Neuroimaging in the Rare Sleep Disorder of Kleine-Levin Syndrome: A Systematic Review.

Kleine-Levin syndrome (KLS) is characterized by episodes of hypersomnia. Additionally, these patients can present with hyperphagia, hypersexuality, abnormal behavior, and cognitive dysfunction. Functional neuroimaging studies such as fMRI-BOLD, Positron Emission Tomography (PET) or SPECT help us understand the neuropathological bases of different disorders. We conducted a systematic review to investigate the neuroimaging features of KLS patients and their clinical correlations. This systematic review was conducted by following the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) and PRISMA protocol reporting guidelines. We aim to investigate the clinical correlation with neuroimaging among patients with KLS. We included only studies written in the English language in the last 20 years, conducted on humans; 10 studies were included. We excluded systematic reviews, metanalysis, and case reports. We found that there are changes in functional imaging studies during the symptomatic and asymptomatic periods as well as in between episodes in patients with K.L.S. The areas most reported as affected were the hypothalamic and thalamic regions, which showed hypoperfusion and, in a few cases, hyperperfusion; areas such as the frontal, parietal, occipital and the prefrontal cortex all showed alterations in cerebral perfusion. These changes in cerebral blood flow and regions vary according to the imaging (SPECT, PET SCAN, or fMRI) and the task performed while imaging was performed. We encountered conflicting data between studies. Hyper insomnia, the main feature of this disease during the symptomatic periods, was associated with decreased thalamic activity. Other features of K.L.S., such as apathy, hypersexuality, and depersonalization, were also correlated with functional imaging changes. There were also findings that correlated with working memory deficits seen in this stage during the asymptomatic periods. Hyperactivity of the thalamus and hypothalamus were the main features shown during the asymptomatic period. Additionally, functional imaging tends to improve with a longer course of the disease, which suggests that K.L.S. patients outgrow the disease. These findings should caution physicians when analyzing and correlating neuroimaging findings with the disease.

Pulvinar Sign, Stroke and Their Relationship with Fabry Disease: A Systematic Review and Metanalysis.

Background: Fabry disease (FD) is the second most common lysosomal storage disorder. This disorder affects multiple systems that include the cardiac, renal, and nervous system. The pulvinar sign (PS) is a relatively common sign seen in patients with FD. The PS is a bilateral, symmetrical pulvinar high signal relative to the signal intensity seen on unenhanced T1-weighted brain MR imaging. Methods: We conducted a systematic review with metanalysis to analyze the pool prevalence of the disorder. We used the Moose Guidelines and PRISMA Protocol for this systematic review and Robins 1 to access the BIAS of the study. To analyze the pool prevalence, we used "Open Meta-Analysis" software for analyzing the study. We used "Review Manager 5.4" to analyze the odds ratio between patients with and without the PS and patients with and without stroke among patients with FD. Results: We gather 12 studies from 2003 to 2021 for the analysis of this study. The pool prevalence of the study was 0.146 (0.076−0.217) (62/385 cases) with a 95% CI (0.0945−0.415) (p < 0.01). The prevalence was much higher in men (59 cases) than in women (3 cases). There was no relationship between the pulvinar sign and patients with stroke among patients with Fabry disease. Odds ratio 1.97 95% CI (0.35−11.21), p = 0.44; Tau2 = 0.77. There seems to be a correlation with renal failure (RF), but there were very few studies to conduct a metanalysis with RF. Conclusions: The prevalence of the PS among all studies was 23.9%; the prevalence of this sign is higher among males. We found that FD patients who had strokes did not have higher odds of presenting with the Pulvinar Sign than the FD patients who did not suffer a stroke. Patients with renal failure and FD seem to have a higher tendency to have the PS, but there were not enough studies to analyze that theory. Overall, we think the pulvinar sign has a poor prognostic value in patients with Fabry's disease.

Arginine for the Treatment of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes: A Systematic Review.

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disease that lacks a definitive treatment. Lately, there has been an increased interest in the scientific community about the role of arginine in the short and long-term settings of the disease. We aim to conduct a systematic review of the clinical use of arginine in the management of MELAS and explore the role of arginine in the pathophysiology of the disease. We used PubMed advanced-strategy searches and only included full-text clinical trials on humans written in the English language. After applying the inclusion/exclusion criteria, four clinical trials were reviewed. We used the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol for this systematic review. We used the Cochrane Collaboration risk-of-bias tool to assess the bias encountered in each study. Overall, IV arginine seems to be effective in improving symptoms during acute attacks of MELAS, while oral arginine supplementation increases endothelial function, preventing further stroke-like episodes.

