Case Report: Neuropsychological Profile of a Patient With Intravascular Large B-Cell Lymphoma Following Infection and Vaccination

Abstract

Objective

Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive lymphoma that can have heterogeneous central nervous system involvement and cerebrovascular complications. The development of IVLBCL can be fatal. Although relatively rare, the development of specific clinical syndromes, such as IVLBCL, has been implicated following infection and vaccination. To our knowledge, this is the first comprehensive neuropsychological evaluation assessing neurocognitive and psychological status after IVLBCL diagnosis.

Methods

The current study presents a right-handed mid-60-year-old male with a university-level education, who was diagnosed with IVLBCL following viral vector SARS-CoV-2 vaccination. He presented with a complex medical history including antiphospholipid syndrome, deafness (prior to cochlear implant), and cardiovascular complications secondary to lymphoma. Brain magnetic resonance imaging showed parietal, frontal, and cerebellar infarcts; encephalomalacia; and periventricular deep chronic ischemic changes. A comprehensive neuropsychological evaluation was completed.

Results

In consideration of an individual with an estimated above-average baseline, his neurocognitive profile demonstrated impairments across multiple domains that were more lateralized to the non-dominant hemisphere including visual attention, visual processing speed, visuo-construction, memory, motor dexterity, and right-sided ataxia (e.g., dysmetria). Clinical elevations for depression, hopelessness, and anxiety were also found.

Conclusions

The current study highlights a novel cognitive profile of IVLBCL and comorbidities with the patient having more predominant nondominant hemispheric-related deficits. There was evidence of disruption to visual processing networks, largely consistent with neuroimaging lesions. The current case also describes the unique experience of an individual coping with a rare condition, especially when resulting in functional decline (e.g., loss of audition). Implications are discussed.

INTRODUCTION

Intravascular large B-cell lymphoma (IVLBCL) is an aggressive lymphoma that is characterized by the abnormal growth of large cells within the lumen of all sized blood vessels and presents without obvious extravascular tumor mass or circulating lymphoma cells (Ponzoni et al., 2018; Roy et al., 2021). IVLBCL involves the intravascular proliferation of neoplastic lymphoid cells, which leads to the occlusion of capillaries, small arteries, and small veins, causing ensuing systemic dysfunction (Breakell et al., 2022). IVLBCL is an extremely rare disorder with an annual incidence of fewer than 0.5 cases per 1,000,000 (Luo et al., 2017) with a typical onset between 60 and 70 years old (Ferreri et al., 2004; Murase et al., 2007; Shimada et al., 2008). Given its low prevalence, much of the current clinical information about IVLBCL comes from case studies (Roy et al., 2021). Although knowledge about the cause of IVLBCL is limited, there have been some links to genetic etiological contributions (Shimada et al., 2021) and other comorbidities (i.e., antiphospholipid syndrome) due to both vaccination and infectious processes (Al-Beltagi et al., 2022; Mendoza-Pinto et al., 2018; Meroni & Riboldi, 2004; Talotta & Robertson, 2021; Visentini et al., 2022).

IVLBCL can affect any bodily system but commonly involves the central nervous system (Fonkem et al., 2014; Fonkem et al., 2016), with one large North American retrospective study showing that 75.9% of the sample had neurological involvement (Brunet et al., 2017). Neurologically, IVLBCL can lead to various symptoms including headache, confusion, cognitive decline, seizure, paralysis, stroke, and motor weakness (Fonkem et al., 2016). It has proven difficult to detect a pattern of deficits that specifically characterizes IVLBCL (Han et al., 2022) due to its heterogeneous presentation. Given the variability, there are many patients who have neurological symptoms without correlating imaging (Ferreri et al., 2004), which can prolong the diagnostic process. Though a specific pattern of symptoms is not entirely established, the overall irregularity and variability of its presentation may be an indicator of IVLBCL itself. For example, patients may present with a broad range of neurological and systemic symptoms that can mimic other conditions such as stroke, multiple sclerosis, vasculitis, or sepsis (Anbil et al., 2021; Kloc et al., 2016; Nguyen et al., 2021; Ponzoni et al., 2018). Given that its presentation can lead to a broad differential diagnosis, it could be argued that unexplained systemic or neurological symptoms may raise suspicion of rare conditions like IVLBCL that necessitate a more comprehensive medical workup. It is clear that IVLBCL has notable cognitive correlates (Fonkem et al., 2016) and, in some cases, can resemble a progressive dementia (Gonçalves et al., 2024; Wu et al., 2021). Although cognitive changes are independently associated with IVLBCL, deficits could be further compounded by the toxic effects of cancer treatments, which may also contribute to a patient’s clinical presentation (Lange et al., 2016; Országhová et al., 2021). The diagnostically elusive nature of IVLBCL may subject itself to delayed treatment, which is often associated with increased illness severity and mortality risk (Hanna et al., 2020).

