. Should this be seen as a consequence of the action of ibrutinib? This seems implausible to us, since from a physiological point of view, the apoptosis resulting from the anti-tumour effect of ibrutinib does not induce an inflammatory reaction.
The treatment of CLL brain localizations is not codified; the few available data are empirical and relate to clinical cases or series of patients. The therapeutic strategies used vary from case to case and may or may not combine systemic chemotherapy, intrathecal chemotherapy or radiotherapy [19]. Their efficacy is variable, however there is no data to date to confirm the superiority of one strategy over another; the efficacy of Ibrutinib in this indication is found in some publications [19] [20].

Conclusions
We infer from this case that the appearance of neurological symptoms or signs in a context of CLL should systematically evoke and search for a neurological localization of CLL regardless of the stage of the disease, its duration of progression, lymphocytes count, clinical presentation, radiological appearance or treatment received. Clinical examination, CSF studies, brain imaging and histology are key means of making the diagnosis.
In the absence of virological evidence in the CSF, any clinical and radiological suspicion of PML in the context of chronic lymphocytic leukemia should lead to the histological study of brain lesions in order to confirm the diagnosis of PML on the one hand and to rule out the possibility of a tumor localization on the other. This distinction is of critical importance because, unlike PML for which there is no effective therapy to date, there are treatments that have been shown to be effective in the management of CLL cerebral localizations.