Prevalence of Fabry Disease in Patients With Cryptogenic Strokes: A Systematic Review.

Fabry disease (FD) is an X-linked disorder involving multiple organs. Stroke is a serious and frequent complication of FD. Cryptogenic stroke is a common presentation of FD, especially in the young population. The etiology of cryptogenic stroke is highly variable and difficult to assess, frequently leaving patients without a primary diagnosis. We conducted a systematic review to investigate the pooled prevalence of FD among patients with cryptogenic stroke, or patients with FD in whom a stroke was the presenting condition. English-language studies involving humans published in the last 20 years were included in this systematic review. FD was more common in male patients and tended to present at an earlier age. The frequency of hemorrhagic and ischemic strokes in this population was similar to that in the general population. There was a high rate of stroke recurrence in the study sample, even among patients undergoing enzyme replacement therapy. We conclude that screening for FD in patients with cryptogenic stroke is low yield and not cost-effective. However, it may be worthwhile to screen for FD among patients with recurrent strokes.

Understanding Parinaud's Syndrome.

Parinaud's syndrome involves dysfunction of the structures of the dorsal midbrain. We investigated the pathophysiology related to the signs and symptoms to better understand the symptoms of Parinaud's syndrome: diplopia, blurred vision, visual field defects, ptosis, squint, and ataxia, and Parinaud's main signs of upward gaze paralysis, upper eyelid retraction, convergence retraction nystagmus (CRN), and pseudo-Argyll Robertson pupils. In upward gaze palsy, three structures are disrupted: the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), interstitial nucleus of Cajal (iNC), and the posterior commissure. In CRN, there is a continuous discharge of the medial rectus muscle because of the lack of inhibition of supranuclear fibers. In Collier's sign, the posterior commissure and the iNC are mainly involved. In the vicinity of the iNC, there are two essential groups of cells, the M-group cells and central caudal nuclear (CCN) group cells, which are important for vertical gaze, and eyelid control. Overstimulation of the M group of cells and increased firing rate of the CCN group causing eyelid retraction. External compression of the posterior commissure, and pretectal area causes pseudo-Argyll Robertson pupils. Pseudo-Argyll Robertson pupils constrict to accommodation and have a slight response to light (miosis) as opposed to Argyll Robertson pupils were there is no response to a light stimulus. In Parinaud's syndrome patients conserve a slight response to light because an additional pathway to a pupillary light response that involves attention to a conscious bright/dark stimulus. Diplopia is mainly due to involvement of the trochlear nerve (IVth cranial nerve. Blurry vision is related to accommodation problems, while the visual field defects are a consequence of chronic papilledema that causes optic neuropathy. Ptosis in Parinaud's syndrome is caused by damage to the oculomotor nerve, mainly the levator palpebrae portion. We did not find a reasonable explanation for squint. Finally, ataxia is caused by compression of the superior cerebellar peduncle.

Understanding Seizures and Prognosis of the Extreme Delta Brush Pattern in Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Systematic Review.

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (ANMDARE) is an autoimmune disorder with neurological and psychiatric features. The disease presents with a viral prodrome, followed by psychiatric manifestations. In the next phase, movement disorders or/and seizures occur. Finally, in the last phase, there is a decrease in the level of consciousness. Central hypoventilation and autonomic dysfunction can occur. Recently a unique EEG (electroencephalogram) pattern has been associated with anti-NMDA receptor encephalitis, the extreme delta brush (EDB). Although the association of the EDB with ANMDARE is known by the medical community, its significance is mainly unknown. A systematic review on NMDARE is also scarce. We decided to conduct a systematic review on this topic to consolidate the knowledge and establish the importance of the EDB as a prognostic factor. To conduct this systematic review, we used only studies conducted in humans, written in English, and published in the last 20 years. We used PubMed as a database and searched the following search terms: ("NMDA encephalitis"[Title/Abstract] AND "Epilepsy"[Title/Abstract]) OR (NMDA encephalitis"[Title/Abstract] AND "seizures" [Title/Abstract]) OR ("NMDA encephalitis"[Title/Abstract] AND "extreme delta brush"[Title/Abstract]). The protocol used for this systematic review was the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) protocol, and to analyze the bias of the studies, we used the ROBINS-1 tool. Eight studies were collected from our search strategy. Our data pulling showed that seizures were present in 178/249 (71.48%) patients. Status Epilepticus was reported in 29/96 (30.20%), and the EBD was seen in 30.89% (55/178) patients with seizures. The range of EDB was 5.9%-33% among the studies. Because the sample size was small, the statistical power was decreased. We had a low overall risk of bias. The wide range in the results could be related to the timing of the EEG recording. EDB was associated overall with increased length of hospital stay, increased ICU admission, and incidence of status epilepticus. The etiology of the EDB remains mainly unknown. However, it has been postulated that in NMDAR encephalitis, there is a disruption of the rhythmic neuronal activity. When antibodies block/target the NMDAR, the rhythmic neuronal activity is disrupted, leading to the unique EDB pattern. Another theory suggests that delta activity is caused because of focal abnormalities in the brain, and the superimposition of the beta waves is related to the alterations of the NMDA receptors.