The psychological effects secondary to IVLBCL are rarely discussed, largely due to its rarity. Research looking at the course of anxiety and depression in patients with non-specific lymphoma and diffuse large B-cell lymphoma found that depression, anxiety, and other behavioral changes occurred at higher rates compared to the normative population (Fischer et al., 2016; Oerlemans et al., 2014). Given the complexity, as well as numerous life-altering circumstances, patients diagnosed with IVLBCL may experience significant distress, common to many rare conditions (Uhlenbusch et al., 2019), which could be particularly illuminated for individuals with complex illnesses that occurred during the SARS-CoV-2 pandemic (Sánchez-García et al., 2021). Since the variance in clinical presentation is wide, most patients are not immediately diagnosed with IVLBCL and are admitted and investigated multiple times before receiving a formal diagnosis (Luo et al., 2017; Yunce et al., 2018), potentially resulting in pronounced psychological consequences (von der Lippe et al., 2017). Loss of independence and occupational limitations often affect a patient’s self-esteem, sense of control, and overall psychological well-being (Magyari et al., 2017), which can occur with rare conditions.

The current case study analyzes the neuropsychological profile of a patient with recurrent stroke and neurological manifestations associated with IVLBCL, which occurred after SARS-CoV-2 infection and receiving an adenovirus vector vaccine. There is limited information regarding the neuropsychological profile of individuals with IVLBCL with comorbid antiphospholipid syndrome and even more so following SARS-CoV-2 infection and subsequent vaccination. For individuals with IVLBCL, a detailed neuropsychological profile in the broader context of the patient experience may provide meaningful insights into this patient population, particularly as it relates to understanding functional status and related treatment implications. The information obtained from the data may further characterize the cognitive and emotional experience of a patient diagnosed with this rare medical condition.

METHODS

Informed consent was provided for publication of the following case. The study was submitted to the local Research Ethics Board and was determined to be exempt.

Medical Course and Diagnostic Process

The patient was a right-handed English-speaking biological male in his mid-60s with a college education. His occupation required sophisticated verbal communication skills. Prior to the current medical course, his medical history was notable for hepatitis C. Following his first SARS-CoV-2 infection within the first year of the pandemic (noted to be moderate in severity with no hospitalization or additional treatment) and a viral vector SARS-CoV-2 vaccine 3 months later, he experienced a 2-month period of intermittent word-finding difficulty, difficulty with reading and texting, dysphagia, headaches, and gait imbalance. On presentation to the emergency department (ED) around 2 months after his vaccination, his neurological exam was positive for confusion, difficulty with concentration, disturbances in coordination, dizziness, speech disturbance, visual change, and headaches. He was admitted, completed a medical workup, and underwent neuroimaging that demonstrated scattered foci of acute/subacute infarcts in the biparietal and bifrontal watershed regions. He was found to have a patent foramen ovale (PFO), underwent PFO closure, and was later discharged. Around a month later, he was readmitted to the ED following a 5-day course of bilateral tinnitus, hearing impairment (reported blood coming from his left ear), and imbalance (“vertigo”) with brain magnetic resonance imaging (MRI) showing further evolution of the same infarcts observed on previous admission, as well as additional mild periventricular and subcortical white matter signal abnormalities.

