Background

Acute disseminated encephalomyelitis (ADEM) is an autoimmune demyelinating syndrome of the central nervous system (CNS) usually following a febrile illness. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is predominantly a respiratory infection with rare direct neurologic involvement. Although neurological symptoms are increasingly reported, it is unclear if these represent a para-infectious or post-infectious manifestation of SARS-CoV-2. We report the first case to our knowledge of pediatric ADEM associated with SARS-CoV-2.

Objectives

We present a case of a 5 year-old boy with ADEM in the setting of SARS-CoV with histopathology showing meningoencephalitis.

Methods

Case report featuring clinical presentation, laboratory, neuroimaging, and histopathology results, and medical decision-making, treatment, and clinical course.

Results

A 5-year-old previously healthy Hispanic boy presented with 3 weeks of headache, right eye blurry vision, and vomiting. Infectious work-up was negative except for SARS-CoV-2 RNA PCR. MRI brain demonstrated multifocal lesions with intense enhancement and diffusion restriction, most prominent in the right frontal lobe, basal ganglia, and cerebellum with vasogenic edema and punctate foci of hemorrhage as well as bilateral swelling of optic nerves and optic chiasm. MRI spine revealed longitudinally extensive myelitis with an intensely enhancing, expansile intramedullary lesion from T1 to T3.

Differential diagnosis included infectious and inflammatory etiologies leading to a brain biopsy which showed foci of lymphohistiocytic perivascular inflammation (predominantly CD3+ T-cells and CD68+ histiocytes, with rare CD20+ B-cells) consistent with meningoencephalitis. There were features suggestive of, but not definitive for demyelination, including occasional macrophages with staining indicating ingestion of myelin breakdown products. No definite viral inclusions were identified by light or electron microscopy.

Neurology was consulted, noting that he was very irritable with decreased upper extremity movements. Based on his clinical syndrome and imaging, ADEM was suspected and started on high dose IV methylprednisolone. Cerebrospinal fluid showed 9 nucleated cells/mm3 (97% lymphocytes), 44 mg/dL protein, 77 mg/dL glucose, enterovirus and herpes simplex virus PCR negative. Due to brain, optic nerve, and spinal cord involvement, MOG related ADEM is suspected (test pending) and PLEX was also initiated.

Conclusions

We report the first case to our knowledge of ADEM in a child in the setting of SARS-CoV2 with histopathology showing meningoencephalitis. Based on his brain, optic nerve, and spinal cord involvement, MOG antibody disease is suspected, presumably triggered by SARS-CoV2 infection rather than resulting from SARS-CoV2 infection itself. Additional studies are needed to further characterize the direct and indirect neurological sequelae of SARS-CoV2.

Background

Anti-CD20 monoclonal antibody (mAb) therapies have shown a marked reduction in multiple sclerosis (MS) inflammatory activity by selectively depleting B lymphocytes. Rituximab is a chimeric mAb whereas ocrelizumab is fully humanized. Clinical trial efficacy and safety data suggest a favorable benefit-to-risk profile. However, there is a paucity of literature on comparative real-world safety profile of rituximab and ocrelizumab.

Objectives

To investigate the adverse events (AEs) associated with rituximab and ocrelizumab reported to the Food and Drug Administration adverse event (AE) Reporting System (FAERS) database.

Methods

The FAERS database query was filtered by reason for use (MS) and suspected active component (rituximab or ocrelizumab). In order to identify drug-AE associations, disproportionality analyses including but not limited to reporting odds ratio (ROR) were conducted. A signal was detected if the lower limit of the 95% two-sided confidence interval of ROR (ROR₀₂₅) exceeded 1.

Results

There were 623 and 7,948 reports for rituximab and ocrelizumab, respectively. The most frequently reported AEs with rituximab and ocrelizumab were infusion related reactions (4.82%) and urinary tract infections (10.52%), respectively. The strongest drug-AE association for rituximab and ocrelizumab were ear pruritus (ROR25 47.53) and oral herpes (ROR₀₂₅ 38.99), respectively. When classified by AE class, ocrelizumab was associated with a nearly two-times higher frequency of infections than rituximab (21.93% vs 11.05%, respectively).

Conclusions

This study revealed notable differences between rituximab and ocrelizumab. Specifically, infections were reported more frequently with ocrelizumab. A potentially more robust B cell depletion by ocrelizumab leading to more profound immunosuppression could explain these findings. Additional studies are needed to further investigate these differences.

Background

Dimethyl fumarate (DMF) is an oral disease-modifying therapy (DMT) that was approved by the FDA to treat relapsing-remitting multiple sclerosis in 2013. Since then, several studies evaluating the safety of this medication have revealed a favorable risk-benefit ratio. The most common adverse events (AEs) are flushing and gastrointestinal symptoms such as nausea or diarrhea. However, there are other less common AE that can potentially be harmful, including persistent lymphopenia. On average, 2.4-7% of the patients on DMF develop grade III lymphopenia (defined as absolute lymphocyte count (ALC) <0.5 × 109 cells/L). In most cases, ALCs reconstitute within weeks to months after discontinuation of DMF.

