Here we present a case of a right-handed 74-year-old man known for indolent non-Hodgkin’s lymphoma (NHL), treated with reduced doses of bendamustine-rituximab. He was initially referred to the outpatient clinic for an atypical tremor of the right upper extremity (UE), and the initial investigation with computed tomography (CT) of the brain revealed a left-sided ischemic thalamocapsular lesion of unknown age, compatible with the actual presentation. Three months later (and six months after his last chemotherapy treatment), the patient consulted the emergency department by himself due to progression of neurological symptoms, including new left and right UE weakness in a pyramidal distribution and a recent onset of dysarthria and dysphonia. A second CT scan of the head showed new, bilateral, and symmetrical subcortical hypodensities affecting the pre-central gyri. Non-contrast magnetic resonance imaging (MRI) showed subcortical white matter T2 hyperintensities involving the U-fibers without mass effect (Figure 1). An extensive workup, including a white cell count, a panel of autoantibodies, and a human immunodeficiency virus (HIV) serology, was unremarkable. The clinical and MRI presentation favored the diagnosis of progressive multifocal leukoencephalopathy (PML) following rituximab chemotherapy. Surprisingly, the first lumbar puncture (LP) was negative for John Cunningham polyomavirus (JCV), while the second one was positive. Unfortunately, the patient’s symptoms continued to progress, and he ultimately passed away while admitted to hospital.

Progressive multifocal leukoencephalopathy is a rare and often fatal demyelinating disease caused by JCV reactivation and occurs almost exclusively in immunosuppressed individuals. HIV-associated disease accounts for 80% of reported cases, while hematological malignancies account for approximately 10%, and the remaining 10% is comprised of patients receiving immunosuppressive treatments, most notably systemic lupus erythematosus [1]. Among those with hematological malignancies, several cases of PML have been associated with rituximab. According to a 2019 National Health Service (NHS) report, there have been an impressive 221 reported cases of rituximab associated PML in NHL-treated patients [2]. Furthermore, another recent study showed that 3 out of 47 patients with follicular lymphoma who were treated with bendamustine-rituximab (followed at the same healthcare center) went on to develop PML [3]. The mortality of PML in HIV-negative patients has been shown to be as high as 90% after rituximab therapy [4]. It is important to note that clinical presentation, radiologic findings, and cerebrospinal fluid (CSF) analyses can be highly variable, rendering the diagnosis of PML challenging. One study found that JCV was negative in almost 23% of drug-induced PML cases, and as much as 33% in cancer-related drugs [5]. That approximately a third of cancer-treatment related cases could not meet the criteria after a single LP is poignant when considering that LP positivity for JCV is a criterion for the diagnosis of definite or probable PML [6], especially knowing that potential treatments for the disease such as PD1 inhibitors (e.g., pembrolizumab) are currently being investigated in ongoing trials [7]. Neuroimaging is an important complementary modality to support the diagnosis, and was crucial in the present case to exclude other possibilities in the differential diagnosis while lending credence to the decision to pursue a second LP (thus avoiding an invasive brain biopsy).

Early recognition of neurological symptoms, appropriate neuroimaging, and a high index of clinical suspicion in patients treated with chemotherapy remain of paramount importance to confirm the diagnosis given the elevated mortality of PML and the potential for treatments in the near future.