Shortly after being discharged, the patient visited his primary care physician after further bilateral hearing loss. A follow-up brain MRI showed a new small infarct in the right posterior cerebellum. Brain magnetic resonance angiography (MRA) was unremarkable. The patient sought consultation with surgical otolaryngology that found no change or improvement in hearing despite a high dose of steroids. Audiologic testing revealed severe-to-profound sensorineural hearing loss in the right ear and severe sensorineural hearing loss in the left ear. Later, he was found to have a positive result for beta-2 glycoprotein-1, which was eventually confirmed to be antiphospholipid syndrome (APS). He was again hospitalized for evolving symptoms and underwent evaluation for systemic vasculitis and a hypercoagulable disorder, which was negative. No new acute or subacute infarcts were observed upon further studies, but vessel wall MRA found multifocal vascular wall thickening and enhancement.

He was admitted to the hospital 2 months later for new subacute infarcts in the right cerebellum and foci of restricted diffusion in the centrum semiovale bilaterally. Repeat labs were positive for immunoglobulin M (IgM) anti-cardiolipin, lupus anticoagulant (LAC), and IgM anti-beta2 glycoprotein, further confirming APS. He had a skin biopsy that showed a Ki-67 of >90%, which is a measure of tumor cell proliferation (Sun & Kaufman, 2018; the higher the percentage, the more aggressive the disease), and was ultimately diagnosed with IVLBCL. Positron emission tomography (PET) demonstrated physiologic fluorodeoxyglucose uptake in the visualized portions of the brain salivary gland tissues, myocardium, the abdominal solid organs, gastrointestinal tract, both kidneys, ureters, and the urinary bladder. Follow-up brain MRI further characterized interval evolution of chronic infarcts within the bilateral deep white matter cerebral hemispheres, right middle cerebellar peduncle, and inferior cerebellar hemispheres. The patient completed R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate) and was later put on Imbruvica for B-cell depletion.

The patient has been followed by outpatient vascular neurology to monitor IVLBCL with no new symptoms. His most recent neuroimaging, which was approximately 1 year and 2 months apart from initial imaging, showed no further cerebrovascular events but displayed the notable changes since medical onset (see Figs 1 and 2). Over the course of the diagnostic process, he developed atrial fibrillation, supraventricular tachycardia, and complete bilateral hearing loss for which he later underwent unilateral cochlear implantation. He was referred for neuropsychological evaluation by vascular neurology to characterize his neuropsychological deficits. An intake interview was completed with the patient and his wife. A comprehensive testing battery was chosen. Effort measures were embedded throughout testing. The evaluation was completed across two sessions.

RESULTS

Clinical Interview and Corroborative Report

Subjective cognitive and physical symptoms

Soon after receiving a viral vector SARS-CoV-2 vaccine, the patient reported several residual cognitive changes associated with the onset of medical course. On interview, he reported heterogeneous deficits in the areas of visual tracking/scanning, proprioception, visual perception, processing speed, set-shifting, word finding, comprehension, and short-term memory. Subtle declines in writing fluency, planning, organization, and spelling were also noted. All symptoms were corroborated by the patient’s wife. Total bilateral hearing loss was developed over the course of the diagnostic process, which was compensated for by using a transcriber. He underwent unilateral cochlear implantation that was turned on and underwent initial tuning between testing sessions one and two, which occurred 9 days apart. Vision was noted to be adequate with bifocals. Neurodevelopmental history was unremarkable.

Motor/Non-motor symptoms

Analysis of potential motor and nonmotor symptoms found subjective complaints of reduced motor planning, ataxia, bradykinesia, problems with balance and coordination, mild dysphagia, urinary urgency, and orthostatic lightheadedness. The patient lost his sense of smell and taste when he contracted SARS-CoV-2, but olfaction and gustatory function returned shortly after recovery from infection. Ambulation was independent without assistive devices. No other motor or nonmotor symptoms were noted.

Sleep, pain, and psychological symptoms

The patient indicated that he did not have any sleep disturbance, obtaining around 7–8 hr of sleep per night, and feeling “relatively well rested” upon awakening. History of sleep apnea or other sleep disorder was denied. The patient and collateral report indicated that he experienced fatigue throughout the day resulting in a routine naps for 2–3 hr. Neuropathy in his legs and feet was noted, but he denied significant acute or chronic pain. Regarding subjective psychological status, the patient’s mood worsened following the onset of physical and cognitive symptoms. Sadness/depression was acknowledged to fluctuate from mild to severe with no history of past or present suicidal ideation, plan, or intent. His appetite was also reduced. Both the patient and his wife commented on a long history of anxiety that further exacerbated after medical onset. No current substance use was noted. However, he indicated prior frequent substance use that started in adolescence and ended in his late 20s, which consisted of elevated alcohol, amphetamine, cocaine, heroin, marijuana, and tobacco consumption.

