A Proposed Approach to Screening and Surveillance Labs for Patients With Multiple Sclerosis on Anti-CD20 Therapy.

Background: Anti-CD20 therapies have proven to be highly effective and safe therapies for multiple sclerosis (MS) and have had rapid uptake in the MS community. However, no clear consensus has arisen regarding an approach to screening or surveillance lab monitoring. Recent Findings: Based on current evidence, for screening labs before anti-CD20 initiation, we propose checking liver function test (LFT), complete blood count with differential (CBC), absolute B-cell count, quantitative immunoglobulins, hepatitis B virus serologies, varicella zoster virus IgG, John Cunningham virus (JCV) status, and age-appropriate vaccination history. For surveillance monitoring in an otherwise asymptomatic individual, we propose biannual LFTs and CBC, quantitative immunoglobulins annually after year 3, absolute B-cell count at month 6 and in the setting of relapse, and JCV only if clinical or radiographic features of progressive multifocal leukoencephalopathy arise. For ublituximab, pregnancy testing is additionally recommended before each infusion. Implications for Practice: We propose evidence-based screening and safety surveillance labs which take into account likelihood of changing management in an otherwise stable or asymptomatic individual.

Revisiting JC virus and progressive multifocal leukoencephalopathy.

Since its definition 65 years ago, progressive multifocal leukoencephalopathy (PML) has continued to devastate a growing population of immunosuppressed patients despite major advances in our understanding of the causative JC virus (JCV). Unless contained by the immune system, JCV lyses host oligodendrocytes collateral to its life cycle, leading to demyelination, neurodegeneration, and death. Novel treatments have stagnated in the absence of an animal model while current antiviral agents fail to address the now ubiquitous polyomavirus. In this review, we highlight the established pathogenesis by which JCV infection progresses to PML, highlighting major challenges that must be overcome to eliminate the underlying virus and, therefore, the debilitating disease.

The CLARION study: first report on safety findings in patients newly initiating treatment with cladribine tablets or fingolimod for multiple sclerosis.

OBJECTIVES: As part of the CLARION study: (1) characterize the incidence of severe infections, herpes zoster, and malignancies in patients newly initiating cladribine or fingolimod for relapsing multiple sclerosis (MS); (2) estimate the incidence of severe lymphopenia among cladribine users; and (3) describe prior/subsequent disease-modifying therapy (DMT) in both cohorts. METHODS: Patients were identified from seven participating MS registries/data sources. The incidence rate (IR) of each outcome per 1000 patient-years and its 95% confidence interval (95%CI) were estimated for cohorts using Poisson regression. RESULTS: By cut-off date (01-April-2020), 742 cladribine and 867 fingolimod users were included. Mean follow-up was ∼1 year. The IR for severe infections from all contributing sources (except Denmark) was: cladribine, 7.37 (2.76,19.6); fingolimod, 6.55 (2.46,17.4). The corresponding IR for herpes zoster was 5.51 (1.78,17.1) and 3.27 (0.82,13.1), respectively, while values for opportunistic infections were 0 (0,6.76) and 1.63 (0.23,11.6), respectively. There were no events of progressive multifocal leukoencephalopathy in either cohort. The IR of severe lymphopenia was 63.9 (40.7,100.1) in 349 cladribine users from contributing sources. The IR of malignancies (cut-off date 01-April-2022) was 3.55 (1.59,7.90) for the cladribine cohort (n = 1035) and 3.55 (1.48,8.52) for the fingolimod cohort (n = 843) from three MS registries/data sources. In the combined data sources, 36.8% of cladribine and 27.4% of fingolimod users were DMT-naïve; after initiation of study treatment, 2.5% and 20.2% switched to another DMT, respectively. CONCLUSION: No new safety signal was observed in patients treated with cladribine tablets, although results are limited by a relatively short duration of follow-up.

Severe Neuroinvasive West Nile Virus in Association With Anti-CD20 Monotherapy for Multiple Sclerosis.

