Cerebrospinal fluid biomarkers in SARS-CoV-2 patients with acute neurological syndromes.

BACKGROUND AND PURPOSE: Mechanisms underlying acute brain injury in SARS-CoV-2 patients remain poorly understood. A better characterization of such mechanisms remains essential to preventing long-term neurological sequelae. Our present aim was to study a panel of biomarkers of neuroinflammation and neurodegeneration in the cerebrospinal fluid (CSF) of NeuroCOVID patients. METHODS: We retrospectively collected clinical and CSF biomarkers data from 24 NeuroCOVID adults seen at the University Hospital of Guadeloupe between March and June 2021. RESULTS: Among 24 NeuroCOVID patients, 71% had encephalopathy and 29% meningoencephalitis. A number of these patients also experienced de novo movement disorder (33%) or stroke (21%). The CSF analysis revealed intrathecal immunoglobulin synthesis in 54% of NeuroCOVID patients (two with a type 2 pattern and 11 with a type 3) and elevated neopterin levels in 75% of them (median 9.1nM, IQR 5.6-22.1). CSF neurofilament light chain (NfL) was also increased compared to a control group of non-COVID-19 patients with psychiatric illnesses (2905ng/L, IQR 1428-7124 versus 1222ng/L, IQR 1049-1566). Total-tau was elevated in the CSF of 24% of patients, whereas protein 14-3-3, generally undetectable, reached intermediate levels in two patients. Finally, CSF Aß1-42 was reduced in 52.4% of patients (median 536ng/L, IQR 432-904) with no change in the Aß1-42/Aß1-40 ratio (0.082, IQR 0.060-0.096). CONCLUSIONS: We showed an elevation of CSF biomarkers of neuroinflammation in NeuroCOVID patients and a rise of CSF NfL, evocative of neuronal damage. However, longitudinal studies are needed to determine whether NeuroCOVID could evolve into a chronic neurodegenerative condition.

Long-term outcomes after NeuroCOVID: A 6-month follow-up study on 60 patients.

BACKGROUND AND PURPOSE: Long-term outcomes after neurological manifestations due to COVID-19 are poorly known. The aim of our study was to evaluate the functional outcome and identify the risk factors of neurologic sequelae after COVID-19 associated with neurological manifestations (NeuroCOVID). METHODS: We conducted a multi-center observational study six months after the acute neurological symptoms in patients from the French NeuroCOVID hospital-based registry. RESULTS: We obtained data on 60 patients. NeuroCOVID had a negative impact on the quality of life (QoL) of 49% of patients. Age was a predictor of residual QoL impairment (OR: 1.06, 95% CI: 1.01-1.13, p=0.026). At six months, a significant residual disability was found in 51.7% of patients, and impaired cognition in 68.9% of cases. The main persistent neuropsychiatric manifestations were a persistent smell/taste disorder in 45% of patients, memory complaints in 34% of patients, anxiety or depression in 32% of patients. CONCLUSIONS: NeuroCOVID likely carries a high risk of long-term neuropsychiatric disability. Long-term care and special attention should be given to COVID-19 patients, especially if they had neurological manifestations during acute infection.

Central nervous system infections in a tropical area: influence of emerging and rare infections.

