Neurology International

With emerging information about the potential for morbidity and reduced life expectancy with long-term use of opioids, it is logical to evaluate nonopioid analgesic treatments to manage pain states. Combinations of drugs can provide additive and/or synergistic effects that can benefit the management of pain states. In this regard, tetrahydrocannabinol (THC) and cannabidiol (CBD) modulate nociceptive signals and have been studied for chronic pain treatment. Psilocybin, commonly known as “magic mushrooms”, works at the serotonin receptor, 5-HT_2A. Psilocybin has been found in current studies to help with migraines since it has a tryptamine structure and works similarly to triptans. Psilocybin also has the potential for use in chronic pain treatment. However, the studies that have looked at alternative plant-based medications such as THC, CBD, and psilocybin have been small in terms of their sample size and may not consider the demographic or genetic differences in the population because of their small sample sizes. At present, it is unclear whether the effects reported in these studies translate to the general population or even are significant. In summary, additional studies are warranted to evaluate chronic pain management with alternative and combinations of medications in the treatment of chronic pain. Full article

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. The clinical spectrum of suspected AD has been extended from mild cognitive impairment (MCI) to preclinical AD which includes people who have typical cognitive function but harbor the underlying biological features of AD. We report the first case of an Italian patient affected by MCI (MMSE 24\30), characterized by a double mutation p.Lys311Arg (K311R) and p.Glu318Gly (E318G) in Presenilin-1 but with the absence of abnormal accumulation of amyloid beta. Full article

Background and aims. Patients with Myasthenia gravis (MG) are considered vulnerable as they may present with respiratory muscle weakness and because they are on immunosuppressive treatment; thereby, COVID-19 may have a detrimental effect on these patients. Vaccines against COVID-19 are currently available and it has been shown as they can prevent severe COVID-19 in vulnerable patients. Notwithstanding their efficacy, vaccine hesitancy has not been completely dispelled in the general population. Unfortunately, there is limited data about the safety of these vaccines in MG patients. The aims of this study are to evaluate the impact of COVID-19 in a MG cohort, the adherence to COVID-19 vaccination in Italy and vaccine safety in MG patients. Methods. A retrospective cohort study of MG patients attending the Neuromuscular Clinic of the University Hospital “Paolo Giaccone” of Palermo, Italy, was performed. Patients underwent telephone interviews with a dedicated questionnaire on SARS-CoV-2 vaccination and infection. Vaccine safety was assessed though the evaluation of vaccine-related adverse events (AEs) and comparisons of MG-ADL scores before and after vaccination. Patient worsening was defined as two or more point increases in MG-ADL scores. Results. From a total of 90 participants, 75 answered the questionnaire and 70.5% of them (n = 53) received the vaccine; ten patients did not receive vaccination and 3 patients were partially vaccinated. Among the vaccinated patients, about 45% (n = 24) experienced at least one AE, with a complete resolution within one week. No serious AEs and life-threatening conditions were observed. Globally, MG-ADL scores did not worsen after vaccination. Nine unvaccinated patients experienced SARS-CoV2 infection and four of them (44%) died—one patient required respiratory support, whereas three patients were asymptomatic. Conclusions. COVID-19 significantly impacted MG patients with an increase in mortality due to respiratory sequelae. Vaccines against SARS-CoV-2 showed good short-term safety in MG patients, who may take advantage of vaccination to avoiding life-threatening complications such as COVID-19 pneumonia. Full article

Stroke is a fatal morbidity that needs emergency medical admission and immediate medical attention. COVID-19 ischemic brain damage is closely associated with common neurological symptoms, which are extremely difficult to treat medically, and risk factors. We performed literature research about COVID-19 and ischemia in PubMed, MEDLINE, and Scopus for this current narrative review. We discovered parallel manifestations of SARS-CoV-19 infection and brain ischemia risk factors. In published papers, we discovered a similar but complex pathophysiology of SARS-CoV-2 infection and stroke pathology. A patient with other systemic co-morbidities, such as diabetes, hypertension, or any respiratory disease, has a fatal combination in intensive care management when infected with SARS-CoV-19. Furthermore, due to their shared risk factors, COVID-19 and stroke are a lethal combination for medical management to treat. In this review, we discuss shared pathophysiology, adjuvant risk factors, challenges, and advancements in stroke-associated COVID-19 therapeutics. Full article