OBJECTIVES: The objective of this study was to report on the development of neuroinvasive West Nile virus (WNV) infection in the context of anti-CD20 monotherapy for multiple sclerosis (MS). METHODS: This is a case series study. RESULTS: In 2021-2022, we observed 4 cases of neuroinvasive WNV infection in our patient population of 2009 patients with MS on ocrelizumab, compared with a total of 46 cases of neuroinvasive WNV infection reported in Pennsylvania and 40 in New Jersey. Odds were 258 times that of the general population (95% confidence interval 97-691), χ2 p < 0.0001). All were women aged 41-61 years with variable disease duration, level of disability, and duration of anti-CD20 therapy. All presented in summer/early fall with fever, headache, and encephalopathy consistent with meningoencephalitis. Three patients had acute cerebellitis. Two had anterior nerve root involvement progressing to quadriparesis, and 1 developed refractory nonconvulsive status epilepticus. All required intubation and experienced significant morbidity. All had CSF pleocytosis. Two patients were WNV IgM positive in both the serum and CSF, 1 patient had positive serum IgM and CSF metagenomic next-generation sequencing (mNGS), while 1 had positive CSF mNGS with negative serum and CSF antibodies. DISCUSSION: Neuroinvasive WNV infection can develop with anti-CD20 monotherapy in the absence of additional immunosuppression. WNV serologies may be negative in the setting of anti-CD20 treatment; in the appropriate clinical context, one should consider direct detection methods such as PCR or mNGS-based testing.

Total Tau Level in Cerebrospinal Fluid as a Predictor of Survival in Creutzfeldt-Jakob Disease: A Retrospective Analysis.

Background and Objectives: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and universally fatal neurodegenerative disorder with highly variable survival times, ranging from weeks to years. However, there are currently no tools for prognosticating a patient's survival time. This study aims to fill this gap by examining the relationship between CSF total tau (t-tau) levels and time to death in patients with CJD. Methods: We use cases with CJD recorded in the electronic health record of a tertiary academic medical center from 2010 to 2022. Results: We identified 29 cases with diagnosis of CJD. Using a Cox proportional hazards model, we find that elevated t-tau levels (>4,000 pg/mL) are associated with 9.62 (95% confidence interval: 1.93-47.92) times the hazard of death compared with CJD patients with t-tau less than 4,000 pg/mL. Discussion: This finding supports the use of CSF t-tau as a prognostic biomarker for CJD.

The First Known Documented Case of Ewingella Americana Urinary Tract Infection.

We present a 73-year-old male with a history of end-stage renal disease (ESRD) on dialysis, type 2 diabetes mellitus, coronary artery disease status post stents, prostate carcinoma status post radiation, and prostatectomy, with recurrent bladder neck contracture requiring suprapubic catheter, left urethral stricture with nephrostomy tube placement, penile implant, and recurrent urinary tract infections, who presented to the emergency room complaining of constant bilateral groin pain for one day. Physical exam was significant for suprapubic tenderness and a chronic suprapubic catheter and left-sided nephrostomy tube. An initial examination of the patient's urine revealed turbid, yellow-colored fluid, positive for white blood cells, leukocyte esterase, and bacteria. A urine culture was obtained, which returned positive for E. americana,  with >100,000colony-forming units (CFUs)as well as Enterococcus faecalis (E. faecalis) demonstrating low colony counts. The patient was treated with a seven-day course of meropenem 1 gm twice daily, which improved of his symptoms, and then completed a 10-day course of ertapenem 500 mg daily. The patient received a five-day course of vancomycin 1 gm on dialysis days for additional coverage of E. faecalis, despite low colony counts. This is the first documented case of a urinary tract infection caused by E. americana. The organism is primarily found in immunocompromised individuals, and a debate is still ongoing as to whether it is a true pathogen or exists primarily as an opportunistic infection. We suggest further inquiry and study of this resistant organism are paramount in establishing its role in both immunocompromised as well as immunocompetent individuals. E. americana is a multidrug-resistant organism, which to date has sparse documentation regarding its prevalence and potential for morbidity, especially in compromised individuals. In the era of increasing antibiotic resistance, we suggest that more research is needed to understand the pathogenicity of E. americana.

