Neurocognitive Features Distinguishing Primary Central Nervous System Lymphoma from Other Possible Causes of Rapidly Progressive Dementia

Infiltrating tumors are an under-recognized cause of rapidly progressive dementia (RPD), defined as a 1- to 2-year course from symptom onset to cognitive and functional debilitation (Geschwind, 2010). Many patients with RPD have a fast deterioration of cognition over weeks to months, with death within 2 years. Clinicians evaluating patients with RPD usually consider sporadic Creutzfeldt-Jakob disease (CJD), autoimmune encephalitides, paraneoplastic encephalitis, infectious conditions, and even neurodegenerative disorders before they consider neoplastic dementias. An important potentially treatable neoplastic dementia is primary central nervous system lymphoma (PCNSL); however, there is little information to guide clinicians on the frequency and characteristics of PCNSL presenting as an RPD. Identifying this lymphomatous dementia as soon as possible and distinguishing it from other RPDs is critical because lymphomatous dementia is treatable but untreated PCNSL is rapidly fatal. PCNSL is a type of non-Hodgkin lymphoma that affects only the central nervous system (CNS), without systemic involvement. PCNSL is uncommon, accounting for only 4% of newly diagnosed CNS tumors, with an incidence of 0.47 per 100,000 person-years (Villano et al, 2011). Brain magnetic resonance imaging (MRI) often shows a single contrast-enhancing lesion and/or restricted diffusion on diffusion weighted imaging (DWI), but the disease can instead be multifocal (Degnan and Levy, 2014b; Lai et al, 2002). The most common sites of involvement are the deep periventricular white matter and the corpus callosum, as well as the thalamus and basal ganglia (Eichler and Batchelor, 2006). Homogeneous contrast enhancement, the classic appearance, can help distinguish PCNSL from other conditions, such as glioblastoma (heterogeneous enhancement) (Omuro and DeAngelis, 2013), progressive multifocal leukoencephalopathy (non-enhancing) (Shah et al, 2010), and Creutzfeldt-Jakob disease (CJD) (FLAIR and DWI hyperintensities in the cortical gyri as well as the caudate, putamen, or thalamus) (Degnan and Levy, 2014a; Geschwind et al, 2008). Uncommonly, PCNSL is widespread, with or without contrast enhancement, and may show only nonspecific T2 hyperintense lesions, known as lymphomatosis cerebri (LC) (Bakshi et al, 1999; Vital and Sibon, 2007; Weaver et al, 2007). In patients with LC, diagnosis can be especially challenging, as illustrated by Figure 1. FIGURE 1 Our evaluation for primary central nervous system lymphoma in a 74-year-old right-handed man with 6 months of progressive personality change, confusion, and impaired gait. On a magnetic resonance imaging scan of his brain, axial FLAIR (Panels A–D) ... A finding of neoplastic lymphocytes in cerebrospinal fluid (CSF), by either cytomorphology or immunophenotyping, is sufficient for a diagnosis of PCNSL with meningeal dissemination (Kiewe et al, 2010); however, because these CSF studies are not very sensitive, multiple samples may be needed to confirm the diagnosis. If the CSF is diagnostic, then a brain biopsy can be avoided. In diagnostically challenging cases, patients may be treated empirically with steroids for presumed demyelinating or autoimmune conditions, but the steroids’ lympholytic effects will further delay definitive diagnosis by CSF or biopsy. Neuropsychiatric symptoms account for about 40% of the presenting symptoms in patients with PCNSL (Bataille et al, 2000), but the distinguishing neurocognitive features have not been further characterized, particularly in comparison to other RPDs. Physicians may not suspect PCNSL, particularly if the neuroimaging is nonspecific and does not show a typical contrast-enhancing lesion. We analyzed case reports of patients with PCNSL presenting with dementia so that we could define their cognitive impairment and neurologic features. Then we compared these characteristics to those of CJD and other causes of RPD.