Functional status

A full review of the patient’s basic activities of daily living (ADLs) and instrumental activities of daily living (IADLs) from both the patient’s and wife’s perspective was gathered through the diagnostic clinical interview and the standard intake packet given to patients before the appointment. In the clinical interview, the patient and his wife reported retained independence for bathing, dressing, grooming, toileting, continence, eating, transferring, and medication management. A decline from premorbid functional capability was noted on tasks of managing finances, completing household activities, cooking, and using technology (primarily associated with profound hearing loss and using the telephone). Dependence was noted for shopping and driving. On the intake form, ADLs and IADLs were characterized by “no difficulty,” “minimal assistance,” “moderate assistance,” and “unable to perform.” Items marked as no difficulty included the following: Bathing yourself, maintaining self-care, toileting/bowel/bladder, dressing/clothing yourself, and feeding yourself. Responses answered as needing minimal assistance included preparing meals/cooking, doing the laundry/cleaning clothes, cleaning the house/home, managing finances/bills, and medication management. No items were endorsed under the moderate assistance category. Dependence was noted for the following items: shopping for groceries, using the telephone, and driving. Loss of some independence across IADLs was mostly attributed to physical changes and hearing loss with a minor contribution from cognitive decline. The patient later underwent cochlear implantation, which improved his functional ability for using technology and shopping for groceries.

Patient Presentation on Evaluation

The patient was casually dressed with good hygiene. He ambulated independently without aid but presented with a slightly unstable gait, notable for being cautious and looking down when walking. There was no evidence of tremors, involuntary movements, facial asymmetry, or nystagmus. On a finger-to-nose task, he demonstrated right-sided ataxia and hypermetria, whereas his left side was unremarkable. Upper extremity motor speed and dexterity were poor bilaterally. Vision was aided by glasses and was adequate. Eye contact was appropriate. During the clinical interview and first day of testing, the patient evidenced complete hearing loss in both ears and needed an electronic transcriber to comprehend questions, directions, and to complete tasks. In between Sessions 1 and 2, his unilateral cochlear implant was turned on and underwent initial tuning. An informal rhythm test was given, and he obtained 100% accuracy. In testing Session 2, auditory measures were completed due to increased hearing capability. A transcriber was utilized at times to aid comprehension if it did not confound the assessment measure.

He was able to communicate effectively, and his speech was intelligible with normal rate and prosody. Speech volume was elevated at times due to hearing deficiencies. Expressive and receptive language was relatively unremarkable. The patient was fully oriented. On observation alone, he demonstrated more frustration and overt difficulty with visually based measures. Processing speed was also slowed with slightly delayed response times. Insight and judgment were deemed fair to good. Emotionally, his mood was initially depressed, but this improved throughout the evaluation due to an easily established and maintained rapport. Affect was consistent with mood and context. No evidence of hallucinations or delusions was identified.

Comprehensive Test Battery

Cognitive and psychological measures

The patient was given a comprehensive neuropsychological assessment to elucidate cognitive strengths and weaknesses. Testing was completed across 2 days. Across both days of the evaluation, tests were given in core cognitive domains. Several informant measures were also given to further characterize observed cognitive, emotional, behavioral, and functional changes. The first session focused on tests that could be given visually or explained using his transcriber. Assessment measures administered on Day 1 included the:

• Abbreviated Parietal Lobe Battery

• Apathy Scale

• Beck Anxiety Inventory (BAI)

• Beck Depression Inventory, Second Edition (BDI-2)

• Beck Hopelessness Scale (BHS)

• Brief Visuospatial Memory Test, Revised (BVMT-R)

• Conners Continuous Performance Test–3 (CPT-3)

• Finger-to-nose/(optic) ataxia exam

• Functional Activities Questionnaire (FAQ)

• Lafayette Grooved Pegboard Test

• Neuropsychiatric Inventory Questionnaire (NPI-Q)

• Neuropsychological Assessment Battery (NAB): Visual Discrimination

• Oculomotor Apraxia Screen

• Orientation Questions

• Pittsburgh Sleep Quality Index (PSQI)