BACKGROUND AND PURPOSE: The frequency of infectious encephalitis and the distribution of causative pathogens in tropical areas are poorly known and may be influenced by emerging and rare infections. The aim was to characterize a large series of acute infectious encephalitis and myelitis in immunocompetent patients from the Caribbean island of Guadeloupe identifying clinical, biological and radiological features according to pathogens. METHODS: Using a hospital database, detailed information on a comprehensive series of immunocompetent patients with acute infectious myelitis and encephalitis over the 2012-2018 period was retrospectively collected. RESULTS: From 259 suspected cases with acute central nervous system infection, 171 cases were included for analysis, comprising 141 encephalitis, 22 myelitis and eight encephalomyelitis. The annual incidence peaked at 15.0/100 000 during the Zika 2016 outbreak. Children accounted for 22.2% of cases. Eight adults died during hospital stay, all encephalitis. Seventeen infectious agents, two of which had never been described in Guadeloupe so far, were identified in 101 cases (59.1%), including 35 confirmed cases (34.7%), 48 probable cases (47.5%), 15 possible cases (14.9%) and three clinical cases (3.0%). The most frequent etiologic agents were Zika virus in 23 cases (13.5%), herpes simplex in 12 (7.0%), varicella zoster virus in 11 (6.4%), dengue virus in 11 (6.4%) and leptospirosis in 11 (6.4%). CONCLUSIONS: The Zika outbreak had a major influence on the annual incidence of acute central nervous system infection. Acute neuroleptospirosis is over-represented in our series. Further efforts are mandatory to develop new diagnostic tools for pathogen profiling.

Acute myelitis associated with dengue infection.

OBJECTIVES: To present a rare neurological complication of dengue fever. PATIENTS AND METHODS: A 24-year-old female presented with acute myelitis seven days after dengue fever onset. RESULTS: The patient presented with intense fever. The day-7 examination revealed a paraparesis, T2 sensory level, and urinary retention. The patient complained of electric discharges in the four limbs. The sitting and standing positions were impossible. An MRI of the spinal cord performed on day 8 revealed diffuse medullar hyper intense lesions on T2-weighted sequences at the cervical and thoracic levels, with enhancement of the thoracic lesion after gadolinium injection. Laboratory tests revealed positive dengue antigen on day 5 and positive IgM/IgG on day 8. Treatment with intravenous pulse methylprednisolone was initiated. CONCLUSION: Dengue virus has not often been reported as a cause of myelitis. Physicians must be aware of this rare complication in patients living in or coming from endemic areas.

Report of three imported cases of neurocysticercosis in Guadeloupe.

BACKGROUND: Neurocysticercosis is endemic in most countries of Central and South America but has rarely been described in the French West Indies. We aimed to better understand the clinical and radiological presentation of our cases. CASE PRESENTATION: We report three cases of neurocysticercosis in patients living in Guadeloupe, with different clinical and radiological presentations. CONCLUSION: Given the eventuality of autochtonous transmission, the diagnosis should be considered in all patients living in Guadeloupe presenting with seizures.

Social deprivation and stroke severity on admission: a French cohort study in Burgundy and the West Indies - Guyana region.

BACKGROUND AND PURPOSE: Although there is growing and convincing evidence that socially deprived patients are at higher risk of stroke and worse outcomes, it remains controversial whether or not they suffer more severe stroke. This study aimed to evaluate the influence of social deprivation on initial clinical severity in patients with stroke. METHODS: A total of 1536 consecutive patients with an acute first-ever stroke (both ischaemic stroke and intracerebral hemorrhage) were prospectively enrolled from six French study centers. Stroke severity on admission was measured by the National Institutes of Health Stroke Scale score. Social deprivation was assessed at the individual level by the Evaluation de la Précarité et des Inégalités de santé dans les Centres d'Examen de Santé (EPICES) score, a validated multidimensional questionnaire, and several additional single socioeconomic indicators. Polytomous logistic regression analyses were performed to evaluate the association between social deprivation and stroke severity. RESULTS: In univariate analysis, the EPICES score (P = 0.039) and level of education (P = 0.018) were the only two socioeconomic variables associated with stroke severity. Multivariate analysis of the association between EPICES and National Institutes of Health Stroke Scale scores showed that more deprived patients presented a significantly higher risk of both mild and moderate/severe stroke (odds ratio for mild versus minor stroke, 1.39; 95% confidence interval, 1.06-1.84; odds ratio for moderate/severe versus minor stroke, 1.44; 95% confidence interval, 1.09-1.92). A non-significant trend towards a higher risk of both mild and moderate/severe stroke in less educated patients was observed. CONCLUSIONS: Social deprivation was associated with a more severe clinical presentation in patients with stroke. These findings may contribute to the worse outcome after stroke in deprived patients, and underline the need for strategies to reduce social inequalities for stroke.

