Impact of a free medication intervention on seizure recurrence and anxious and depressive symptoms in people living with epilepsy in the Republic of Guinea.

BACKGROUND AND OBJECTIVE: Of ~5 million people living with epilepsy (PLWE) in Sub-Saharan Africa, roughly one-third experience depression and over one third experience anxiety. In Guinea, these issues may be compounded by fewer available resources, such as appropriate anti-seizure medications (ASMs). We aim to quantify seizure frequency, anxiety and depression in PLWE in Guinea, before and after a free ASM intervention and neurologist's consultation. METHODS: Guinean participants >12 years old with ≥2 unprovoked seizure were prospectively recruited. As part of a broader interview, participants reported prior 30-day seizure frequency and screened for depression (PHQ-9) (range 0-27 points) and anxiety (GAD-7) (range 0-21 points) with re-evaluation at 90 days. RESULTS: Of 148 participants enrolled (mean age = 27.3 years, range 12-72; 45% female), 62% were currently taking ASMs. For the 30 days pre-enrolment, average seizure frequency was 3.2 (95%CI 2.3, 4.2); 28% of participants were seizure-free. ASM regimens were modified for 95% of participants, mostly initiating levetiracetam (n = 115, 80% of modifications). 90-day study retention was 76% (n = 113) among whom 87% reported full adherence to the ASM. After 90 days, the average seizure frequency over the prior 30 days was 1.5 (95%CI 0.5, 2.6), significantly lower than at baseline (p = 0.002). 66% were seizure-free. At baseline, average PHQ-9 score was 21.2 (95%CI [20.2, 22.2]), indicating severe depressive symptoms. Average GAD-7 score was 16.5 [15.6, 17.4], indicating severe anxious symptoms. At 90-days, average PHQ-9 score was 17.5[16.4, 18.5] and significantly lower than baseline (p < 0.001). Average GAD-7 score was 14.4 [13.6, 15.3] and significantly lower than baseline (p = 0.002). Seizure frequency was not correlated with PHQ-9 nor GAD-7 scores at baseline but was at 90 days for both PHQ-9 (r = 0.24, p = 0.01) and GAD-7 (r = 0.22, p = 0.02) scores. The prevalence of suicidal ideation dropped from 67% to 47% of participants (p = 0.004). DISCUSSION: ASM management has dual importance for PLWE in resource-limited settings, improving both seizure control and mental health.

In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis.

Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In six animals followed with multisequence 7 T MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in four of six marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.

Assessing risk factors associated with breakthrough early post-traumatic seizures in patients receiving phenytoin prophylaxis.

Objective: Post-traumatic seizure (PTS) is a well-known complication of traumatic brain injury (TBI). The objective of this study was to identify risk factors associated with breakthrough early PTS in TBI patients receiving phenytoin prophylaxis. Methods: This was a single-centered retrospective study including adult patients admitted to the intensive care unit (ICU), had a TBI, and started on phenytoin for seizure prophylaxis within 24 h of admission. The primary outcome was the incidence and factors associated with early PTS, defined as a confirmed seizure on a continuous electroencephalogram within 7 days of TBI. Secondary outcomes included the association between early post-traumatic seizures and ICU length of stay, hospital length of stay, and in-hospital mortality. Results: A total of 105 patients were included in the final analysis. Patients with early PTS were older (65 vs. 48 years old, p = 0.01), had a higher Marshall score (5 vs. 2, p = 0.01), were more likely to have a Marshall score > 2 (73 vs. 37%, p = 0.01), and had more neurosurgeries for hematoma evacuation (57 vs. 19%, p = 0.01). In patients with early PTS, 57% had a level at the time of seizure, and of those, 87.5% had a therapeutic level (>10 mcg/mL). Patients with early PTS had a longer ICU length of stay (14.7 vs. 5.9 days, p = 0.04) and a greater proportion of hospital mortality (21 vs. 2%, p = 0.02). Conclusion: Patients with higher age, Marshall score, and neurosurgical procedures for hematoma evacuation had higher incidences of breakthrough early PTS despite the use of phenytoin prophylaxis. The majority of patients with early PTS had therapeutic phenytoin levels at the time of seizure when a level was available; however, approximately half (43%) did not have a level.