• Rey Complex Figure and Recognition Test (RCFT)

• Right–Left Orientation

• Short Form of the Informant Questionnaire on Cognitive Decline in the Elderly (Short IQCODE)

• Simultanagnosia Test

• Test of Premorbid Functioning (TOPF)

• Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV): Block Design, Coding, Matrix Reasoning, and Symbol Search

Prior to the first testing session, it was not known that he was going to complete a post-cochlear implant tuning. Given this information, the patient was asked to come back for a second session, which occurred 9 days later. When he returned to the clinic, he was able to adequately process auditory information and hold conversation, mostly without his transcriber. Thus, the second session included measures mediated by auditory processing. Assessment measures administered on Day 2 included the:

• Boston Diagnostic Aphasia Examination (BDAE): Complex Ideational Material

• Behavior Rating Inventory of Executive Function, Adult (BRIEF-A)

• California Verbal Learning Test, Third Edition (CVLT-3)

• Controlled Oral Word Association Test (COWAT): FAS and Animal Naming

• Delis–Kaplan Executive Function System (D-KEFS): Color-Word Interference

• Frontal Systems Behavior Scale (FrSBe)

• Grooved Pegboard Test

• Hooper Visual Organization Test (HVOT)

• Neuropsychological Assessment Battery (NAB): Daily Living Memory, Naming, Reading Comprehension, and Writing

• Peabody Picture Vocabulary Test, Fourth Edition (PPVT-4)

• Subjective Auditory Rhythm Test

• Trail Making Test A & B

• Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV): Digit Span, Similarities, and Vocabulary

• Wechsler Memory Scale, Fourth Edition (WMS-IV): Logical Memory

• Wide Range Assessment of Memory and Learning, Third Edition (WRAML-3): Sentence Memory

Effort measures and observations

The patient appeared to accomplish all tasks with good motivation, frustration tolerance, and persistence. He experienced occasional fatigue but was provided with periodic breaks during testing to maintain motivation and effort. Several embedded performance validity indicators were included and evenly distributed throughout the testing battery. The findings of testing were valid, and an accurate depiction of his current cognitive status was obtained.

Normative Descriptors

Due to the patient’s high premorbid level and cognitive reserve, the Heaton norms (Heaton et al., 2004) were used as the preferred descriptors to characterize the patient’s cognitive strengths and weaknesses. A breakdown of these descriptors can be found in Table 1.

Cognitive and Psychological Testing Results

A detailed view of individual test results can be found in Table 2. His baseline functioning can be classified as within the above-average range based on his performance on the TOPF and other background demographic variables. This classification was used as a point of functional status comparison for other performance metrics. In comparison to the patient’s baseline, his global cognitive functioning as measured by his Full-Scale Intelligence Quotient revealed a mild decrement, with a meaningful discrepancy between more preserved verbal skills compared to his weaker nonverbal skills. He demonstrated impairment on measures of visual sustained and selective attention, visual processing speed, visual scanning, and visuo-construction. Thus, many tests placing increased demands on visual processing revealed decrements from premorbid expectations. His performance on tasks assessing executive functions was intact with the exclusion of visual set-shifting; however, his reduced performance on visual set-shifting was likely affected by reduced visual attention, processing speed, and scanning in the absence of making any errors. Most language performances were largely within baseline expectations even when mediated by auditory processing. The only language performance that was in the impaired range was sentence repetition. Working memory performances showed some variability when comparing performances of digit manipulation to tasks where he was presented with large amounts of information at one time, particularly recalling items on the first trial of memory tests. Sentence repetition may also fall into this category, as it gets gradually longer and more complex as the items progress; however, this discrepancy could also be explained by hearing inefficiency (i.e., auditory processing affected by modest adjustment to cochlear implant) or normal variability. Visuo-perceptual skills were generally within normative expectations with the exception of circumscribed difficulties on tasks mediated by visuoconstruction (simple and complex). Additionally, his performance on tasks known to correlate with left parietal lobe functions was within normal limits, excluding a slight reduction in external right–left orientation. His memory profile was variable, but there were some deficiencies when learning new verbal and visual information. Visual processing speed and attention difficulties affected visual memory performances, but there was also evidence of vulnerabilities in verbal memory, which can be accounted for by challenges in self-organizing verbally encoded memories. Motorically, motor speed and dexterity were impaired bilaterally, and cerebellar signs were positive for right upper extremity ataxia and hypermetria. Regarding his psychological status, self-report forms revealed mild depression, moderate hopelessness, and severe anxiety. Poor sleep quality was endorsed on a formal self-report measure, but it should be noted that there was a discrepancy between his responses in the clinical interview, where he reported no significant sleep disturbance.

