Natalizumab concentrations during pregnancy in three patients with multiple sclerosis

In women with very active multiple sclerosis (MS), natalizumab can be continued during pregnancy to prevent rebound disease activity. Our aim was to evaluate changes in serum natalizumab trough concentrations during pregnancy. Blood samples of 3 patients were collected before, during, and after pregnancy. Natalizumab trough concentrations gradually decreased during pregnancy. The patient with the lowest trough concentrations during the third trimester was treated with extended interval dosing (EID). After delivery, natalizumab concentrations increased to similar levels as before pregnancy. All patients remained clinically and radiologically stable. MS neurologists should be aware of decreasing natalizumab concentrations during pregnancy, especially in patients with low initial trough concentrations and patients with EID.

Highly Active Multiple Sclerosis

A 16-year-old girl was evaluated for symptoms of thoracic myelitis with sensory loss below T12, gait difficulty, constipation, and incomplete bladder emptying. On evaluation, she had a flat affect, normal cranial nerve function, and normal motor examination findings. Deep tendon reflexes were symmetric, and plantar responses were flexor. She had a sensory level at T12 with diminished vibratory sense distal to the knees and normal coordination and gait. Magnetic resonance imaging of the brain, cervical spine, and thoracic spine showed a high burden of disease, with multiple enhancing lesions indicative of highly active disease. Spinal fluid analysis showed 16 white blood cells/µL with 95% lymphocytes; protein, 70 mg/dL; 7 unique oligoclonal bands; and immunoglobulin G index, 0.87. Neurocognitive testing showed normal scores overall, and psychiatric evaluation indicated major depressive disorder. She was given a diagnosis of relapsing-remitting multiple sclerosis, highly active. On initial evaluation for thoracic myelitis, intravenous methylprednisolone was given, with resolution of bladder and bowel symptoms and 75% recovery of sensory loss. High-dose interferon beta-1a was then initiated. At age 28 years, she had worsening left hemiparesis of 1 month’s duration. Neurologic examination showed word-finding difficulty, gaze-evoked horizontal nystagmus, moderate left-sided spastic hemiparesis in a pyramidal distribution, brisk reflexes with an extensor plantar response on the left, sensory ataxia in the left leg, and a hemiparetic gait. Intravenous methylprednisolone was given, with minimal improvement. She then received plasmapheresis with about 50% recovery of power. The patient was seropositive for antibodies to JC polyoma virus. Despite the increased risk of progressive multifocal leukoencephalopathy, natalizumab was reinitiated considering the even higher risk of long-term disability due to continued active disease (highly active multiple sclerosis). Her therapy was transitioned to teriflunomide. Six months later she returned with new right leg weakness and received high-dose intravenous corticosteroids for 5 days, followed by rituximab infusion. On follow-up neuroimaging, breakthrough disease activity was noted, and her therapy was switched to alemtuzumab. Highly active multiple sclerosis is characterized by frequent clinical episodes, with or without high disease activity on neuroimaging as evidenced by multiple enhancing lesions or interval new lesion formation, and disability accrual. It includes a spectrum of patients with clinical and radiologic evidence of ongoing disease activity who have no response to adequate treatment with multiple sclerosis disease-modifying therapy.

Potential of PINK1 and PARKIN Proteins as Biomarkers for Active Multiple Sclerosis: A Japanese Cohort Study

BackgroundMitochondrial dysfunction has been suggested to play an important role in all stages of multiple sclerosis (MS).ObjectiveTo determine the expression of two mitophagy-related proteins, PTEN-induced kinase 1 (PINK1) and PARKIN, in a cohort of Japanese patients with different neuroinflammatory disorders.MethodsProtein concentrations were measured using commercial ELISA in paired cerebrospinal fluid (CSF) and serum samples from patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody disorders (MOGAD), and from age- and sex-matched controls.ResultsCSF and serum concentrations of PINK1 were higher in patients with MS than in patients with NMOSD (p = 0.004 and p < 0.001, respectively), MOGAD (p = 0.008 and p = 0.011, respectively), and controls (p = 0.021 and p = 0.002, respectively). CSF and concentrations of PARKIN were elevated in patients with MS in comparison with those in controls (p = 0.016 and p = 0.05, respectively).ConclusionsOur study highlighted the importance of mitophagy in MS and suggested the potential application of PINK1 and PARKIN as biomarkers to predict disease activity.

Possible progressive multifocal leukoencephalopathy and active multiple sclerosis under dimethyl fumarate: the central role of MRI in informing therapeutic decisions

Background Progressive multifocal leukoencephalopathy (PML) can rarely occur in Multiple Sclerosis (MS) patients undergoing dimethyl fumarate (DMF) treatment. Our case stresses the limits of current diagnostic and stratification risk criteria, highlighting the potential role of Magnetic Resonance Imaging (MRI) in advising clinical choices. Case presentation A 54 years old MS male patient treated with DMF, after 3 years of clinical stability developed a subacute clinical worsening. He had no severe lymphopenia but MRI signs suggestive of a coexistence of PML and MS activity. Although his viral title was negative, DMF was discontinued, with clinical and radiological improvement. Conclusions This case highlights the challenges behind PML diagnosis, especially in patients not fulfilling the risk stratification criteria and that might present with concurrent disease activity, stressing the potential role of MRI in informing therapeutic decisions.