Metabolic and Toxic Myelopathies.

OBJECTIVE: This article reviews the clinical presentation, diagnostic evaluation, and treatment of metabolic and toxic myelopathies resulting from nutritional deficiencies, environmental and dietary toxins, drugs of abuse, systemic medical illnesses, and oncologic treatments. LATEST DEVELOPMENTS: Increased use of bariatric surgery for obesity has led to higher incidences of deficiencies in nutrients such as vitamin B12 and copper, which can cause subacute combined degeneration. Myelopathies secondary to dietary toxins including konzo and lathyrism are likely to become more prevalent in the setting of climate change leading to drought and flooding. Although modern advances in radiation therapy techniques have reduced the incidence of radiation myelopathy, patients with cancer are living longer due to improved treatments and may require reirradiation that can increase the risk of this condition. Immune checkpoint inhibitors are increasingly used for the treatment of cancer and are associated with a wide variety of immune-mediated neurologic syndromes including myelitis. ESSENTIAL POINTS: Metabolic and toxic causes should be considered in the diagnosis of myelopathy in patients with particular clinical syndromes, risk factors, and neuroimaging findings. Some of these conditions may be reversible if identified and treated early, requiring careful history, examination, and laboratory and radiologic evaluation for prompt diagnosis.

Impact of steatotic liver disease and non-alcoholic steatohepatitis on cognitive impairment in people living with HIV: A cross-sectional study.

INTRODUCTION: The link between fatty liver diseases and cognitive impairment among people living with HIV (PLWH) remains unclear. We investigated the association of steatotic liver disease (SLD), advanced liver fibrosis and non-alcoholic steatohepatitis (NASH) with significant activity and liver fibrosis with cognitive impairment in PLWH. METHODS: Cognitive performance was assessed for PLWH aged ≥50 years on stable antiretroviral therapy (ART) with the Thai-validated version of the Montreal Cognitive Assessment (MoCA), and a cut-off of <25/30 was used to define cognitive impairment. SLD and NASH with significant activity and liver fibrosis were defined as having a controlled attenuation parameter value ≥248 dB/m and a FibroScan-AST (FAST) score ≥0.67, respectively. Multivariable logistic regression was employed to investigate the association of cognitive impairment with SLD or NASH. RESULTS: Of the 319 PLWH (63.3% male and 98% had HIV-1 RNA ≤50 copies/mL) included, 74 (38%) had SLD. NASH with significant activity and liver fibrosis was present in 66 (20.1%) participants. Some 192 (60.2%) participants had cognitive impairment. In a multivariable analysis, NASH with significant activity and liver fibrosis was significantly associated with cognitive impairment (adjusted odds ratio [aOR] 2.01, 95% CI 1.02-3.98, p = 0.04), after adjusting for HIV-related parameters, age, sex, body mass index, employment status, education, income level, smoking, alcohol use, diabetes mellitus, hypertension and HIV-related parameters. The association of a lone diagnosis of SLD and cognitive impairment was not statistically significant. CONCLUSIONS: NASH with significant activity and liver fibrosis was associated with lower cognitive performance, even after controlling for demographics and HIV disease parameters. Additional research is needed to better understand the underlying mechanisms.

Historical Perspectives on the Neurologic Manifestations of Viral Pandemics.

Neurologic symptoms have been reported in over 30% of hospitalized patients with coronavirus disease 2019 (COVID-19), but the pathogenesis of these symptoms remains under investigation. Here, we place the neurologic complications of COVID-19 within the context of three historical viral pandemics that have been associated with neurologic diseases: (1) the 1918 influenza pandemic, subsequent spread of encephalitis lethargica, and lessons for the study of COVID-19-related neuroinflammation; (2) the controversial link between the 1976 influenza vaccination campaign and Guillain-Barré Syndrome and its implications for the post- and parainfectious complications of COVID-19 and COVID-19 vaccination; and (3) potential applications of scientific techniques developed in the wake of the human immunodeficiency virus pandemic to the study of postacute sequelae of COVID-19.

Central Nervous System Neuroimmunologic Complications of COVID-19.