Informant-report results

Forms were filled out by the patient’s partner. There was some variability in the collateral data. Specifically, elevations in apathy and executive dysfunction were noted prior to and following illness onset within one questionnaire, although another form did not identify any significant executive dysfunction. Mood problems were identified as mild depression/dysphoria, apathy/indifference, irritability/lability, and nighttime behaviors. Functional decline was noted in shopping, daily business affairs, and traveling independently, as well as a slight decline in everyday functioning due to memory problems.

DISCUSSION

Case Conclusions

Overall, the patient’s neuropsychological profile demonstrated weaknesses from premorbid levels with the most notable deficits involving visual attention, visual processing speed, and visuo-construction (i.e., constructing simple and complex figures). Visual processing speed and attention deficiencies had a negative impact on other cognitive functions including memory and set-shifting, especially in the context of no sequencing or set-loss errors. Both verbal and visual memory were vulnerable to frontal subcortical dysfunction, but visual memory performances were particularly susceptible given the lateralization of deficits to the non-dominant hemisphere. Regarding verbal memory, he had trouble self-organizing verbally encoded memories for later recall, which was demonstrated across measures involving an unstructured wordlist and daily living prompts (e.g., asked to remember medication instructions, a name, an address, and a phone number). On the contrary, recall of contextual information (i.e., story recall) was robust and similar to other domains. Sentence repetition was the only language test that was below expectation, but this could be attributable to imperfect cochlear implant tuning and/or normal variability, although it is a distinct possibility that there was some reduced working memory performance when presented with a large amount of information at one time. Informal assessment also found cerebellar ataxia characterized as hypermetria on a finger to nose test and unstable gait. Bilateral motor speed and dexterity were lower than anticipated and could have resulted from cerebral and cerebellar insults.

The characterization of his cognitive deficits were relatively consistent with IVLBCL-associated lesions and encephalomalacia from cerebrovascular events that were demonstrated throughout the cerebral hemispheres and right cerebellum on neuroimaging, which could have been further compounded by APS. Psychologically, the patient presented with significantly elevated depression, hopelessness, and anxiety that was primarily associated with adjustment to his medical condition including a long diagnostic and treatment process, frequent medical visits, and complications related to IVLBCL. Informant measures further corroborated significant changes in mood including depression, apathy, and irritability, as well as a slight functional decline. While factors extraneous to organic brain pathology could account for some variability of functional capability in day-to-day functions, the neuropsychological test data confirm dysfunction secondary to neurologic manifestations.

Several recommendations were made during the feedback portion of the evaluation taking into account his clinical presentation. Many of these recommendations were focused on the patient engaging in follow-up medical care, evidence-based brain training/cognitive rehabilitation programs, outpatient psychotherapy, pharmacological intervention, and daily habits to optimize vascular health. Given the quality of his deficits, it was also suggested that the patient continues to receive some support for IADLs given his recent cochlear implant tuning, as well as to not return to driving without undergoing a formal driving evaluation. Several compensatory strategies were reviewed including repetition of information, external memory aids, and breaking down tasks into more manageable pieces. Presenting information in a verbal modality was also recommended and was directly informed by the success of cochlear implantation and tuning in combination with his cognitive performance showing robust verbal skills. He was largely receptive to feedback, expressed motivation to engage in the provided recommendations, and was thankful for the evaluation.

