Presentation and Outcome in S1P-RM and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: A Multicenter Cohort Study.

BACKGROUND AND OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) is a severe neurologic disease resulting from JC virus reactivation in immunocompromised patients. Certain multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with PML risk, such as natalizumab and, more rarely, sphingosine-1-phosphate receptor modulators (S1P-RMs). Although natalizumab-associated PML is well documented, information on S1P-RM-associated PML is limited. The aim of this study is to compare clinical presentations and outcomes between the 2 groups. METHODS: A retrospective multicenter cohort study included patients with PML from 2009 to 2022 treated with S1P-RMs or natalizumab. Data on clinical and radiologic presentation, outcomes, immune reconstitution inflammatory syndrome (IRIS), survival, disability (using the modified Ranking scale-mRS), and MS relapses post-PML were analyzed. RESULTS: Of 88 patients, 84 were analyzed (20 S1P-RM, 64 natalizumab). S1P-RM-associated PML was diagnosed in older patients (median age 52 vs 44 years, p < 0.001) and after longer treatment duration (median 63.9 vs 40 months, p < 0.001). Similarly, S1P-RM patients were more prone to show symptoms at diagnosis (100 vs 80.6%, p = 0.035), had more disseminated lesions (80% vs 34.9%, p = 0.002), and had higher gadolinium enhancement (65% vs 39.1%, p = 0.042). Natalizumab patients had a higher IRIS development rate (OR: 8.3 [1.92-33.3]). Overall, the outcome (mRS) at 12 months was similar in the 2 groups (OR: 0.81 [0.32-2.0]). Yet, post-treatment MS activity was higher in S1P-RM cases (OR: 5.7 [1.4-22.2]). DISCUSSION: S1P-RM-associated PML shows reduced IRIS risk but higher post-treatment MS activity. Clinicians should tailor post-PML treatment based on pre-PML medication.

Teaching NeuroImage: Cryptococcus in a Woman With Multiple Sclerosis on Fingolimod.

A 33-year-old woman with relapsing remitting multiple sclerosis who was on fingolimod for 5 years presented with a solitary skin lesion on her abdomen (Figure 1) for 2 months, which was unresponsive to antibiotics. The neurologic examination was normal. She denied having infectious symptoms, chest pain, shortness of breath, recent travel, trauma to the area, or animal exposure. Her most recent absolute lymphocyte count was 0.22 × 109/L (reference 1.2-4.0 109/L). The differential diagnosis included skinfold friction, dermatofibroma, pyoderma gangrenosum, and basal cell carcinoma. Although a dermatologist did not initially recommend a biopsy because the lesion was not ulcerated, she obtained one based on the recommendation of her neurologist. Shave biopsy revealed cryptococcal fungal infection (Figure 2). There was no evidence of asymptomatic disseminated cryptococcus. The proposed mechanism for the lesion involves a latent infection while immunocompetent with reactivation once immunocompromised.1 Cryptococcus infections are associated with immunosuppression, most often due to human immunodeficiency virus infection, and only 6 fingolimod-associated cutaneous infections have been reported in the literature.2 Patients with MS on immunosuppressant medication should be carefully screened for cutaneous infections.

Patient-reported outcomes based on discontinuation or continuous treatment with natalizumab: New York State Multiple Sclerosis Consortium (NYSMSC) study.

BACKGROUND: Patient-reported outcomes (PRO) are increasingly utilized as part of the routine clinical assessment in people with multiple sclerosis (pwMS). The long-term effect of disease modifying therapies (DMTs) and their discontinuation on PRO measures remains largely unknown. METHODS: Two pwMS groups treated with natalizumab were selected from the New York State MS Consortium (NYSMSC) database. The first group utilized long-term follow-up data of pwMS that either still continue natalizumab treatment or discontinued. Minimal requirement of three visits (before natalizumab initiation, during treatment and after discontinuation/latest follow-up) was implemented. The second group consisted of pwMS that completed PRO questionnaire on the day of the infusion and 7 days later PROs were assessed using the LIFEware System™ that assesses limitations in multiple physical and psychosocial domains. Additional physical disability was assessed using Expanded Disability Status Scale (EDSS) and Timed 25-ft walk test (T25FWT). PRO reports were Rasch-transformed, ranging from 0 to 100, with higher scores indicating a better outcome. Linear mixed-effect models and paired analyses were utilized. RESULTS: Within the prospective cohort, 242 pwMS were followed on average of 6.5 years. Greater number of PRO domains worsened in the 141 pwMS that discontinued natalizumab when compared to 101 pwMS that remained on the drug (10 vs. 2 PRO domains). PwMS that discontinued natalizumab had significant decline in PROs regarding lower extremities, bladder and bower control and psychosocial aspects (feeling lonesome). Contrarily, pwMS that continued natalizumab had significant improvement in bladder and bowel PRO measures. Seven days after the natalizumab infusion, the 67 pwMS from the prospective cohort reported improvement in PRO measures of fatigue (62.8 vs. 66.4, p = 0.019), bladder limitations (80.3 vs. 85.0, p = 0.012), and feelings of lonesomeness (81.2 vs. 88.0, p = 0.009). CONCLUSION: Continuous natalizumab treatment provides long-term stability or improvement in PRO measures. Natalizumab also provides short term improvements recorded after the infusion.