Autoimmune disorders of the central nervous system following COVID-19 infection include multiple sclerosis (MS), neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, autoimmune encephalitis, acute disseminated encephalomyelitis, and other less common neuroimmunologic disorders. In general, these disorders are rare and likely represent postinfectious phenomena rather than direct consequences of the SARS-CoV-2 virus itself. The impact of COVID-19 infection on patients with preexisting neuroinflammatory disorders depends on both the disorder and disease-modifying therapy use. Patients with MS do not have an increased risk for severe COVID-19, though patients on anti-CD20 therapies may have worse clinical outcomes and attenuated humoral response to vaccination. Data are limited for other neuroinflammatory disorders, but known risk factors such as older age and medical comorbidities likely play a role. Prophylaxis and treatment for COVID-19 should be considered in patients with preexisting neuroinflammatory disorders at high risk for developing severe COVID-19.

Quantifying the economic burden to patients of relapse events from neuromyelitis optica spectrum disorders: A cross-sectional survey.

We surveyed 103 adults (mean age 46 years; 85% female) with neuromyelitis optica spectrum disorders (NMOSD) through social media about their personal economic burden of NMOSD emergency department visits and hospitalizations ("relapse events"). The average number of relapse events over the prior 3 years was 5.3. Participants reported direct, out-of-pocket costs for 52% of events (mean cost per event 3326 USD, 95% CI [2378,4274]) and indirect costs (e.g., childcare) for 26% (mean cost per event 1907 USD, 95% CI [1159,2655]). Sixty-nine percent reported lost income due to hospital visits. Future work should identify and support subgroups with higher economic burden from NMOSD.

Neurologic disease activity in people with multiple sclerosis treated with immune checkpoint inhibitors.

BACKGROUND: There is concern that immune checkpoint inhibitors (ICPIs) can provoke relapses in people with multiple sclerosis (pwMS). OBJECTIVE: Analyze outcomes of pwMS who received ICPI treatment for malignancy. METHODS: We electronically identified pwMS who received ICPI treatment at Mass General Brigham hospital system. We retrospectively obtained information about patients' MS, cancer, treatment, and outcomes. RESULTS: Sixteen patients were identified with an average (standard deviation (SD)) age of 67.4 (11.9) years. Eleven (68.8%) had no relapses since MS diagnosis. None had MS relapses after ICPI treatment or new MS lesions. CONCLUSION: ICPI use was not associated with increased clinical disease activity in this cohort of older patients with inactive MS.

Use of Transcranial Doppler as a Biomarker of CAR T Cell-Related Neurotoxicity.

Background and Objectives: To examine the relationship between transcranial Doppler (TCD) mean flow velocity (MFV) and the severity and temporal onset of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed lymphoma. Methods: We identified a cohort of 165 patients with relapsed or refractory B-cell lymphoma who received CAR T-cell therapy. TCDs were performed at baseline, treatment day 5, and throughout hospitalization based on development of neurologic symptoms. We assessed the percent change in velocity from baseline in each of the 6 major supratentorial arteries and the relationship of these values to development and timing of neurotoxicity. Results: Our cohort was 30% female with an average age of 60 years. Of patients with TCDs performed, 63% developed neurotoxicity, and 32% had severe neurotoxicity. The median time of neurotoxicity onset was day 7. Higher maximum percent change in MFV across all vessels was significantly associated with likelihood of developing neurotoxicity (p = 0.0002) and associated with severe neurotoxicity (p = 0.0421). We found that with increased percent change in MFV, the strength of correlation between day of TCD velocity change and day of neurotoxicity onset increased. There was no single vessel in which increase in MFV was associated with neurotoxicity. Discussion: Our study demonstrates an association between increase in TCD MFV and the development of neurotoxicity, as well as timing of neurotoxicity onset. We believe that TCD ultrasound may be used as a bedside functional biomarker in CAR T-cell patients and may guide immunologic interventions to manage toxicity in this complex patient group.

Humoral response to COVID-19 vaccination in MS patients on disease modifying therapy: Immune profiles and clinical outcomes.