Safety, Efficiency, and Efficacy of Protocolized Contrast-Enhanced Imaging in Acute Stroke Evaluation.

BACKGROUND AND PURPOSE: Computed tomography angiography and perfusion studies have increasingly become a part of acute stroke evaluation. However, the volume, benefit, and scope of need for imaging is sometimes debated. PURPOSE: This study evaluated the safety, efficiency, and efficacy of changes to the acute stroke evaluation protocol at our academic institution. Previously, contrast-enhanced imaging was "opt-in" and ordered upon suspicion of large vessel occlusion. This was subsequently transitioned to one where contrast-enhanced imaging was automatically ordered for all patients with "opt-out" of imaging if felt appropriate. METHODS: We performed a retrospective, case-control study that included patients evaluated for acute stroke management before and after the protocol change. Six hundred forty-seven patients met criteria for study involvement, of which 258 were in the preprotocol and 389 in the postprotocol group. RESULTS: There was no significant difference in rate of acute kidney injury and no delay in door-to-needle time. There was significant improvement in door-to-groin puncture times (49.9 minutes) for typical cases and increase in monthly rate of endovascular therapy (EVT). CONCLUSION: Protocolization of contrast-enhanced imaging for acute stroke evaluation proved safe with respect to renal function, did not delay door-to-needle time, improved door-to-groin puncture time, and lead to higher rates of EVT.

Magnetic resonance imaging in multiple sclerosis animal models: A systematic review, meta-analysis, and white paper.

Magnetic resonance imaging (MRI) is the most important paraclinical tool for assessing drug response in multiple sclerosis (MS) clinical trials. As such, MRI has also been widely used in preclinical research to investigate drug efficacy and pathogenic aspects in MS animal models. Keeping track of all published preclinical imaging studies, and possible new therapeutic approaches, has become difficult considering the abundance of studies. Moreover, comparisons between studies are hampered by methodological differences, especially since small differences in an MRI protocol can lead to large differences in tissue contrast. We therefore provide a comprehensive qualitative overview of preclinical MRI studies in the field of neuroinflammatory and demyelinating diseases, aiming to summarize experimental setup, MRI methodology, and risk of bias. We also provide estimates of the effects of tested therapeutic interventions by a meta-analysis. Finally, to improve the standardization of preclinical experiments, we propose guidelines on technical aspects of MRI and reporting that can serve as a framework for future preclinical studies using MRI in MS animal models. By implementing these guidelines, clinical translation of findings will be facilitated, and could possibly reduce experimental animal numbers.

Potential role of iron in repair of inflammatory demyelinating lesions.

Inflammatory destruction of iron-rich myelin is characteristic of multiple sclerosis (MS). Although iron is needed for oligodendrocytes to produce myelin during development, its deposition has also been linked to neurodegeneration and inflammation, including in MS. We report perivascular iron deposition in multiple sclerosis lesions that was mirrored in 72 lesions from 13 marmosets with experimental autoimmune encephalomyelitis. Iron accumulated mainly inside microglia/macrophages from 6 weeks after demyelination. Consistently, expression of transferrin receptor, the brain's main iron-influx protein, increased as lesions aged. Iron was uncorrelated with inflammation and postdated initial demyelination, suggesting that iron is not directly pathogenic. Iron homeostasis was at least partially restored in remyelinated, but not persistently demyelinated, lesions. Taken together, our results suggest that iron accumulation in the weeks after inflammatory demyelination may contribute to lesion repair rather than inflammatory demyelination per se.

The "central vein sign" in inflammatory demyelination: The role of fibrillar collagen type I.