The amygdala is a prominent region of the brain that plays a critical role in the pathophysiology of major depressive disorder (MDD). The amygdala is formed from a collection of interconnected substructures (nuclei) that relay signals from multiple brain areas, which suggests that the amygdala has different functions depending on its subregion. There are two main alleles of serotonin transporter gene polymorphism (5-HTTLPR): a 44-bp insertion (l-allele) or deletion (s-allele). The transcriptional activity of the l-allele of the gene is twice that of the s-allele. The present study aimed to investigate the association between the volume of the whole amygdala and subregions of the amygdala in 25 first-episode and drug-naive patients with MDD and 46 healthy controls (HCs) with the s/s genotype of 5-HTTLPR and plasma levels of brain-derived neurotrophic factor (BDNF) or cortisol. No significant difference was observed in the amygdala total and subregion volumes between the HC and MDD groups. No significant difference was found in the plasma levels of BDNF and cortisol between the two groups. In addition, no correlations were found between the total and subregion amygdala volume and plasma levels of cortisol or BDNF. Full article

The COVID-19 pandemic poses an ongoing global challenge, and several risk factors make people with multiple sclerosis (pwMS) particularly susceptible to running a severe disease course. Although the literature does report numerous articles on the risk factors for severe COVID-19 and vaccination response in pwMS, there is a scarcity of reviews integrating both these aspects into strategies aimed at minimizing risks. The aim of this review is to describe the risk of vulnerable pwMS exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the issues related to the SARS-CoV-2 vaccine and to evidence possible future strategies in the clinical management of pwMS. The authors searched for papers on severe COVID-19 risk factors, SARS-CoV-2 vaccination and people with multiple sclerosis in support of this narrative literature review. We propose a multilevel strategy aimed at: the evaluation of risk factors for severe COVID-19 in people with multiple sclerosis, identifying the most appropriate vaccination schedule that is safe for people on disease-modifying drugs (DMDs) and a strict follow-up of high-risk people with multiple sclerosis to allow for the prompt administration of monoclonal antibodies to manage COVID-19 risks in this patient population. Full article

New diagnostic methods have been developed for the early diagnosis of Alzheimer’s disease (AD) with the primary purpose of intercepting the transition-phase (mild cognitive impairment, MCI) between normal aging and dementia. We aimed to explore whether the five-word test (FWT) and the mini-mental state examination (MMSE) are predictive for the early diagnosis of MCI due to AD (AD-MCI). We computed ROC analyses to evaluate the sensitivity and specificity of MMSE and FWT in predicting abnormal CSF (t-Tau, p-Tau₁₈₁, Aβ_1–42) and amyloid-PET biomarkers. AD-MCI patients showed lower MMSE and FWT scores (all p < 0.001) than non-AD-MCI. The best predictor of amyloid plaques’ presence at amyloid-PET imaging was the encoding sub-score of the FWT (AUC = 0.84). Both FWT and MMSE had low/moderate accuracy for the detection of pathological CSF Aβ₄₂, t-Tau and p-Tau₁₈₁ values, with higher accuracy for the t-Tau/Aβ_1–42 ratio. In conclusion, the FWT, as a single-domain cognitive screening test, seems to be prompt and moderately accurate tool for the identification of an underlying AD neuropathological process in patients with MCI, supporting the importance of associating biomarkers evaluation in the work-up of patients with dementing neurodegenerative disorders. Full article

Ataxia is increasingly being recognized as a cardinal manifestation in primary mitochondrial diseases (PMDs) in both paediatric and adult patients. It can be caused by disruption of cerebellar nuclei or fibres, its connection with the brainstem, or spinal and peripheral lesions leading to proprioceptive loss. Despite mitochondrial ataxias having no specific defining features, they should be included in hereditary ataxias differential diagnosis, given the high prevalence of PMDs. This review focuses on the clinical and neuropathological features and genetic background of PMDs in which ataxia is a prominent manifestation. Full article