[Descriptive epidemiology of neuromyelitis optica in the Caribbean basin]. / Epidémiologie descriptive de la neuromyélite optique dans le bassin caraïbéen.

INTRODUCTION: Data on epidemiology of neuromyelitis optica (NMO) remained scarce in the last century, but the recent development of diagnostic criteria now enables inclusion of both monophasic and relapsing NMO in epidemiologic studies. Given the rarity of NMO, multicentric studies are needed to confirm a presumed higher frequency in women and in populations of black/Asian ancestry. The Caribbean basin is a suitable area for collecting a large NMO cohort and to assess the prevalence, incidence, and mortality of this disorder. PATIENTS AND METHODS: This population-based survey of the NMO spectrum in the French West Indies (FWI) and Cuba included 151 cases. RESULTS: Ninety-eight patients (female/male ratio: 9.8) had NMO. Age of onset in NMO patients was 30.9 years. Mean annual incidence of NMO in the French West Indies for the period July 2002 to June 2007 was 0.20/100,000 inhabitants (IC 95% 0.05-0.35). Incidence rates were steady in the FWI during the 1992 to 2007 period. Decreasing mortality in the FWI during the 1992 to 2007 period explained the increasing prevalence which was 4.20/100,000 inhabitants (IC 95% 3.7-5.7) in June 2007. The prevalence of NMO in Cuba on November302004 was 0.52/100,000 inhabitants. (IC 95% 0.39-0.67). Prevalence rates did not differ significantly by ethnic group in Cuba, however, black Cubans exhibited the highest prevalence. DISCUSSION: Epidemiologic studies on NMO in each population are needed to determine whether aggressive therapies can reduce the mortality of this devastating disorder. CONCLUSION: In the Caribbean basin, NMO involves almost exclusively young women; the epidemiologic data confirm its predilection for populations of African ancestry. In the FWI, recent and aggressive therapy has lowered mortality but with an increase in the prevalence of NMO.

Molecular analyses of the LRRK2 gene in European and North African autosomal dominant Parkinson's disease.

BACKGROUND: Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (ADPD), the most common of which is the p.G2019S substitution that has been found at varying frequencies worldwide. Because of the size of the LRRK2 gene, few studies have analysed the entire gene in large series of ADPD families. METHODS: We performed extensive mutation analyses of all 51 coding exons of the LRRK2 gene in index cases from 226 Parkinson's disease families compatible with autosomal dominant inheritance, mostly from France (n = 182) and North Africa (n = 14). RESULTS: We found 79 sequence variants, 29 of which were novel. Eight potentially or proven pathogenic mutations were found in 22 probands (9.7%). There were four novel amino acid substitutions that are potentially pathogenic (p.S52F, p.N363S, p.I810V, p.R1325Q) and two novel variants, p.H1216R and p.T1410M, that are probably not causative. The common p.G2019S mutation was identified in 13 probands (5.8%) including six from North Africa (43%). The known heterozygous p.R1441H and p.I1371V mutations were found in two probands each, and the p.E334K variant was identified in one single patient. Most potentially or proven pathogenic mutations were located in the functional domains of the Lrrk2 protein. CONCLUSION: This study leads us to conclude that LRRK2 mutations are a common cause of autosomal dominant Parkinson's disease in Europe and North Africa.

Is atypical parkinsonism in the Caribbean caused by the consumption of Annonacae?