Accumulating evidence corroborates the role of the "central vein sign" in the radiological diagnosis of multiple sclerosis (MS). Here, we report human magnetic resonance imaging (MRI) and corresponding pathological data that inflammation-dependent intracerebral remodeling of the vessel wall is directly associated with the prominence of intralesional veins on susceptibility-based MRI. In adult marmosets with experimental autoimmune encephalomyelitis, vessel-wall fibrosis was detected early in the demyelinating process, even in lesions <2 weeks old, though fibrosis was more evident after 6 weeks. Vascular remodeling consisted of both luminal enlargement and eccentric thickening of the perivascular space (fibrillar collagen type I deposition) and affected almost exclusively white matter, but not subpial cortical, lesions. The long-term effect of vessel remodeling in MS lesions is currently unknown, but it might potentially affect tissue repair. ANN NEUROL 2019;85:934-942.

Herpesvirus trigger accelerates neuroinflammation in a nonhuman primate model of multiple sclerosis.

Pathogens, particularly human herpesviruses (HHVs), are implicated as triggers of disease onset/progression in multiple sclerosis (MS) and other neuroinflammatory disorders. However, the time between viral acquisition in childhood and disease onset in adulthood complicates the study of this association. Using nonhuman primates, we demonstrate that intranasal inoculations with HHV-6A and HHV-6B accelerate an MS-like neuroinflammatory disease, experimental autoimmune encephalomyelitis (EAE). Although animals inoculated intranasally with HHV-6 (virus/EAE marmosets) were asymptomatic, they exhibited significantly accelerated clinical EAE compared with control animals. Expansion of a proinflammatory CD8 subset correlated with post-EAE survival in virus/EAE marmosets, suggesting that a peripheral (viral?) antigen-driven expansion may have occurred post-EAE induction. HHV-6 viral antigen in virus/EAE marmosets was markedly elevated and concentrated in brain lesions, similar to previously reported localizations of HHV-6 in MS brain lesions. Collectively, we demonstrate that asymptomatic intranasal viral acquisition accelerates subsequent neuroinflammation in a nonhuman primate model of MS.

Spatiotemporal distribution of fibrinogen in marmoset and human inflammatory demyelination.

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although it has been extensively studied, the proximate trigger of the immune response remains uncertain. Experimental autoimmune encephalomyelitis in the common marmoset recapitulates many radiological and pathological features of focal multiple sclerosis lesions in the cerebral white matter, unlike traditional experimental autoimmune encephalomyelitis in rodents. This provides an opportunity to investigate how lesions form as well as the relative timing of factors involved in lesion pathogenesis, especially during early stages of the disease. We used MRI to track experimental autoimmune encephalomyelitis lesions in vivo to determine their age, stage of development, and location, and we assessed the corresponding histopathology post-mortem. We focused on the plasma protein fibrinogen-a marker for blood-brain barrier leakage that has also been linked to a pathogenic role in inflammatory demyelinating lesion development. We show that fibrinogen has a specific spatiotemporal deposition pattern, apparently deriving from the central vein in early experimental autoimmune encephalomyelitis lesions <6 weeks old, and preceding both demyelination and visible gadolinium enhancement on MRI. Thus, fibrinogen leakage is one of the earliest detectable events in lesion pathogenesis. In slightly older lesions, fibrinogen is found inside microglia/macrophages, suggesting rapid phagocytosis. Quantification demonstrates positive correlation of fibrinogen deposition with accumulation of inflammatory cells, including microglia/macrophages and T cells. The peak of fibrinogen deposition coincides with the onset of demyelination and axonal loss. In samples from chronic multiple sclerosis cases, fibrinogen was found at the edge of chronic active lesions, which have ongoing demyelination and inflammation, but not in inactive lesions, suggesting that fibrinogen may play a role in sustained inflammation even in the chronic setting. In summary, our data support the notion that fibrinogen is a key player in the early pathogenesis, as well as sustained inflammation, of inflammatory demyelinating lesions.

Hexa (ethylene glycol) derivative of benzothiazole aniline promotes dendritic spine formation through the RasGRF1-Ras dependent pathway.