Case in the Context of the Literature

In the current case study, given that the patient demonstrated modest impairment in multiple domains of cognitive function with reductions in ADLs and IADLs that were mostly associated with hearing loss and other physical changes, he was diagnosed with mild neurocognitive disorder. This was accompanied by acute adjustment difficulties with depression and anxiety that were clinically impairing. Neurological correlates and cognitive decline have been commonly associated with IVLBCL (Tahsili-Fahadan et al., 2016; Wu et al., 2021); however, due to its rarity (Luo et al., 2017), most studies have not included comprehensive neuropsychological evaluation formally assessing cognitive and psychological outcomes. His cognitive profile demonstrated weaknesses that correlate with greater lateralization to the right hemisphere, with relative preservation of left hemisphere functions excluding sentence repetition and aspects of auditory memory. Many of his frontally mediated weaknesses may be accounted for by frontal subcortical pathology (Achim & Lepage, 2005; Barbey et al., 2013; Reed et al., 2000). Auditory inefficiency may be partially contributory to reductions in select verbally mediated performances given his recent cochlear implantation (Boisvert et al., 2020), as auditory improvement can be seen for several months after initial tuning. The discrepancy between verbal and visual functions was also noted across intelligence testing, where his verbal comprehension was significantly higher than his perceptual reasoning skills. It is possible that there was a premorbid discrepancy to some degree prior to IVLBCL, as it is common for individuals to have some variability across index scores (Grégoire et al., 2011). However, specific lesions in the non-dominant hemisphere have also been shown to result in this difference (Gläscher et al., 2009). IVLBCL and APS are associated with cerebrovascular events (Radin et al., 2018; Yunce et al., 2018). His neuroimaging showed bilateral lesions and encephalomalacia that were relatively evenly distributed, which was further supported by bilateral weaknesses in motor speed and dexterity. Cognitive reserve theory describes the brain’s ability to adapt and persist through neuroanatomical insults (Stern et al., 2020) and may explain his predominantly preserved dominant hemispheric functions. Moreover, based on the patient’s academic and occupational history, he likely has robust verbal skills, which allowed for cognitive maintenance despite neurological damage (Livingston et al., 2020).

Several non-dominant hemispheric deficits were observed in his cognitive profile ranging from more anterior to posterior regions of the brain, consistent with parietal and frontal chronic infarcts. The parietal regions, particularly the right hemisphere, are critically involved for several visually based skills, notably visual attention (e.g., sustained), tracking/scanning, perception, and other visuospatial abilities (Battelli et al., 2009; Berryhill & Olson, 2008; Dziedzic et al., 2021) given it is an area that involves several white matter tracts (Fernández Coello et al., 2013). Similarly, processing speed is highly reliant on functional white matter pathways, especially in the frontal-subcortical regions, and is commonly affected by cerebrovascular-related pathologies (Duering et al., 2013; Duering et al., 2014). Not only do cerebral lesions explain the current patient’s non-dominant visually based deficits, but there is also possible contribution from positive findings in the right cerebellum due to research pointing to its involvement in higher-order cognitive functions, notably perception, proprioception, visual divergent thinking, ocular motor control and scanning, and aspects of visual learning (Baumann et al., 2015; Deluca et al., 2014; Gao et al., 2020; Kheradmand & Zee, 2011). The unique integration between motor and visual skills in the cerebellum would further explain his prominent right-sided cerebellar signs including ataxia and hypermetria (Manto, 2009; Radmard et al., 2023). His combination of deficits likely describes network-related dysfunction when taking into account the extensive neural connectivity between the cerebral and cerebellar regions (Dum & Strick, 2003; Schmahmann & Pandya, 1991; Schmahmann & Pandya, 1997a; Schmahmann & Pandya, 1997b).

Given the impact IVLBCL has on cognitive functioning, there is ample opportunity for cognitive rehabilitation as a post-feedback recommendation. Although there is no specific protocol for IVLBCL, cognitive rehabilitation has been utilized for other rare medical conditions with some efficacy (Maresca et al., 2021). As with other more common neurological conditions, there is a benefit from engaging in both restorative and compensatory interventions (Guideline Development Panel et al., 2022). Interventions would have to be tailored to the individual, particularly in patients with IVLBCL, given its heterogeneous presentation (Han et al., 2022). However, individualized care and treatment plans often lead to better outcomes, particularly when they involve neurological conditions (Graessel et al., 2024; Sandison et al., 2023). In addition, due to a higher level of complexity, individuals with rare conditions like IVLBCL would benefit from the involvement of multidisciplinary teams, as it often leads to patients receiving higher quality care and better overall outcomes (Joneborg et al., 2023; Miller et al., 2009; Van Groenendael et al., 2015).

