Management of Paraneoplastic Syndromes in the Era of Immune Checkpoint Inhibitors.

OPINION STATEMENT: Our understanding of paraneoplastic neurologic syndromes (PNS) has blossomed over the past few decades. Clinicians have access to more robust diagnostic criteria and have a heightened index of suspicion for these disorders. Nonetheless, treatment, which typically includes immunosuppression, and response to treatment, varies. Due to persistent difficulty in making a definitive diagnosis, we favor empiric treatment when a possible diagnosis of PNS is suspected, and other alternative causes have substantially been excluded (e.g., infections, toxic-metabolic derangements, metastasis, or leptomeningeal disease). Treatment of the underlying cancer, if identified, is the first therapeutic step and can prevent disease worsening and in rare cases, can reverse neurologic symptoms. In addition to anti-cancer treatment, first line immunotherapies, which include corticosteroids, intravenous immunoglobulins (IVIG), or plasma exchange (PLEX) are typically used. If partial or no benefit is seen, second line immunotherapeutic agents such as rituximab are considered. Additionally, the severity of the initial presentation and possible risk for relapse influences the use of the latter agents. Symptomatic management is also an important component in our practice and will depend on the syndrome being treated. One of the more novel entities we are facing currently is the management of immune checkpoint (ICI)-induced PNS. In those cases, current American Society of Clinical Oncology (ASCO) guidelines are followed.

GFAP astrocytopathy presenting with profound intracranial hypertension and vision loss.

BACKGROUND: Glial fibrillary acidic protein (GFAP) astrocytopathy is a steroid-responsive autoimmune meningoencephalomyelitis commonly preceded by a viral illness. It is clinically characterized by encephalopathy, myelopathy and papillitis without significant effect on visual acuity. It can be associated with an underlying malignancy or autoimmune condition. OBJECTIVE: To report a novel case of GFAP astrocytopathy presenting with profound intracranial hypertension and bilateral vision loss. METHODS: Case report. RESULTS AND CONCLUSION: GFAP astrocytopathy should be considered when evaluating patients with intracranial hypertension or bilateral vision loss, particularly when other features of autoimmune encephalitis are present.

Difficult Discharges to Skilled Nursing Facilities Attributed to Multiple Sclerosis Medications: An Observational Study.

BACKGROUND: The costs of multiple sclerosis (MS) disease-modifying therapies (DMTs) and certain symptomatic treatments (ie, dalfampridine [DFP]) are high. Consolidated billing models require that medication costs be covered by skilled nursing facilities (SNFs) after hospitalization. As a result, patients may experience suboptimal discharge, off of medication or without rehabilitation. METHODS: To characterize the frequency with which MS pharmaceutical costs lead to suboptimal discharge, we performed a retrospective chart review of admissions to a large academic medical center from January 2013 to December 2017 among patients with MS on DMT and/or DFP with SNF rehabilitation recommendations. We quantified the burden of suboptimal discharge due to medication discontinuation, limited medication supplies, or forgone rehabilitation. RESULTS: Among 169 admissions of patients with MS with discharge recommendations for SNF rehabilitation, there were 57 (33.7%) admissions across 49 patients with MS on DMT/DFP. Overall, 39 (68%) of 57 admissions (71% of patients) experienced a suboptimal discharge. Overall, 29 (65%) discontinued DMT/DFP, 9 (16%) took their remaining home supply of medications during rehabilitation (including 5 admissions also affected by a discontinuation), and 6 (11%) were discharged home to remain on DMT. Among those discharged to rehabilitation, discharge to a hospital-owned SNF was associated with a routine discharge with no lapse in medication (n = 11/15 vs 7/36, P < .001). CONCLUSIONS: High costs of MS medications in conjunction with SNF consolidated payment models result in misaligned incentives and often lead to medication discontinuation or other suboptimal discharge for patients with MS.

The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies.

Alemtuzumab was designed to reduce the immunogenicity of the parent CD52-specific rat immunoglobulin. Although originally marketed for use in cancer (Mabcampath®), alemtuzumab is currently licensed and formulated for the treatment of relapsing multiple sclerosis (Lemtrada®). Perhaps due to its history as the first humanized antibody, the potential of immunogenicity of the molecule has been considered inconsequential, and anti-drug antibodies (ADA) responses were similarly reported as being clinically insignificant. Nonetheless, despite humanization and depletion of peripheral T and B cells, alemtuzumab probably generates the highest frequency of binding and neutralizing ADA of all humanized antibodies currently in clinical use, and they occur rapidly in a large majority of people with MS (pwMS) on alemtuzumab treatment. These ADA appear to be an inherent issue of the biology of the molecule-and more importantly, the target-such that avoidance of immunogenicity-related effects has been facilitated by the dosing schedule used in clinical practice. At the population level this enables the drug to work in most pwMS, but in some individuals, as we show here, antibody neutralization appears to be sufficiently severe to reduce efficacy and allow disease breakthrough. It is therefore imperative that efficacy of lymphocyte depletion and the anti-drug response is monitored in people requiring additional cycles of treatment, notably following disease breakthrough. This may help inform whether to re-treat or to switch to another disease-modifying treatment.

Initiation of rituximab therapy for new onset neuromyelitis optica spectrum disorder during pregnancy.

BACKGROUND: Aquaporin-4 IgG (AQ4-IgG)-neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory CNS disease that is predominantly characterized by severe relapses of optic neuritis and longitudinally extensive transverse myelitis (LETM). Women are disproportionately affected by AQ4-NMOSD, usually with disease onset occurring between the ages of 35-45. This has significant implications during pregnancy, as disease activity in NMOSD does not remit during gestation. The optimal treatment of NMOSD during pregnancy has not been established. METHODS: Case report. RESULTS: A 35-year old woman, 10 weeks pregnant, presented with bilateral optic neuritis and intractable hiccups. Workup revealed seropositive aquaporin-4 IgG. She was treated with pulse intravenous methylprednisolone and plasma exchange. Because of high risk for future relapse, Rituximab 1000 mg was given at weeks 15 and 17 of pregnancy. She had no further relapses during pregnancy. She delivered her daughter at 39 weeks without complication. CONCLUSION: This case demonstrated a favorable outcome in administering rituximab for NMOSD with disease onset during pregnancy. This description of therapy for disease onset during pregnancy is novel, and adds to the few existing case reports of administering rituximab during pregnancy.

Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial.

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS. METHODS: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation. RESULTS: VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment-related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer ≥100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations ≤0.3 µg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for ≥155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance. CONCLUSIONS: These results support the continued investigation of VX15/2503 in neurodegenerative diseases. CLINICALTRIALSGOV IDENTIFIER: NCT01764737. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that anti-semaphorin 4D antibody VX15/2503 at various doses was safe and well tolerated vs placebo, although an increase in treatment-emergent adverse events in the treatment group could not be excluded (risk difference -0.7%, 95% CI -28.0% to 32.7%).

Symptomatic management in multiple sclerosis.

The development of immunomodulatory therapies for multiple sclerosis (MS) has had significant impact in altering the natural history of the disease. Although these agents reduce relapse rate and MRI-associated disease activity, they are only partially effective and do not ameliorate irreversible axonal injury, which produces much of the symptomatic burden of MS. Treatment of MS-associated symptoms remains an essential cornerstone of comprehensive care of patients with MS and, arguably, more favorably enhances quality of life than do the disease-modifying medications. This article reviews strategies of symptom management in patients with MS.