Efficacy and Toxicity of Fexinidazole and Nifurtimox Plus Eflornithine in the Treatment of African Trypanosomiasis: A Systematic Review.

Human African trypanosomiasis (HAT), or sleeping sickness disease, is an infection caused mainly by Trypanosoma brucei gambiense-human African trypanosomiasis (g-HAT) and is transmitted by tsetse flies. The disease goes through two stages: hemolymphatic and meningo-encephalic phases. The treatment for the second stage has changed from melarsoprol or eflornithine to nifurtimox-eflornithine combination therapy (NECT) and fexinidazole. We aimed to systematically review the literature on the efficacy and toxicity of fexinidazole and NECT. We used PubMed advanced strategy and Google Scholar databases, including clinical trials and observational studies on humans in the last 20 years in the English literature. Applying the inclusion/exclusion criteria, we reviewed eight studies. We used Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) protocol. For assessing bias, we used the Cochrane Collaboration's tool for risk assessment of the clinical trials and the Robins-I tool for the observational studies. Overall, the clinical trials showed that NECT was non-inferior to eflornithine. The proportion of patients discharged alive is higher in patients treated with NECT vs. patients treated with eflornithine. Gastrointestinal complaints are a common side effect of NECT therapy, while fearful but relatively rare convulsions can also occur. The main limitation among the studies of NECT was the lack of blinding because most of them were open-label. Fexinidazole, the new oral medication showed is effective and safe for the treatment of g-HAT infection. Because of their convenience, fexinidazole is preferred over NECT therapy, oral vs. IV infusion in the first and second stages of the disease. Compared to older therapies, fexinidazole and NECT are more effective and safer than eflornithine and melarsoprol monotherapy.

Opioid Antagonist in the Treatment of Ischemic Stroke.

Stroke is a leading cause of death and disability, and novel treatments need to be found, particularly drugs with neuroprotective and restorative effects. Lately, there has been an increased interest in the relationship between opioids and ischemic stroke. To further appreciate this association between opioids and stroke, we conducted a systematic review to investigate anti-opioid medication's effectiveness in treating ischemic stroke. We used PubMed advanced-strategy and Google Scholar searches and only included full-text clinical trials on humans and written in the English language. After applying the inclusion/exclusion criteria, seven clinical trials were reviewed. Only one of the naloxone and nalmefene clinical trials showed statistically favorable results. Overall, the nalmefene clinical trials used more updated measures (NIHSS, GOS) to evaluate recovery and functional status in ischemic stroke patients than the naloxone clinical trials. There was less bias in the nalmefene clinical trials. Animal and in vitro studies have showed promising results. Additional research should be conducted with new clinical trials of both drugs with larger samples in patients less than 70 years old and moderate to severe infarcts.

A Unique Case of Pyruvate Carboxylase Deficiency.

Pyruvate carboxylase (PC) converts pyruvate to oxaloacetate, which is an important step in gluconeogenesis. Pyruvate carboxylase deficiency (PCD) is a rare inherited metabolic disorder characterized by movement disorders, neurologic disturbances, hypoglycemia, lactic acidosis, hyperammonemia, and elevated levels of pyruvate and alanine in plasma. The prognosis for PCD is poor. Most children die within the first six months of life, and those who survive longer have neurological damage and mental disability. This is due to the accumulation of lactic acid and toxic components in the blood. Here we describe the case of a 21-month-old male presenting with abnormal movements and new-onset seizures. His family history is relevant because of parental consanguinity. A genetic analysis showed a novel mutation, homozygous c. 2630A>G (p. Gln877Arg) variant, in the PC gene, a mutation not previously described in the English literature.

Refractory Seizure in a Patient With Griscelli Syndrome: A Unique Case With One Mutation and a Novel Deletion.