BACKGROUND: Patients with multiple sclerosis (MS) on some disease modifying therapies (DMTs), particularly anti-CD20 and sphingosine-1-phosphate (S1P) modulators, are at increased risk of severe Coronavirus Disease 19 (COVID-19) and death. COVID-19 vaccinations are effective in preventing infection and severe disease, but humoral response to vaccination and outcomes of COVID-19 infection after vaccination in MS patients on DMTs remain less understood. METHODS: In this retrospective single-center study, patients enrolled in the CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital) study and biorepository who had been vaccinated against COVID-19 and had SARS-CoV-2 spike antibody (anti-SARS-CoV-2 S Roche-Elecsys) testing were identified and compared to healthy controls. Demographic data, serum immune profiles including lymphocyte count, B-cell count, and immunoglobulins, and clinical outcome of COVID-19 infection were collected. RESULTS: 254 patients (73.2% female, mean (SD) age 52.9 (11.2) years) were identified. When controlling for age, time since vaccination, and vaccine type, patients on fingolimod, ocrelizumab, rituximab, mycophenolate mofetil, natalizumab and teriflunomide had significantly lower levels of spike antibodies compared to healthy controls (n = 34). Longer duration of treatment was associated with lower spike antibody levels in patients on anti-CD20 therapy (p = 0.016) and S1P modulators (p = 0.016) compared to healthy controls. In patients on anti-CD20 therapy, higher spike antibody levels were associated with higher CD20 cell count (p<0.001), and longer time since last anti-CD20 therapy infusion (p<0.001). 92.8% (13/14) vaccine responders (spike antibody titer >100 ug/dL) on anti-CD20 therapy demonstrated B-cell reconstitution (mean CD20 3.6%). Only 1 out of 86 patients with CD20 of 0% had a measurable spike antibody response to vaccination. During follow-up (mean 270 days), five patients were diagnosed with COVID-19 after vaccination (incidence 1.9%), all of whom had spike antibody < 20 ug/dL. No patients required ICU care or died. CONCLUSIONS: Patients on some DMTs demonstrate reduced humoral immunity after Sars-CoV-2 vaccination. Longer duration of anti-CD20 therapy and reduced CD20 cell count is associated with blunted humoral response to vaccination. CD20 reconstitution >0.1% appears necessary, but not always sufficient, for humoral response to vaccination. Breakthrough COVID-19 infection in our cohort of MS patients on DMT was higher than in population studies. We propose that adjustment of B-cell therapy administration to allow for B-cell reconstitution prior to vaccination should be considered.

Disease modifying therapy management of multiple sclerosis after stem cell therapies: A retrospective case series.

BACKGROUND: Stem cell therapies (SCT) have not received formal regulatory approval for the treatment of people with multiple sclerosis (PwMS), but PwMS may seek various options on their own accord. The current literature largely focuses on the efficacy and safety of SCT in PwMS in clinical trials, in particular autologous hematopoietic stem cell transplantation (aHSCT), in carefully selected participants. There is little reported on the MS disease modifying therapy (DMT) management of PwMS who choose to undergo SCT outside of these trials. METHODS: We identified PwMS from two academic centers who had MS diagnosis fulfilling 2017 McDonald criteria and received SCT (methodologies permitted: aHSCT, umbilical-derived mesenchymal stem cells and/or adipose-derived mesenchymal stem cells (AdMSC)), with the goal to treat MS, between 1/1/2015 and 11/30/2021. RESULTS: Nine PwMS (five females; age range at SCT treatment 25-69 years old; MS disease duration 1-12 years; six relapsing-remitting, three secondary progressive, one primary progressive) underwent a total of eleven SCTs (nine aHSCT, two AdMSC, one umbilical-derived MSC) with the goal to treat MS. Two of six PwMS who underwent SCT <10 years from MS diagnosis, and one of three PwMS who underwent stem cell therapies >10 years from MS diagnosis were clinically stable thereafter. An MS DMT was resumed in five PwMS afterwards, including rituximab, ocrelizumab, siponimod, and glatiramer acetate: one remained clinically stable, whereas four clinically progressed. Four PwMS remained off of a DMT: three were clinically stable, whereas one clinically progressed. All nine patients demonstrated radiographic stability by MRI after SCT. Only one met formal criteria to consider aHSCT for MS. CONCLUSIONS: We demonstrate the heterogeneous real-world experience of treating MS after patient-chosen experimental SCTs, detailing the range of DMT management in various patient circumstances. Limitations of our study include its small sample size and the variety of stem cell therapies received.

Neurologic Complications in Patients with Cancer.