Implant-based Breast Reconstruction Infections: The Importance of Recognizing Local Pathogens.

BACKGROUND: Implant-based breast reconstruction (IBR) is the most common method of reconstruction for breast cancer. Bacterial infection is a well-known risk with reported rates ranging from 1% to 43%. The most common pathogens of breast implant infection described in the literature are Staphylococcus aureus, Staphylococcus epidermidis, and coagulase-negative staphylococci. However, the prevalence of other pathogens and their antibiotic sensitivity profile differs profoundly in different parts of the world. OBJECTIVES: To review the current literature and protocols with respect to our region and to determine a more accurate antibiotic protocol aimed at our specific local pathogens. METHODS: A retrospective review was conducted of all cases of clinically infected implant-based breast reconstruction in our institution from June 2013 to June 2019, as well as review of microbiologic data from around the world based on current literature. RESULTS: A total of 28 patients representing 28 clinically infected implant-based breast reconstruction were identified during the studied period. Thirteen patients (46.4%) had a positive bacterial culture growth, with P. aeruginosa being the most common microorganism identified (46.1%). Review of international microbiological data demonstrated significant variation at different places and time periods. CONCLUSIONS: Microbiological data in cases of infected breast reconstructions should be collected and analyzed in every medical center and updated every few years due to the variations observed. These data will help to adjust the optimal empirical antibiotic regimens given to patients presenting with infections after breast reconstruction.

Management approach including pembrolizumab for fingolimod-associated progressive multifocal leukoencephalopathy in a patient with relapsing-remitting multiple sclerosis.

A 62-year-old man with relapsing-remitting multiple sclerosis developed progressive multifocal leukencephalopathy (PML) after 6 years on fingolimod. The fingolimod was immediately discontinued and preexisting mirtazepine increased. Three weeks later, with brain magnetic resonance imaging (MRI) appearances worsening and cerebrospinal fluid (CSF) JC virus (JCV) titres increasing, maraviroc was introduced. At 6 weeks, subtle punctate contrast enhancement raised the possibility of immune reconstitution inflammatory syndrome (IRIS), followed by a single focal-to-generalised tonic clonic seizure and a further deterioration in clinical disability. Mefloquine was commenced alongside three doses of pembrolizumab administered a month apart. Serial CSF examinations and several imaging modalities including spectroscopy and fused FDG-PET-MRI (18F-fluoro-deoxy-glucose-positron emission tomography-magnetic resonance imaging) were used to help distinguish between PML, PML-IRIS and rebound MS activity and guide optimal management at each stage. A handful of small, enhancing ovoid lesions developed between the first two doses of pembrolizumab, probably representative of a mild rebound phenomenon. A sustained improvement became obvious thereafter with CSF JCV-DNA undetectable 16 weeks following fingolimod withdrawal. To our knowledge, this is the first case of combined therapy and use of pembrolizumab in a fingolimod-associated PML.

Amebic infections of the central nervous system.