Our recent study demonstrated that an amyloid-ß binding molecule, BTA-EG4, increases dendritic spine number via Ras-mediated signaling. To potentially optimize the potency of the BTA compounds, we synthesized and evaluated an amyloid-ß binding analog of BTA-EG4 with increased solubility in aqueous solution, BTA-EG6. We initially examined the effects of BTA-EG6 on dendritic spine formation and found that BTA-EG6-treated primary hippocampal neurons had significantly increased dendritic spine number compared to control treatment. In addition, BTA-EG6 significantly increased the surface level of AMPA receptors. Upon investigation into the molecular mechanism by which BTA-EG6 promotes dendritic spine formation, we found that BTA-EG6 may exert its effects on spinogenesis via RasGRF1-ERK signaling, with potential involvement of other spinogenesis-related proteins such as Cdc42 and CDK5. Taken together, our data suggest that BTA-EG6 boosts spine and synapse number, which may have a beneficial effect of enhancing neuronal and synaptic function in the normal healthy brain.

Defective Age-Dependent Metaplasticity in a Mouse Model of Alzheimer's Disease.

Much of the molecular understanding of synaptic pathology in Alzheimer's disease (AD) comes from studies of various mouse models that express familial AD (FAD)-linked mutations, often in combinations. Most studies compare the absolute magnitudes of long-term potentiation (LTP) and long-term depression (LTD) to assess deficits in bidirectional synaptic plasticity accompanying FAD-linked mutations. However, LTP and LTD are not static, but their induction threshold is adjusted by overall neural activity via metaplasticity. Hence LTP/LTD changes in AD mouse models may reflect defects in metaplasticity processes. To determine this, we examined the LTP/LTD induction threshold in APPswe;PS1ΔE9 transgenic (Tg) mice across two different ages. We found that in young Tg mice (1 month), LTP is enhanced at the expense of LTD, but in adults (6 months), the phenotype is reversed to promote LTD and reduce LTP, compared to age-matched wild-type (WT) littermates. The apparent opposite phenotype across age was due to an initial offset in the induction threshold to favor LTP and the inability to undergo developmental metaplasticity in Tg mice. In WTs, the synaptic modification threshold decreased over development to favor LTP and diminish LTD in adults. However, in Tg mice, the magnitudes of LTP and LTD stayed constant across development. The initial offset in LTP/LTD threshold in young Tg mice did not accompany changes in the LTP/LTD induction mechanisms, but altered AMPA receptor phosphorylation and appearance of Ca(2+)-permeable AMPA receptors. We propose that the main synaptic defect in AD mouse models is due to their inability to undergo developmental metaplasticity. SIGNIFICANCE STATEMENT: This work offers a new insight that metaplasticity defects are central to synaptic dysfunctions seen in AD mouse models. In particular, we demonstrate that the apparent differences in LTP/LTD magnitude seen across ages in AD transgenic mouse models reflect the inability to undergo a normal developmental shift in metaplasticity.

Antihypertensive drug Valsartan promotes dendritic spine density by altering AMPA receptor trafficking.

Recent studies demonstrated that the antihypertensive drug Valsartan improved spatial and episodic memory in mouse models of Alzheimer's Disease (AD) and human subjects with hypertension. However, the molecular mechanism by which Valsartan can regulate cognitive function is still unknown. Here, we investigated the effect of Valsartan on dendritic spine formation in primary hippocampal neurons, which is correlated with learning and memory. Interestingly, we found that Valsartan promotes spinogenesis in developing and mature neurons. In addition, we found that Valsartan increases the puncta number of PSD-95 and trends toward an increase in the puncta number of synaptophysin. Moreover, Valsartan increased the cell surface levels of AMPA receptors and selectively altered the levels of spinogenesis-related proteins, including CaMKIIα and phospho-CDK5. These data suggest that Valsartan may promote spinogenesis by enhancing AMPA receptor trafficking and synaptic plasticity signaling.