Neurologic symptoms are commonly seen in patients with cancer and can be among the most challenging to diagnose and manage. It is often difficult to determine if new neurologic symptoms are secondary to direct effects of a malignant lesion, systemic complications of disease, paraneoplastic disorders, or side effects of cancer treatment itself. However, early diagnosis and treatment of each of these conditions can improve patients' quality of life and long-term functional outcomes. In this review, we describe a systematic approach to the diagnosis of new neurologic symptoms in patients with known malignancy. We have categorized the neurologic complications of cancer through a mechanistic approach, with an emphasis on ascertaining underlying pathophysiology to guide treatment choice. This review focuses on the acute neurologic complications of cancer that require hospital admission.

Intrathecal inflammatory responses in the absence of SARS-CoV-2 nucleic acid in the CSF of COVID-19 hospitalized patients.

OBJECTIVE: Little is known about CSF profiles in patients with acute COVID-19 infection and neurological symptoms. Here, CSF was tested for SARS-CoV-2 RNA and inflammatory cytokines and chemokines and compared to controls and patients with known neurotropic pathogens. METHODS: CSF from twenty-seven consecutive patients with COVID-19 and neurological symptoms was assayed for SARS-CoV-2 RNA using quantitative reverse transcription PCR (RT-qPCR) and unbiased metagenomic sequencing. Assays for blood brain barrier (BBB) breakdown (CSF:serum albumin ratio (Q-Alb)), and proinflammatory cytokines and chemokines (IL-6, IL-8, IL-15, IL-16, monocyte chemoattractant protein -1 (MCP-1) and monocyte inhibitory protein - 1ß (MIP-1ß)) were performed in 23 patients and compared to CSF from patients with HIV-1 (16 virally suppressed, 5 unsuppressed), West Nile virus (WNV) (n = 4) and 16 healthy controls (HC). RESULTS: Median CSF cell count for COVID-19 patients was 1 white blood cell/µL; two patients were infected with a second pathogen (Neisseria, Cryptococcus neoformans). No CSF samples had detectable SARS-CoV-2 RNA by either detection method. In patients with COVID-19 only, CSF IL-6, IL-8, IL-15, and MIP-1ß levels were higher than HC and suppressed HIV (corrected-p < 0.05). MCP-1 and MIP-1ß levels were higher, while IL-6, IL-8, IL-15 were similar in COVID-19 compared to WNV patients. Q-Alb correlated with all proinflammatory markers, with IL-6, IL-8, and MIP-1ß (r ≥ 0.6, p < 0.01) demonstrating the strongest associations. CONCLUSIONS: Lack of SARS-CoV-2 RNA in CSF is consistent with pre-existing literature. Evidence of intrathecal proinflammatory markers in a subset of COVID-19 patients with BBB breakdown despite minimal CSF pleocytosis is atypical for neurotropic pathogens.

Update on neuromyelitis optica spectrum disorder.

PURPOSE OF REVIEW: Neuromyelitis optica spectrum disorder is an autoimmune disease that causes optic neuritis and transverse myelitis. Attacks can cause severe neurological damage leading to blindness and paralysis. Understanding of the immunopathogenesis of this disease has led to major breakthroughs in diagnosis and treatment. In the past 18 months, three successful phase 3 clinical trials have been published using targeted approaches to preventing relapses. RECENT FINDINGS: Updates in epidemiology, imaging, quality of life and treatment for acute relapse and prevention have been published in the past 18 months. Epidemiology studies are distinguishing patients based on their antigen specificity for aquaporin-4 and myelin oligodendrocyte glycoprotein, which are increasingly recognized as separate immunological conditions. Imaging by MRI and optical coherence tomography continue to be developed as tools to distinguish neuromyelitis optica spectrum disorders (NMOSD) from other diseases. This is especially relevant as the recent clinical trials showed differences in response between aquaporin-4 seropositive and seronegative patients. The three drugs that were tested for prevention of NMOSD relapses were eculizumab, inebilizumab, and satralizumab. All of the trials were worldwide, placebo-controlled, double-masked studies that demonstrated a clear benefit with each approach. SUMMARY: Recent research in NMOSD has resulted in improved diagnosis and approved treatments.

Light therapy for multiple sclerosis-associated fatigue: a randomized, controlled phase II trial.