Individuals with rare conditions (RCs), like the current patient, face many challenges that may be uncommon to those with familiar diseases (von der Lippe et al., 2017). Salient to most RCs, patients face a long and complicated diagnostic process (Benito-Lozano et al., 2022), and IVLBCL is no exception. In addition, there are a host of other unique challenges that patients with RCs experience, which can result in thoughts and feelings of dependence, lack of freedom, being misunderstood, and insecurity, as well as a loss of confidence in the medical system (von der Lippe et al., 2017). RC-associated challenges can lead to significant psychological consequences (Uhlenbusch et al., 2019), which was observed in the current patient with severe anxiety, mild depression, and moderate hopelessness. One major contributor to reduced quality of life in the elderly is hearing loss, thus reducing communication and increasing loneliness, isolation, dependence, and frustration (Ciorba et al., 2012). Over the course of his illness, the patient experienced complete bilateral hearing loss, necessitating the use of a transcriber until he received his unilateral cochlear implant. Thus, IVLBCL and its associated external stressors were not the only contributors to the patient’s psychological disturbance and reduced quality of life (Delaye et al., 2022), whereas internal stressors also played a significant role in exacerbating his psychological symptoms. This was particularly true of his hearing loss, which has the potential to contribute to symptoms of depression and anxiety directly (Löhler et al., 2019). The starkest finding, however, was his moderate levels of hopelessness, which may be a result of having an RC, as it exposes individuals to recurrent and successive negative life events contributing to a negative cognitive style proposed by the hopelessness theory of depression (Abramson et al., 1989).

It is clear that there are several psychosocial factors that can contribute to emotional distress in RCs. However, symptoms of depression and anxiety can also be directly related to the underlying neurological pathology (Winstein et al., 2016). As such, it is well proven that cerebrovascular conditions and lesions can directly contribute to persistent emotional distress patterns (Huang et al., 2024; Lan et al., 2022), particularly when it involves the prefrontal cortex. The current patient has several vascular-related lesions and areas of encephalomalacia, so it is likely that his underlying emotional symptoms are due to both organic and reactionary factors. Overall, RCs present with unique challenges that most individuals do not experience, especially in the context of a condition with an annual incidence rate of fewer than 0.5 cases per 1,000,000 (Luo et al., 2017).

There are some limitations to the current study. The current patient’s medical course was still during an active period of the SARS-CoV-2 pandemic, so it is possible that the heightened level of stress in someone with a chronic history of anxiety influenced the psychological and cognitive findings to some degree (da Silva Castanheira et al., 2021; Glinianowicz et al., 2023; Langhammer et al., 2022), although pandemic specific distress is difficult to measure independently. In addition, the patient’s high cognitive reserve could have had a masking effect on some of his cognitive difficulties, given that cognitive reserve can lead to a higher level of compensatory mechanisms and neuroprotective effects (Bettcher et al., 2019; Corbo et al., 2023).

Nonetheless, the current findings elucidate the unique cognitive and psychological profile of a patient with IVLBCL and, to our knowledge, is the first known comprehensive neuropsychological evaluation in the literature. Due to IVLBCL’s rarity and heterogeneous presentation, it would be beneficial for future studies to compare cognitive outcomes to the current findings and to potentially identify cognitive patterns and treatment recommendations. Similar to other RCs, multidisciplinary teams are likely ideal in IVLBCL given the overall complexity of its presentation (Han et al., 2022; Hayeems et al., 2022). Future directions should also focus on the outcomes of IVLBCL patients when receiving extensive multidisciplinary care compared to the current standard of care, particularly as it relates to time to diagnosis and the associated deficits. Lastly, the current study also highlights the ongoing need for research on the unique psychological experiences of those with RCs.

CONFLICT OF INTEREST

None declared.

ACKNOWLEDGEMENTS

The authors would sincerely like to thank the patient and his family for their support in this endeavor. The patient and family were grateful for the provided neuropsychological services.

AUTHOR CONTRIBUTIONS

Justin Misterka (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Visualization, Writing—original draft, Writing—review & editing), Andrew Wong (Writing—review & editing), Liorah Sabbah-Talasazan (Writing—review & editing), Shant Rising (Writing—original draft), Ann Gottuso (Supervision), and Jefferey Wertheimer (Writing—review & editing).

References