An abnormally frequent atypical levodopa-unresponsive, akinetic-rigid syndrome with some similarity to PSP was identified in the Caribbean island Guadeloupe, and was associated with the consumption of plants of the Annonacea family, especially Annona muricata (corossol, soursop) suggesting a possible toxic etiology. Annonaceae contain two groups of potential toxins, alkaloids and acetogenins. Both alkaloids and annonacin, the most abundant acetogenin, were toxic in vitro to dopaminergic and other neurons. However we have focused our work on annonacin for two reasons: (1) annonacin was toxic in nanomolar concentrations, whereas micromolar concentrations of the alkaloids were needed, (2) acetogenins are potent mitochondrial poisons, like other parkinsonism-inducing compounds. We have also shown that high concentrations of annonacin are present in the fruit or aqueous extracts of the leaves of A. muricata, can cross the blood brain barrier since it was detected in brain parenchyma of rats treated chronically with the molecule, and induced neurodegeneration of basal ganglia in these animals, similar to that observed in atypical parkinsonism. These studies reinforce the concept that consumption of Annonaceae may contribute to the pathogenesis of atypical parkinsonism in Guadeloupe.

The mitochondrial complex I inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism.

The death of dopaminergic neurons induced by systemic administration of mitochondrial respiratory chain complex I inhibitors such as 1-methyl-4-phenylpyridinium (MPP(+); given as the prodrug 1-methyl-1,2,3,6-tetrahydropyridine) or the pesticide rotenone have raised the question as to whether this family of compounds are the cause of some forms of Parkinsonism. We have examined the neurotoxic potential of another complex I inhibitor, annonacin, the major acetogenin of Annona muricata (soursop), a tropical plant suspected to be the cause of an atypical form of Parkinson disease in the French West Indies (Guadeloupe). When added to mesencephalic cultures for 24 h, annonacin was much more potent than MPP(+) (effective concentration [EC(50)]=0.018 versus 1.9 microM) and as effective as rotenone (EC(50)=0.034 microM) in killing dopaminergic neurons. The uptake of [(3)H]-dopamine used as an index of dopaminergic cell function was similarly reduced. Toxic effects were seen at lower concentrations when the incubation time was extended by several days whereas withdrawal of the toxin after a short-term exposure (<6 h) arrested cell demise. Unlike MPP(+) but similar to rotenone, the acetogenin also reduced the survival of non-dopaminergic neurons. Neuronal cell death was not excitotoxic and occurred independently of free radical production. Raising the concentrations of either glucose or mannose in the presence of annonacin restored to a large extent intracellular ATP synthesis and prevented neuronal cell demise. Deoxyglucose reversed the effects of both glucose and mannose. Other hexoses such as galactose and fructose were not protective. Attempts to restore oxidative phosphorylation with lactate or pyruvate failed to provide protection to dopaminergic neurons whereas idoacetate, an inhibitor of glycolysis, inhibited the survival promoting effects of glucose and mannose indicating that these two hexoses acted independently of mitochondria by stimulating glycolysis. In conclusion, our study demonstrates that annonacin promotes dopaminergic neuronal death by impairment of energy production. It also underlines the need to address its possible role in the etiology of some atypical forms of Parkinsonism in Guadeloupe.

Risk factors associated with ischaemic stroke in Guadeloupe

We carried out a case control study at the University Hospital of Pointe-Ó-Pitre, Guadeloupe, during eight months. Seventy patients with ischaemic stroke and seventy age- and sex-matched controls were involved. A standard questionnaire reported clinical characteristics and medical history. Seventy-six per cent of patients suffered from hypertension. Obesity and diabetes were more frequent in the case group than in the control group. Serum creatinine concentration (86 vs 74 mumol/l; p < 0.001), total cholesterol (5.9 vs. 5.2 mmol/l; p < 0.001), apolipoprotein B (1.2 vs 1.0 g/l; p < 0.001) and lipoprotein (a) (82 vs 48 mg/dl; p < 0.001) were significantly higher in patients than controls. Multiple logistic regression analysis revealed that in addition to serum creatinine, serum apolipoprotein B, hypertension, obesity, serum lipoprotein (a) and diabetes mellitus were associated independently and significantly with ischaemic stroke. These findings have implications for clinical practice and further research particularly with respect to serum creatinine concentration as a marker of renal damage from hypertension and as a risk factor itself for cerebrovascular disease.

