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Objective: To characterize EEG findings in anti-NMDAR encephalitis patients looking for the proportion of EEGs that were abnormal, presence of extreme delta brush (EDB), and to relate EEG findings to clinical outcomes (Glasgow Outcome Scale (GOS) at 6 months, need for ICU admission, and death).Methods: This retrospective cohort single center study included patients with anti-NMDAR encephalitis who had ≥1 EEGs obtained from 2014 to 2021. EEGs were retrospectively analyzed by 2 reviewers. Clinical outcomes of interest were extracted through hospital and clinic chart review.Results: Twenty-one patients with anti-NMDAR encephalitis were included. Sixty-four EEGs were analyzed. Four EEGs (6.3%) were within normal limits. Focal or generalized slowing (without EDB) was seen on 44 EEGs (68.8%). EDB was seen on 16 EEGs (25.0%) in 9 of 21 patients (42.9%). The presence of EDB was significantly associated with need for ICU admission (p = 0.02), poorer outcome at 6 months as per the GOS (p = 0.002), and with death (p=0.02). EDB was present on ≥1 EEG of every patient who died.Conclusions: The presence of EDB on EEG in anti-NMDAR encephalitis patients is associated with increased need for ICU admission, worse functional outcomes at 6 months, and risk of death.

A 51-year-old man had a 4-month history of back pain and progressive leg weakness. The back pain was on the left side, radiating down his left buttock and leg to the dorsum of the foot. He had gradually developed bilateral leg weakness with a right foot drop such that he required a four-wheeled walker. There was accompanying left anterior thigh numbness and saddle anaesthesia, together with urinary urgency and one episode of faecal incontinence. He had been previously well, though 13 years before had sustained a non-specific back injury in a motor vehicle collision that did not require surgical intervention. On examination, there were lower limb hyperreflexia, patchy sensory loss in all modalities in both legs, a positive Beevor’s sign (upward movement of the umbilicus with attempted neck flexion due to weakness of the lower rectus abdominis)1 and absent rectal tone. Muscle strength was normal in the upper limbs, but 2/5 bilaterally in hip flexion, 4/5 bilaterally in knee flexion and extension, and 4–/5 …

This primer summarizes the diagnosis, treatment, complications, and prognosis of anti-N-methyl-d-aspartate receptor encephalitis for healthcare professionals, especially those in acute care specialities. Anti-N-methyl-d-aspartate receptor encephalitis is an immune-mediated encephalitis that is classically paraneoplastic and associated with ovarian teratomas in young women. Other less common neoplastic triggers include testicular cancers, Hodgkin lymphoma, lung and breast cancers. It may also be triggered by infection, occurring as a para-infectious phenomenon, seen most commonly after herpes simplex-1 encephalitis. Presentation varies but typically consists of behavioural and cognitive manifestations, seizures, dysautonomia, movement disorders, central hypoventilation, and coma, necessitating intensive care unit admission. Diagnosis of anti-N-methyl-d-aspartate receptor encephalitis requires high clinical suspicion plus ancillary testing, the most sensitive being cerebrospinal fluid analysis for anti-N-methyl-d-aspartate receptor antibodies. Imaging in search of an ovarian teratoma should be exhaustive and tumours need to be surgically treated. Treatment should be expeditious with pulsed steroids and either plasma exchange or intravenous immunoglobulin. Second-line treatments include intravenous rituximab, cyclophosphamide, azathioprine, and intrathecal methotrexate. Most patients recover to be functionally independent, but the in-hospital course can be months long followed by extensive rehabilitation. Given the lengthy course of illness, we explain why education and debriefing are important for staff, and where families can obtain additional help.

Background Susceptibility weighted imaging (SWI) has detected veins in the center of white matter lesions and alterations in veins themselves in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, the relationship between SWI-detected venous alterations and disease progression is unclear. The objective of this study was to assess alterations in the lumbar spinal cord veins in EAE mice over the disease course using serial SWI. Methods EAE mice (n = 8) underwent imaging for SWI using a 9.4T Bruker Avance console at baseline, 7 days (pre-motor dysfunction), 12 days (typical motor dysfunction onset), and 16–18 days (typical peak disease) post-immunization. Naive controls were imaged alongside EAE mice (n = 3). SWI hypointensities were counted by two subjects and compared between time points. Results SWI hypointensities appeared before motor dysfunction onset in most EAE mice. The ratio of SWI hypointensities to baseline was highly variable for EAE mice (0.45–6.75) while less so for controls (0.80–1.31). The time point for the maximum number of SWI hypointensities always preceded or coincided with maximum motor disability. Conclusion Venous alterations are detected before the onset of motor disability in some EAE mice using SWI which may relate to inflammation and/or tissue hypoxia.

Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma with few cases reported. Here, we describe the case of a patient with clinical presentation, imaging, and biopsy in keeping with aggressive multiple sclerosis (MS) such as that in Marburg variant. He deteriorated clinically over 9 months. Post-mortem examination yielded a diagnosis of LC with B-cell lymphoma. LC is notoriously difficult to diagnose, as it can present in various ways and biopsy of unaffected areas will be non-diagnostic. In our case, diagnosis was made more challenging by the patient's dramatic response to treatment with steroids and cyclophosphamide.

Immune checkpoint inhibitors such as antibodies to cytotoxic lymphocyte-associated protein 4 (ipilimumab) and programmed cell-death 1 (pembrolizumab, nivolumab) molecules have been used in non-small cell lung cancer, metastatic melanoma, and renal-cell carcinoma, among others. With these agents, immune-related adverse events (irAEs) can occur, including those affecting the neurological axis. In this review, high-grade neurological irAEs associated with immune checkpoint inhibitors including cases of Guillain-Barré syndrome (GBS) and myasthenia gravis (MG) are analyzed. Based on current literature and experience at our institution with 4 cases of high-grade neurological irAEs associated with immune checkpoint inhibitors (2 cases of GBS, 1 case of meningo-radiculitis, and 1 case of myelitis), we propose an algorithm for the investigation and treatment of high-grade neurological irAEs. Our algorithm incorporates both peripheral nervous system (meningo-radiculitis, GBS, MG) and central nervous system presentations (myelitis, encephalopathy). It is anticipated that our algorithm will be useful both to oncologists and neurologists who are likely to encounter neurological irAEs more frequently in the future as immune checkpoint inhibitors become more widely used.

Depression is a common comorbidity in patients with multiple sclerosis (MS). Those with MS and concurrent depression have poorer quality of life and are also less likely to be compliant with disease-modifying treatment, which may ultimately affect their MS disease course. Treating depression in MS with pharmacological agents can improve not only depression, but may also impact the MS disease course. However, no guidelines exist around treating depression in MS. Few randomized-controlled trials using antidepressants in MS exist. Here, we briefly review trials using antidepressant medications to treat depression in MS. We also propose individualizing treatment of depression in MS, as the depressive symptoms and MS symptoms and disease course differ significantly between patients. We explore the heterogeneity in presentation of depression through different comorbid symptoms in MS, and discuss which antidepressant options would be appropriate in each situation. We propose that future clinical trials should incorporate differences in issues between those with depression (e.g. sexual dysfunction, urinary incontinence) into analysis. As MS is incredibly heterogeneous, treating concurrent depression on a case-by-case basis may enable for improving quality of life and the MS disease course.

Background Multiple sclerosis (MS) has a significant inflammatory component and may have significant gray matter (GM) pathophysiology. Brain oxygenation is a sensitive measurement of the balance between metabolic need and oxygen delivery. There is evidence that inflammation and hypoxia are interdependent. In this paper, we applied novel, implanted PO2 sensors to measure hypoxia in cortical and cerebellar GM, in an inflammation-induced mouse model of MS. Objective Quantify oxygenation in cortical and cerebellar GM in the awake, unrestrained experimental autoimmune encephalomyelitis (EAE) mouse model and to relate the results to symptom level and disease time-course. Methods C57BL/6 mice were implanted with a fiber-optic sensor in the cerebellum (n = 13) and cortex (n = 24). Animals were induced with stimulation of the immune response and sensitization to myelin oligodendrocyte glycoprotein (MOG). Controls did not have MOG. We measured PO2 in awake, unrestrained animals from pre-induction (baseline) up to 36 days post-induction for EAE and controls. Results There were more days with hypoxia than hyperoxia (cerebellum: 34/67 vs. 18/67 days; cortex: 85/112 vs. 22/112) compared to time-matched controls. The average decline in PO2 on days that were significantly lower than time-matched controls was -8.8±6.0 mmHg (mean ± SD) for the cerebellum and -8.0±4.6 for the cortex. Conversely, the average increase in PO2 on days that were significantly hyperoxic was +3.2±2.8 mmHg (mean ± SD) for the cerebellum and +0.8±2.1 for the cortex. Cortical hypoxia related to increased behavioral deficits. Evidence for hypoxia occurred before measurable behavioral deficits. Conclusions A highly inflammatory condition primed to a white matter (WM) autoimmune response correlates with significant hypoxia and increased variation in oxygenation in GM of both cerebellum and cortex in the mouse EAE model of MS.