BACKGROUND: Bright white light therapy (LT) can improve fatigue in several disease states but has not been studied in multiple sclerosis (MS). OBJECTIVE: To determine whether controlled home-based LT is feasible, tolerable, and well-adhered to in MS-associated fatigue. METHODS: A randomized, controlled trial of twice-daily 1-h bright white LT (BWLT) (10,000 lx, active arm) versus dim red LT (DRLT) (< 300 lx, control arm) was performed. Adults with MS-associated fatigue were enrolled for 10 weeks: 2-week baseline, 4-week intervention, 4-week washout. RESULTS: 41 participants were enrolled; 35 were randomized (average age 42 years, 80% female; BWLT n = 20; DRLT n = 15). 31 were in the intention to treat analysis. The average duration of LT sessions was similar between groups (BWLT 60.9 min, DRLT 61.5 min, p = 0.70). The most commonly reported adverse event was headache. There were no events that led to discontinuation. Baseline fatigue was severe in both arms (each 53/63 points on the Fatigue Severity Scale (FSS), p = 0.92). FSS was lower following BWLT (FSS 45.8 post-LT, p = 0.04; 44.9 post-washout, p = 0.02 intra-group compared to baseline FSS) and DRLT (FSS 46.7 post-LT, p = 0.03; 43.9 post-washout, p = 0.002 intragroup compared to baseline FSS). There was no difference between BWLT and DRLT groups in the magnitude of reduction of FSS scores (p = 0.81 after LT; p = 0.77 after washout for between group comparisons). Similarly, MS quality of life metrics improved in both arms but were not significantly different between groups after LT (p = 0.22) or washout. CONCLUSIONS: LT is safe, feasible, and well-tolerated in people with MS-associated fatigue. Improvement in both light spectra likely indicates a strong placebo effect for the DRLT group.

Neurologic Complications of Acute HIV Infection.

PURPOSE OF REVIEW: This review focuses on the pathophysiology of acute HIV infection (AHI) and related central nervous system (CNS) pathology, the clinical characteristics of neurologic complications of AHI, and the implications of the CNS reservoir and viral escape for HIV treatment and cure strategies. RECENT FINDINGS: Recent studies in newly seroconverted populations show a high prevalence of peripheral neuropathy and cognitive dysfunction in AHI, even though these findings have been classically associated with chronic HIV infection. HIV cure strategies such as the "shock and kill" strategy are currently being studied in vitro and even in small clinical trials, though the CNS as a reservoir for latent HIV poses unique barriers to these treatment strategies. SUMMARY: Limited point of care diagnostic testing for AHI and delayed recognition of infection continue to lead to under-recognition and under-reporting of neurologic manifestations of AHI. AHI should be on the differential for a broad range of neurological conditions, from Bell's palsy, peripheral neuropathy, and aseptic meningitis, to more rare manifestations such as ADEM, AIDP, meningo-radiculitis, transverse myelitis, and brachial neuritis. Treatment for these conditions involves early initiation of antiretroviral therapy (ART) and then standard presentation-specific treatments. Current HIV cure strategies under investigation include bone marrow transplant, viral reservoir re-activation and eradication, and genome and epigenetic viral targeting. However, CNS penetration by HIV-1 occurs early on in the disease course with the establishment of the CNS viral reservoir and is an important limiting factor for these therapies.

Multiple Sclerosis, Anxiety, and Depression in the United Arab Emirates: Does Social Stigma Prevent Treatment?

BACKGROUND: Depression rates in the multiple sclerosis (MS) population in the Arab world have rarely been reported despite people with MS generally having higher rates of depression. We examined depression rates in 416 people with MS versus the general population of Abu Dhabi, United Arab Emirates, and their treatment. METHODS: A retrospective medical record review of 416 people with MS (age range, 16-80 years) followed up at four large government hospitals in Abu Dhabi was conducted to determine the percentage of people with MS diagnosed as having depression or anxiety. RESULTS: The depression rate in people with MS (10.8%) was close to that in the general population of Abu Dhabi. The adjusted odds ratios of depression by selected variables showed that there was a significant difference (P = .003) between females and males in reporting depression, with more females reporting depression than males. Greater MS duration was also associated with a higher likelihood of being depressed (P = .025). The anxiety rate in the cohort (4.8%) was lower than that in the general Abu Dhabi population (18.7%). CONCLUSIONS: The depression rate in people with MS in Abu Dhabi was close to that of the general Abu Dhabi population, but the anxiety rate in people with MS was lower. Explanations for these low rates include possible underreporting by patients and physician factors such as time limitations in busy clinics. Cultural aspects such as strong family support systems and religious factors in this predominantly Muslim population are also possible factors that warrant further investigation.