Risk factors associated with ischaemic stroke in Guadeloupe

We carried out a case control study at the University Hospital of Pointe-a-Pitre, Guadeloupe, during eight months. Seventy patients with ischaemic stroke and seventy age- and sex matched controls were involved. A standard questionnaire reported clinical characteristics and medical history. Seventy-six per cent of patients suffered from hypertension. Obesity and diabetes were more frequent in the case group than in the control group. Serum creatinine concentration (86 vs 74umol/l; p <0.001), total cholesterol (5.9 vs 5.2 mmol/l; p < 0.001), apolipoprotein B (1.2 vs 1.0 g/l' p < 0.001) and lipoprotein (a) (82 vs 48 mg/dl; p< 0.001) were significantly higher in patients than controls. Multiple logistic regression analysis revealed that in addition to serum creatinine, serum apolipoprotein B, hypertension, obesity, serum lipoprotein (a) and diabetes mellitus were associated independently and significantly with ischaemic stroke. These findings have implications for clinical practice and further research particularly with respect to serum creatinine concentration as a marker of renal damage from hypertension and as risk factor itself for cerebrovascular disease.(Au)

Risk factors associated with ischaemic stroke in Guadeloupe.

We carried out a case control study at the University Hospital of Pointe-à-Pitre, Guadeloupe, during eight months. Seventy patients with ischaemic stroke and seventy age- and sex-matched controls were involved. A standard questionnaire reported clinical characteristics and medical history. Seventy-six per cent of patients suffered from hypertension. Obesity and diabetes were more frequent in the case group than in the control group. Serum creatinine concentration (86 vs 74 mumol/l; p < 0.001), total cholesterol (5.9 vs. 5.2 mmol/l; p < 0.001), apolipoprotein B (1.2 vs 1.0 g/l; p < 0.001) and lipoprotein (a) (82 vs 48 mg/dl; p < 0.001) were significantly higher in patients than controls. Multiple logistic regression analysis revealed that in addition to serum creatinine, serum apolipoprotein B, hypertension, obesity, serum lipoprotein (a) and diabetes mellitus were associated independently and significantly with ischaemic stroke. These findings have implications for clinical practice and further research particularly with respect to serum creatinine concentration as a marker of renal damage from hypertension and as a risk factor itself for cerebrovascular disease.

[Epidemiology of stroke in Guadeloupe and role of sickle cell trait]. / Epidémiologie des accidents vasculaires cérébraux en Guadeloupe et rôle du trait drépanocytaire.

Sickle cell disease (homozygotes SS) is known as a risk factor for both ischemic and hemorrhagic stroke, but heterozygotes AS seem to be spared. We carried out a retrospective study to assess the main risk factors and the influence of hemoglobin abnormalities on stroke in Guadeloupe. The percentages of AS, AC, and AA on 295 patients admitted for stroke were compared to the prevalence obtained on 72,000 newborn babies. Ischemic, hemorrhagic stroke and stroke complications represented respectively 83 p. 100, 10 p. 100 and 7 p. 100. Seventy one per 100 of patients had hypertension and 19 p. 100 had an association of diabetes and hypertension. The percentage of heterozygotes AS was significantly lower in the group with ischemic stroke (4 p. 100) in comparison with controls (8.5 p. 100), while AS were more represented in hemorrhagic stroke (16 p. 100). The risk of hemorrhagic stroke was 10 fold higher in AS patients admitted for stroke and the risk of ischemic stroke was reduced by 15 fold. These data suggest that the sickle cell trait could be associated to red cell and/or endothelial specificities which could prevent for ischemic stroke. The influence of AS heterozygote on the occurrence of stroke needs to be examined in a longitudinal, prospective study.