Objectives

Understanding the AE profile of a medication is important in order to ensure patient safety and provide the most appropriate care.

Methods

Here we report three cases of RRMS presenting with severe persistent lymphopenia of at least one-year duration after DMF discontinuation.

Results

One of the patients continues to have severe lymphopenia 4 years after cessation of DMF. No other anti-proliferative agents were administered to these individuals.

Conclusions

The most important risk factors for developing lymphopenia are increased age, lower baseline ALC, and previous treatment with natalizumab. There are has been a report of 38 cases of severe, prolonged lymphopenia after DMF discontinuation. However, the majority of these patients had grade III lymphopenia persisting for ≥6 months by 3 years on DMF treatment, yet treatment continued for a median of 2.9 years. The unique characteristic of our three patients is that DMF treatment duration was <2 years before grade III lymphopenia onset and despite discontinuation of DMF within 1-year of severe lymphopenia onset, their ALCs didn’t recover. To date, they continue to have severe lymphopenia. This clinical experience highlights the importance of considering lymphopenia as a possible AE prior to starting DMF. Furthermore, it also emphasizes the need to establish protocols to manage DMF induced lymphopenia, especially in situations that require immune-competence for.

Background

Anti-CD20 monoclonal antibody (mAb) therapies have shown a marked reduction in multiple sclerosis (MS) inflammatory activity by selectively depleting B lymphocytes. Rituximab is a chimeric mAb whereas ocrelizumab is fully humanized. Clinical trial efficacy and safety data suggest a favorable benefit-to-risk profile. However, there is a paucity of literature on comparative real-world safety profile of rituximab and ocrelizumab.

Objectives

To investigate the adverse events (AEs) associated with rituximab and ocrelizumab reported to the Food and Drug Administration adverse event (AE) Reporting System (FAERS) database.

Methods

The FAERS database query was filtered by reason for use (MS) and suspected active component (rituximab or ocrelizumab). In order to identify drug-AE associations, disproportionality analyses including but not limited to reporting odds ratio (ROR) were conducted. A signal was detected if the lower limit of the 95% two-sided confidence interval of ROR (ROR₀₂₅) exceeded 1.

Results

There were 623 and 7,948 reports for rituximab and ocrelizumab, respectively. The most frequently reported AEs with rituximab and ocrelizumab were infusion related reactions (4.82%) and urinary tract infections (10.52%), respectively. The strongest drug-AE association for rituximab and ocrelizumab were ear pruritus (ROR25 47.53) and oral herpes (ROR₀₂₅ 38.99), respectively. When classified by AE class, ocrelizumab was associated with a nearly two-times higher frequency of infections than rituximab (21.93% vs 11.05%, respectively).

Conclusions

This study revealed notable differences between rituximab and ocrelizumab. Specifically, infections were reported more frequently with ocrelizumab. A potentially more robust B cell depletion by ocrelizumab leading to more profound immunosuppression could explain these findings. Additional studies are needed to further investigate these differences.

Background

Dimethyl fumarate (DMF) is an oral disease-modifying therapy (DMT) that was approved by the FDA to treat relapsing-remitting multiple sclerosis in 2013. Since then, several studies evaluating the safety of this medication have revealed a favorable risk-benefit ratio. The most common adverse events (AEs) are flushing and gastrointestinal symptoms such as nausea or diarrhea. However, there are other less common AE that can potentially be harmful, including persistent lymphopenia. On average, 2.4-7% of the patients on DMF develop grade III lymphopenia (defined as absolute lymphocyte count (ALC) <0.5 × 109 cells/L). In most cases, ALCs reconstitute within weeks to months after discontinuation of DMF.

Objectives

Understanding the AE profile of a medication is important in order to ensure patient safety and provide the most appropriate care.

Methods

Here we report three cases of RRMS presenting with severe persistent lymphopenia of at least one-year duration after DMF discontinuation.

Results

One of the patients continues to have severe lymphopenia 4 years after cessation of DMF. No other anti-proliferative agents were administered to these individuals.

Conclusions

The most important risk factors for developing lymphopenia are increased age, lower baseline ALC, and previous treatment with natalizumab. There are has been a report of 38 cases of severe, prolonged lymphopenia after DMF discontinuation. However, the majority of these patients had grade III lymphopenia persisting for ≥6 months by 3 years on DMF treatment, yet treatment continued for a median of 2.9 years. The unique characteristic of our three patients is that DMF treatment duration was <2 years before grade III lymphopenia onset and despite discontinuation of DMF within 1-year of severe lymphopenia onset, their ALCs didn’t recover. To date, they continue to have severe lymphopenia. This clinical experience highlights the importance of considering lymphopenia as a possible AE prior to starting DMF. Furthermore, it also emphasizes the need to establish protocols to manage DMF induced lymphopenia, especially in situations that require immune-competence for.