Prevalence and characteristics of transverse myelitis and neuromyelitis optica spectrum disorders in the United Arab Emirates: A multicenter, retrospective study.

OBJECTIVE: To determine the epidemiology and characteristics of transverse myelitis (TM) and neuromyelitis optica spectrum disorders (NMOSD) in Abu Dhabi, United Arab Emirates. METHODS: Retrospective chart review at four large government-run hospitals in Abu Dhabi between 2010 and 2016. Data collected included year of onset, presentation, laboratory results including aquaporin-4 immunoglobulin G (IgG)/myelin oligodendrocyte glycoprotein IgG antibodies and the occurrence of any relapses. RESULTS: A total of 46 individuals were identified. Of these, 23 (50%) were Emirati citizens. Within the overall group including pediatrics, the crude prevalence rate for monophasic TM was 1.0 per 100 000, and for NMOSD was 0.34 per 100 000. Incidence rates within the overall group for TM and NMOSD were 0.18 per 100 000 and 0.05 per 100 000, respectively. For Emirati citizens aged ≥20 years, the prevalence rate for monophasic TM was 2.46 per 100 000 and 1.76 per 100 000 for NMOSD, and the incidence was 0.57 per 100 000 and 0.17 per 100 000, respectively. The incidence of monophasic TM and NMOSD within the Emirati pediatric population (aged ≤19 years) was 0.18 per 100 000 and 0.06 per 100 000, respectively. The mean age of onset for monophasic TM was 36 years, and for NMOSD was 43 years. Nine patients had a positive aquaporin-4 IgG or anti-myelin oligodendrocyte glycoprotein IgG antibody result. Of the 30 participants with available laboratory cerebrospinal fluid analysis, 36.6% had elevated white blood counts (>5.0 × 106/L), and 43% had elevated protein levels. A total of 19 participants had documentation of oligoclonal bands or IgG index, and just four (21%) had either oligoclonal bands or elevated IgG index. CONCLUSION: The present study describes the epidemiology and characteristics of TM and NMOSD among populations in Abu Dhabi. The adult prevalence rate for Emirati citizens was 2.46 per 100 000 for monophasic TM, and 1.76 per 100 000 for NMOSD. The overall incidence was 0.18 per 100 000 and 0.05 per 100 000, respectively.

Novel mutation in the KCNJ10 gene in three siblings with seizures, ataxia and no electrolyte abnormalities.

We report a consanguineous family with three affected siblings with novel mutation in the KCNJ10 gene. All three presented with central nervous system symptoms in the form of infantile focal seizures, ataxia, slurred speech with early developmental delay and intellectual disability in two siblings. None had any associated electrolyte abnormalities and no symptomatic hearing deficits were observed.

JC virus granule cell neuronopathy onset two months after chemotherapy for low-grade lymphoma.

BACKGROUND: Granule cell neuronopathy (GCN) is a rare disease caused by the JC virus, leading to degeneration of cerebellar granule cell neurons. Primarily described in patients with AIDS, it has also been diagnosed in patients with lymphoproliferative diseases and after long-term treatment with immune-suppressing medications such as natalizumab. CASE PRESENTATION: A 69 year old woman presented with progressive ataxia which began 2 months after initiation of treatment for follicular low-grade B cell lymphoma with rituximab/bendamustine, and progressed for 2 years prior to admission. Extensive prior evaluation included MRI that showed atrophy of the cerebellum but normal CSF analysis and serum studies. Neurologic exam on admission was notable for severe appendicular ataxia and fatigable end-gaze direction-changing horizontal nystagmus. FDG-PET/CT scan was unremarkable and repeat lumbar puncture revealed 2 WBCs/mm3, 148 RBCs/mm3, glucose 70 mg/dL, protein 37.7 mg/dL and negative flow cytometry/cytopathology. Standard CSF JC virus PCR testing was negative, but ultrasensitive TaqMan real-time JC virus PCR testing was positive, consistent with JC virus-related GCN. CONCLUSIONS: Because of the diagnostic challenges in identifying GCN, a high threshold of suspicion should be maintained in patients with an immune-suppressing condition such as lymphoma or on immune-suppressing agents such as rituximab, even shortly after initiation of therapy.