Griscelli syndrome (GS) is a rare syndrome characterized by hypopigmentation, immunodeficiency, and neurological features. The genes Ras-related protein (RAB27A) and Myosin-Va (MYO5A) are involved in this condition's pathogenesis. We present a GS type 1 (GS1) case with developmental delay, hypotonia, and refractory seizures despite multiple medications, which included clobazam, cannabinol, zonisamide, and a ketogenic diet. Lacosamide and levetiracetam were added to the treatment regimen, which decreased the seizures' frequency from 10 per day to five per day. The patient had an MYO5A mutation and, remarkably, a deletion on 18p11.32p11.31. The deletion was previously reported in a patient with refractory seizures and developmental delay. We reviewed all cases of GS that presented with seizures. We reviewed other cases of GS and seizures described in the literature and explored possible seizure mechanisms in GS. Seizure in GS1 seems to be related directly to the MYO5A mutation. The neurological manifestations in GS2 seem to be caused indirectly by the accelerated phase of Hemophagocytic syndrome (HPS), which is characteristic of GS2. By having the MYO5A gene mutation combined with the 18p11.32p11.31 deletion, the prognosis and severity of the patient's condition are poor. This is the first report of GS1 with a deletion in 18p11.32p11.31.

A bibliometric analysis of COVID-19 research in Latin America and the Caribbean / Un análisis bibliométrico de la investigación sobre COVID-19 en Latinoamérica y el Caribe

Abstract Introduction: Latin America and the Caribbean (LAC) is one of the regions most affected by the COVID-19 pandemic. Yet, there is scarce literature addressing the research strategies developed in LAC to face COVID-19. Objective: To quantify and assess the production of scientific publications about COVID-19 in 32 countries of LAC between January 1 and July 31, 2020. Materials and methods: Bibliometric study. Scientific papers on COVID-19 conducted in LAC or reporting data pertaining to LAC and published between January 1 to July 31, 2020, were searched in the Scopus, PubMed, and LILACS databases. A subgroup analysis including only original research articles was performed to determine the contribution of LAC countries to research on COVID-19, and standardization measures (# of articles per million people) were applied to compare the country-specific production of this type of articles. Results: A total of 1 291 publications were retrieved. Overall, most of them were non-original research articles (81.72%), and the countries with the highest scientific production were Brazil (43.91%) and Mexico (9.14%). However, after applying the standardization measures, Chile was the country with the highest production of original articles (0.58 per million inhabitants). Regarding original studies (n=236), cross-sectional design was the most common (25.84%). Diagnosis and treatment of the disease was the main research focus (n=354; 27.42%). However, in the subgroup analysis (n=236), epidemiology and surveillance were the most prevalent research focus (n=57; 24.15%). Conclusions: During the study period, non-original research articles were predominant in the scientific production of the LAC region, and interventional studies were scarce among original articles, while the cross-sectional design predominated. Further research with a better quality of evidence should be performed in these countries to contribute to the making of health policies aimed at easing the burden of COVID-19 in the region and preparing for future pandemics.

Resumen Introducción. Latinoamérica y el Caribe (LAC) es una de las regiones más afectadas por la pandemia por COVID-19. Sin embargo, hay poca literatura sobre las estrategias de investigación desarrolladas en la región para confrontar esta enfermedad. Objetivo. Cuantificar y evaluar la producción de publicaciones científicas sobre COVID-19 en 32 países de LAC entre el 1 de enero y el 31 de julio del 2020. Materiales y métodos. Estudio bibliométrico. Se realizó una búsqueda de artículos científicos sobre COVID-19 realizados en LAC o con datos de LAC, y publicados entre enero 1 y julio 31 de 2020 en Scopus, PubMed y LILACS. Se realizó un análisis de subgrupos en el que se incluyeron solo artículos de investigación original para determinar la contribución de los países de la región a la investigación sobre COVID-19; además, se utilizaron medidas de estandarización (# artículos por millón de habitantes) para comparar la producción de este tipo de artículos por país. Resultados. Se identificaron 1 291 artículos. La mayoría no eran investigaciones originales (81.72%), y los países con más producción fueron Brasil (43.91%) y México (9.14%). Sin embargo, luego de aplicar las medidas de estandarización, Chile fue el país con mayor producción de artículos originales (0.58 por millón de habitantes). Respecto a los artículos originales (n = 236), el tipo de diseño de estudio más común fue el transversal (25.84%). El diagnóstico y tratamiento de COVID-19 fue el tema más investigado en todas las publicaciones (n = 354, 27.42%), pero en el análisis de subgrupo (n=236), el enfoque de investigación más frecuente fue epidemiologia y vigilancia (n = 57, 24.15%). Conclusiones. En el periodo de estudio, los artículos no originales predominaron en la producción científica de LAC, y, entre las investigaciones originales, los estudios intervencionales escasearon, mientras que los transversales predominaron. Se requiere realizar más investigación con una mejor calidad de evidencia en los países de la región para contribuir en la formulación de políticas de salud dirigidas a aliviar la carga de la COVID-19 y para prepararse para futuras pandemias.