The report of death of a person from amebic meningoencephalitis, the proverbial "brain-eating ameba," Naegleria fowleri, acquired in a state park lake in Iowa in July 2022 has once again raised the seasonal alarms about this pathogen. While exceptionally rare, its nearly universal fatality rate has panicked the public and made for good copy for the news media. This review will address free-living ameba that have been identified as causing CNS invasion in man, namely, Naegleria fowleri, Acanthamoeba species, Balamuthia mandrillaris, and Sappinia diploidea (Table 1). Of note, several Acanthamoeba spp. and Balamuthia mandrillaris may also be associated with localized extra-CNS infections in individuals who are immunocompetent and disseminated disease in immunocompromised hosts. These ameba are unique from other protozoa in that they are free-living, have no known insect vector, do not result in a human carrier state, and are typically unassociated with poor sanitation. Table 1 Free-living ameba that have been identified as causing CNS invasion in man, namely, Naegleria fowleri, Acanthamoeba species, Balamuthia mandrillaris, and Sappinia diploidea Entity Pathogenic ameba Predisposing disorders Portal of entry Incubation period Clinical features Radiographic findings CSF finding Diagnostic measures Primary amebic meningoencephalitis Naegleria fowleri; N. australiensis; N. italica Previously healthy children or young adults Olfactory epithelium 2-14 days (average 5 days) Headache, fever, altered mental status, meningeal signs; seizures Brain edema; meningeal enhancement; hydrocephalus; basal ganglia infarctions Increased opening pressure; neutrophilic pleocytosis (~ 1000 cells/cu mm); low glucose Brain biopsy, CSF wet prep, IIF culture or PCR Granulomatous amebic encephalitis Acanthamoeba spp.; Balamuthia mandrillaris; Sappinia diploidea Typically, immunocompromised individual Skin sinuses; olfactory epithelium respiratory tract Weeks to months Headache; altered mental status seizures, focal neurological findings Focal parenchymal lesions with edema; hemorrhagic infarctions; meningeal enhancement Generally, LP contraindicated; when performed lymphocytic pleocytosis; increased protein; low glucose Brain biopsy, CSF culture, wet prep, IIF, or PCR IIF indirect immunofluorescence, LP lumbar puncture, PCR polymerase chain reaction.

Looks Like Neurosyphilis, Feels Like Guillain-Barre: At the Confluence of Infection and Immunology.

We present a 51-year-old male, with a past medical history of type 2 insulin-dependent diabetes mellitus (T2IDDM) without neuropathy, coronavirus disease 2019 (COVID-19) in April 2020 without residual symptoms, Raynaud's, and recent occupational outdoor exposure to insects as a construction manager who came to the emergency room complaining of a three-week history of bilateral progressive numbness and weakness beginning in his lower extremities and ascending toward his pelvis. Notably, he received the second dose of his Moderna COVID-19 vaccine one week prior to symptom onset and four weeks prior to admission. He also reported a recent appearance of a maculopapular rash on his upper extremities and flanks. Physical exam was remarkable for bilateral distal motor weakness in the upper and lower extremities with associated paresthesia and decreased reflexes in the lower extremities. The patient had slight ataxia and difficulty with heel walk and toe walk. Notably, the cranial nerve exam was normal, and the patient was afebrile. Intravenous immune globulin (IVIG) was started empirically for the treatment of Guillain-Barre syndrome (GBS), and doxycycline 100mg intravenous twice a day and ceftriaxone 2g intravenous daily were started for possible tick-borne disease. Subsequently, rapid plasma reagin (RPR) returned reactive at 1:64, and cerebral spinal fluid (CSF) venereal disease research laboratory (VDRL) test was reactive at 1:2 with markedly elevated protein and pleocytosis. Human immunodeficiency virus (HIV) testing was negative. Lyme disease testing was negative. Nerve conduction studies (NCS) and electromyography (EMG) showed a sensorimotor polyneuropathy with mixed demyelinating and axonal features. IVIG was continued for a total of five days, and antibiotics were changed to penicillin G (PCN G) for a total of 14 days for definitive treatment of early neurosyphilis (NS). While both clinical and laboratory findings confirm a positive diagnosis of NS, the patient's CSF composition showed very elevated total protein levels and pleocytosis. Additionally, his early peripheral neuropathy and EMG findings are not characteristics of a single disease and, instead, suggested a mixed pathology. We postulate that this patient had confirmed secondary syphilis with early NS associated with, and possibly correlated with, a simultaneous episode of acute inflammatory demyelinating polyneuropathy (AIDP) and/or a vaccine-related phenomenon.

A Tale of Two Twins: Discordant Presentation of COVID-19 in Identical Twins.