Vaginal Herpes Zoster While Under Treatment for Relapsing-Remitting Multiple Sclerosis With Diroximel Fumarate.

Multiple sclerosis (MS) is an autoimmune demyelinating disorder that disproportionately affects middle-aged women, and is capable of resulting in severe disability. However, the use of disease-modifying therapies has profoundly contributed to the improvement in the morbidity of the disorder. Diroximel fumarate (DRF) is a second-generation drug that has seen success in the treatment of relapsing-remitting MS (RRMS). While its relatively mild side effects of gastrointestinal discomfort are known, the less common complications are often missed in clinical settings. This includes a resulting susceptibility to opportunistic infections. In this case report, we describe a patient who experienced lymphopenia, recurrent yeast infections, and labial shingles while on the medication. This case highlights the side effects and the rare complications of the immunomodulator, DRF.

Magnetic Resonance Imaging-Negative Varicella Zoster Virus Plexopathy in a Young Patient: A Case Report.

Varicella zoster virus (VZV)-associated plexopathy mainly occurs in patients over 60 years old. Postherpetic neuralgia is a well-known complication of herpes zoster (HZ); however, segmental zoster paresis secondary to HZ was reported in 1-20% of cases in the literature. Magnetic resonance imaging (MRI) findings may be positive in up to 70% of the patients. We describe a 43-year-old male patient with a history of grade two left frontal oligodendroglioma, which was treated with two partial resections, radiation treatment and procarbazine/lomustine, who presented with left upper extremity pain and developed a blistering rash in a dermatomal pattern in the left proximal upper extremity two weeks after the initial symptoms. He was diagnosed with shingles and treated with steroids and acyclovir with minimal improvement. Six weeks after the initial symptoms, a physical exam revealed left deltoid, supraspinatus and infraspinatus weakness with normal muscle stretch reflexes and decreased sensation on the C5 dermatome. Electromyography (EMG) revealed absent left lateral antebrachial cutaneous sensory nerve action potentials (SNAP) amplitude and a small left radial SNAP amplitude compared to the right side. Evidence of ongoing denervation with reinnervation was seen in the left upper trunk-supplied muscles. MRI of the brachial plexus was negative for any abnormalities. The patient was diagnosed with VZV-associated plexopathy, which improved with pregabalin and physical therapy. Our patient was significantly younger than expected in the HZ group. MRI usually shows T2 hyperintensities and thickening of the nerve roots in patients with VZV-associated plexopathy. However, the presentation, onset of symptoms, characteristics of the rash, and clinical course were diagnostic of HZ, and the weakness pattern, supported by the EMG findings, was diagnostic of VZV-associated plexopathy.

Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics.

Axonal damage is a prominent cause of disability and yet its pathogenesis is incompletely understood. Using a xenogeneic system, here we define the bioenergetic changes induced in rat neurons by exposure to cerebrospinal fluid samples from patients with multiple sclerosis compared to control subjects. A first discovery cohort of cerebrospinal fluid from 13 patients with multiple sclerosis and 10 control subjects showed that acute exposure to cerebrospinal fluid from patients with multiple sclerosis induced oxidative stress and decreased expression of neuroprotective genes, while increasing expression of genes involved in lipid signalling and in the response to oxidative stress. Protracted exposure of neurons to stress led to neurotoxicity and bioenergetics failure after cerebrospinal fluid exposure and positively correlated with the levels of neurofilament light chain. These findings were validated using a second independent cohort of cerebrospinal fluid samples (eight patients with multiple sclerosis and eight control subjects), collected at a different centre. The toxic effect of cerebrospinal fluid on neurons was not attributable to differences in IgG content, glucose, lactate or glutamate levels or differences in cytokine levels. A lipidomic profiling approach led to the identification of increased levels of ceramide C16:0 and C24:0 in the cerebrospinal fluid from patients with multiple sclerosis. Exposure of cultured neurons to micelles composed of these ceramide species was sufficient to recapitulate the bioenergetic dysfunction and oxidative damage induced by exposure to cerebrospinal fluid from patients with multiple sclerosis. Therefore, our data suggest that C16:0 and C24:0 ceramides are enriched in the cerebrospinal fluid of patients with multiple sclerosis and are sufficient to induce neuronal mitochondrial dysfunction and axonal damage.

Interferon beta and glatiramer acetate therapy.

Interferon beta and glatiramer acetate have been mainstays of treatment in relapsingremitting multiple sclerosis for two decades. Remarkable advances in our understanding of immune function and dysfunction as well as increasingly sophisticated clinical trial design have stemmed from efforts to better understand these drugs. In this chapter, we review the history of their development and elaborate on known and theorized mechanisms of action. We describe the pivotal clinical trials that have led to their widespread use. We evaluate the clinical use of the drugs including tolerability, side effects, and efficacy measures. Finally, we look to the future of interferon beta and glatiramer acetate in the context of an ever growing armamentarium of treatments for relapsing remitting multiple sclerosis.