Subtle blood-brain barrier (BBB) disruption is involved in numerous neurological conditions. This disruption is found diffusely in the brain and requires quantitative methods for assessment. We propose a statistical method to identify individual voxels where the BBB is disrupted using T1-weighted MRI. We used models of severe and focal vs. mild and generalized disruption of the BBB to show proof of principle with the cold injury model, hypoxia, and a model of inflammation using low- and high-dose lipopolysaccharide (LPS) treatment. Using voxel-based analysis, we found that mild hypoxia resulted in diffuse disruption of the BBB, whereas more severe hypoxia and high-dose LPS treatment resulted in prominent leakage, particularly in the periventricular area, suggestive of blood-cerebrospinal fluid (CSF) barrier disruption. Our data suggest that the periventricular area may be compromised first in conditions of inflammation and hypoxia. Voxel-based analysis could be used in future studies assessing subtle blood-CSF or BBB disruption.

Background: Susceptibility-weighted imaging (SWI) is an iron-sensitive magnetic resonance imaging (MRI) method that has shown iron-related lesions in multiple sclerosis (MS) patients. The contribution of deoxyhemoglobin to the signals seen in SWI has not been well characterized in MS. Objectives: To determine if SWI lesions (seen as focal hypointensities) exist in the experimental autoimmune encephalomyelitis (EAE) animal model of MS, and to determine whether the lesions relate to iron deposits, inflammation, demyelination, and/or deoxyhemoglobin in the vasculature. Methods: We performed SWI on the lumbar spinal cord and cerebellum of EAE and control mice (both complete Freund’s adjuvant/pertussis toxin (CFA/PTX)-immunized and naive). We also performed SWI on mice before and after perfusion (to remove blood from vessels). SWI lesions were counted and their locations were compared to histology for iron, myelin and inflammation. Results: SWI lesions were found to exist in the EAE model. Many lesions seen by SWI were not present after perfusion, especially at the grey/white matter boundary of the lumbar spinal cord and in the cerebellum, indicating that these lesion signals were associated with deoxyhemoglobin present in the lumen of vessels. We also observed SWI lesions in the white matter of the lumbar spinal cord that corresponded to iron deposition, inflammation and demyelination. In the cerebellum, SWI lesions were present in white matter tracts, where we found histological evidence of inflammatory perivascular cuffs. Conclusions: SWI lesions exist in EAE mice. Many lesions seen in SWI were a result of deoxyhemoglobin in the blood, and so may indicate areas of hypoxia. A smaller number of SWI lesions coincided with parenchymal iron, demyelination, and/or inflammation.

Susceptibility-weighted imaging (SWI) detects hypointensities due to iron deposition and deoxyhemoglobin. Previously it was shown that SWI detects hypointensities in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), most of which are due to intravascular deoxyhemoglobin, with a small proportion being due to iron deposition in the central nervous system parenchyma and demyelination. However, animals had to be sacrificed to differentiate these two types of lesions which is impractical for time course studies or for human application. Here, we proposed altering the inspired oxygen concentration during imaging to identify deoxyhemoglobin-based hypointensities in vivo. SWI was performed on lumbar spinal cords of naive control and EAE mice using 30% O2 then 100% O2. Some mice were imaged using 30% O2, 100% O2 and after perfusion. Most SWI-visible hypointensities seen with 30% O2 changed in appearance upon administration of 100% O2, and were not visible after perfusion. That hypointensities changed with hyperoxygenation indicates that they were caused by deoxyhemoglobin. We show that increasing the inspired oxygen concentration identifies deoxyhemoglobin-based hypointensities in vivo. This could be applied in future studies to investigate the contribution of vascular-based hypointensities with SWI in EAE and MS over time.