Coronavirus disease 2019 (COVID-19) is a highly contagious viral illness caused by the RNA virus Coronaviridae subtype severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Rapid infection caused by this virus became overwhelming and resulted in millions of deaths worldwide. The effects of smoking have been heavily studied and lead to increased occurrence of COVID-19 viral infections and mortality. The phenomenon of cytokine storm has been shown as one of the leading factors of mortality. However, the question remains as to what factors, either genetic or environmental, ultimately lead to the increased incidence of cytokine storms compared to others. We present a case of two cohabitating, 57-year-old, male, identical twins (Twin A and Twin B) who contracted SARS-CoV-2 simultaneously. Both Twin A and Twin B had similar medical histories, except for Twin A being a former smoker while Twin B a current smoker. While both twins presented with cough and shortness of breath, Twin A also presented with hypoxia, leukocytosis, evidence of acute kidney injury, and transaminitis while Twin B presented normoxic with solely tachycardia. Due to his presentation and vital signs, Twin B received Bamlanivimab but developed hypoxia during the infusion. Both twins were subsequently initiated on Remdesivir, dexamethasone, and supplemental oxygen daily. After completion of treatment courses, both twins had improvement in their laboratory values and were subsequently discharged with supplemental oxygen to be further weaned in the outpatient setting. Due to the twins' cohabitation, contracting SARS-CoV-2 simultaneously, and similar medical history, we highlight the potential mechanism of nicotine's chemical ability to blunt the subsequent inflammatory process of COVID-19. Despite nicotine's potential ability to dampen cytokine storms, smoking has well-documented adverse effects and we, like many experts, entirely discourage it. However, given the rare situation of identical twins contracting SARS-CoV-2, we can extrapolate information regarding the effects of the virus without obfuscation from genetic and environmental factors to identify areas of research for new therapies.

Cryptococcal Meningitis Reported With Fingolimod Treatment: Case Series.

BACKGROUND AND OBJECTIVES: To describe the characteristics of patients with MS reporting cryptococcal meningitis (CM) while treated with fingolimod. METHODS: The Novartis safety database was searched for cases with CM between January 26, 2006, and February 28, 2020. The reporting rate of CM was estimated based on the case reports received and exposure to fingolimod in the postmarketing setting during the relevant period. RESULTS: A total of 60 case reports of CM were identified, mostly from the United States. The median age was 48 years, and 51.8% were women. Most of the patients had recovered or were recovering at the time of final report. A fatal outcome occurred in 13 cases. During the study period, the rate of CM in patients with MS receiving fingolimod was estimated to be 8 per 100,000 patient-years (95% CI: 6.0; 10.0). The incidence of CM seemed to increase with duration of treatment; however, this relationship remains uncertain due to wide CIs and missing data. DISCUSSION: The causal relationship between fingolimod treatment and CM is not yet fully understood. The CM mortality rate in fingolimod-treated patients is similar to that reported in HIV-negative patients. Vigilance for signs and symptoms of CM in patients receiving fingolimod, particularly the new onset of headaches and altered mental status, is essential. Early diagnosis and treatment are critical to reducing CM-associated mortality.

Molluscum contagiosum in the setting of Fingolimod: The experience at one institution.

Fingolimod treatment has been associated with opportunistic infections, most notably PML and cryptococcal meningitis. There are rare reports of other infections like molluscum contagiosum which are typically associated with impaired cellular immunity as seen in AIDS. Upon review of our multiple sclerosis patient database, we identified eight patients undergoing fingolimod treatment who developed molluscum contagiosum infections. We suspect that this association is a class effect and may also be observed with other S1P receptor modulators. While molluscum contagiosum infection is not life-threatening, it can be extremely distressing for patients, and resolution may require discontinuation of fingolimod.

The elimination of circulating Epstein-Barr virus infected B cells underlies anti-CD20 monoclonal antibody activity in multiple sclerosis: A hypothesis.

Multiple sclerosis is a chronic immune-mediated disease of the central nervous system that has aspects of repetitive inflammatory activity as well as a slow neurodegenerative process. The immune assault on the nervous system is triggered by a complex interaction between immunogenetic and environmental factors. Among the different environmental factors, a compelling case, buttressed by strong epidemiological, serological and other data, has been made for the role of Epstein-Barr virus (EBV) in the pathogenesis of MS. However, the ubiquity of EBV, lack of a well understood role in MS pathogenesis, and controversies regarding its presence in brains of people with MS has caused debate as to how exactly it contributes to MS. Recent years have seen the remarkable effect of anti-CD20 therapies on the inflammatory component of MS. How B cell depletion results in a salutary effect in MS remains incompletely understood. It has been proposed that depletion of CD20+ B-cells disrupts other pro-inflammatory pathways in the immune system, especially T-cells. In this paper, we make the case that the robust effect of anti-CD20 therapies on MS activity could actually be from removal of circulating EBV-infected memory B-cells that drive CNS inflammation and not through other immune pathways - in essence that this is from an anti-viral effect, and not necessarily an immuno-modulatory effect.

Staphylococcus lugdunensis Urinary Tract Infection With Associated Neutropenic Fever.

We present a 62-year-old woman with a history of uterine cancer status post-total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) on paclitaxel, who presented to the emergency department febrile at 101.7 Fahrenheit and complaining of fatigue and urinary incontinence. Laboratory testing revealed neutropenia and urinalysis showed elevated bacteria with minimal white blood cells, and negative leukocyte and negative nitrites. Urine cultures ultimately showed Staphylococcus lugdunensis with negative blood cultures. S. lugdunensis is a less frequently speciated Staphylococcus and has been increasingly found due to advances in identification using matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). S. lugdunensis are Gram-positive cocci, nonsporulating, nonmotile, facultatively anaerobic, catalase-positive, coagulase-negative, oxidase-negative, delta-hemolytic organism. Traditionally, it is seen in skin and soft-tissue infections, as well as vascular infections, however, has minimal occurrences in urinary tract infections. The risk of infection is increased in immunocompromised states and empiric treatment is warranted while waiting for definitive results. Our patient was started on cefepime, valacyclovir, fluconazole, and a single dose of vancomycin while in the emergency department. Worsening thrombocytopenia during her antibiotic course necessitated the re-evaluation of antibiotic agents which can cause thrombocytopenia. Subsequently, due to the patient's improved clinical status, and low risk of severe outcome, fluconazole and valacyclovir were discontinued, and cefepime was changed to ceftriaxone.

Podcast on B Cell-Targeting Therapies and Other Multiple Sclerosis Concerns During COVID-19.

The ongoing coronavirus disease 2019 (COVID-19) pandemic continues to raise questions for people living with multiple sclerosis (MS) and their healthcare providers. Common questions have included whether people living with MS are at higher risk of COVID-19 or of severe disease, whether certain disease-modifying therapies (DMTs) for MS heighten COVID-19 risk, and if/how COVID-19 vaccinations should be administered in relation to MS treatments. Anti-CD20 therapies, which target B cells, have been of particular interest given the role B cells play in the response to both the virus that causes COVID-19 (SARS-CoV-2) and vaccines. As more data surfaces and the pandemic evolves, additional questions have emerged regarding the administration of booster shots and differences between B cell-targeting therapies and other DMTs in terms of their immunomodulatory effects. In this podcast article, MS specialists discuss these challenges to MS care during the COVID-19 pandemic and the recent data which are currently informing their clinical decision-making. As the pandemic evolves, providers should continually partner with people living with MS to achieve MS treatment goals informed by the latest developments in COVID-19. Video: Podcast Video (MP4 388175 KB).

Gastrointestinal pathologic findings of teriflunomide associated diarrhea.

BACKGROUND: Diarrhea is generally a benign and self-limited adverse effect of teriflunomide. Small intestinal pathology has yet to be described with teriflunomide associated diarrhea. OBJECTIVE: To report small intestinal pathology in teriflunomide associated diarrhea. METHODS: Small intestinal and colonic biopsies were obtained from a patient with teriflunomide associated diarrhea. RESULTS: Small intestinal biopsy demonstrated blunting of villi, increased intraepithelial lymphocytes and expansion of lamina propria. Gliadin and t-transglutaminase antibodies were negative. Diarrhea resolved following elimination of teriflunomide with cholestyramine. CONCLUSION: This is the first reported case of small intestinal inflammation similar to celiac disease in teriflunomide associated diarrhea.