In subacute stroke patients we studied cortical oxygenation changes by near-infrared spectroscopy (NIRS) during a motor task performed with the hemiparetic arm (15 s of reaching and grasping, 45 s of rest, repeated 6 times). Twenty-three subjects were included at baseline, compared with six healthy subjects, and restudied after 6 weeks of rehabilitation. Motor/premotor cortical changes in oxyhemoglobin detected by NIRS were quantified as the area under the curve (AUC) for the total cortex (TOT-_AUC) and for both affected (AFF-_AUC) and unaffected hemispheres (UN-_AUC). The ratio between AUC and the number of task repetitions performed identified the cortical metabolic cost (CMC) or the oxygenation increase for a single movement. Fugl–Meyer assessment of the upper extremity (FMA-UE) was also performed. At baseline, both total and hemispheric CMC were significantly higher in stroke patients than in healthy subjects and inversely correlated with FMA-UE. After rehabilitation, changes in total-CMC and unaffected-CMC, but not Affected-CMC, were inversely correlated with variations in the FMA-UE score. A value > 5000 a.u. for the ratio baseline TOT-_CMC/days since stroke was associated with not reaching the clinically important difference for FMA-UE after rehabilitation. In subacute stroke the CMC, a biomarker assessed by NIRS during a motor task with the hemiparetic arm, may describe cortical time/treatment reorganization and favor patient selection for rehabilitation. Full article

Depression is a leading cause of disability globally, with a prevalence of 3.8% among the whole population, 5% of the adult population, and 5.7% of the elderly population over 60 years of age. There is evidence that depression is linked to certain neurodegenerative diseases, one being Alzheimer’s disease (AD). The efficacy of conventional antidepressants to treat depression in AD is conflicting, especially regarding selective serotonin reuptake inhibitors (SSRIs). A recent systemic review and meta-analysis of 25 randomized controlled trials including fourteen antidepressant medications showed no high efficacy in treating AD patients’ symptoms. However, ketamine, a nonselective N-methyl-D-aspartate (NMDA) receptor antagonist, can mediate a wide range of pharmacological effects, including neuroprotection, anti-inflammatory and anticancer properties, multimodal analgesia, and treatment of depression, suicidal attempts, and status epilepticus. Esketamine, which is ketamine formulated as a nasal spray, was approved by the Federal Drug Administration (FDA) in March 2019 as an adjuvant drug to treat treatment-resistant depression. NMDA receptor antagonists treat AD through offsetting AD-related pathological stimulation of subtypes of glutamate receptors in the central nervous system. Recent clinical findings suggest that ketamine may provide neuroprotection and reduce neuropsychiatric symptoms associated with AD. In the present investigation, we evaluate the potential role of ketamine and its postulated mechanism in AD management. Full article

Schizophrenia is a psychotic disorder that exists at the more extreme end of a spectrum of diseases, and significantly affects daily functioning. Cardiovascular adverse effects of antipsychotic medications are well known, and include changes in blood pressure and arrhythmias. Sudden cardiac death is the leading cause of death worldwide, and antipsychotic medications are associated with numerous cardiac side effects. A possible link exists between antipsychotic medications and sudden cardiac death. Common prescribing patterns that may influence cardiovascular events include the use of multiple antipsychotics and/or additional drugs commonly prescribed to patients on antipsychotics. The results of this review reflect an association between antipsychotic drugs and increased risk of ventricular arrhythmias and sudden cardiac death by iatrogenic prolongation of the QTc interval. QTc prolongation and sudden cardiac death exist in patients taking antipsychotic monotherapy. The risk increases for the concomitant use of specific drugs that prolong the QTc interval, such as opioids, antibiotics, and illicit drugs. However, evidence suggests that QTc intervals may not adequately predict sudden cardiac death. In considering the findings of this narrative review, we conclude that it is unclear whether there is a precise association between antipsychotic polypharmacy and sudden cardiac death with QTc interval changes. The present narrative review warrants further research on this important potential association. Full article

Here, a study of NMOSD in Central America and the Caribbean with a multinational collaborative, multicentric and descriptive approach involving 25 institutions from 9 countries is presented. Demographics, clinical manifestations, expanded disability scale status (EDSS), brain and spinal cord MRI, serological anti-AQP4-IgG and anti-MOG-IgG antibodies, and cerebrospinal fluid (CSF) oligoclonal bands were included. A central serological repository utilized the cell-based assay. The specimens outside of this network employed diverse methodologies. Data were collected at the Gorgas Commemorative Institute of Health Studies (ICGES), Panama, and included 186 subjects, of which 84% were females (sex ratio of 5.6:1). Mestizos constituted 72% of the study group. The median age was 42.5 years (IQR: 32.0–52.0). Associated autoimmune diseases (8.1%) were myasthenia gravis, Sjögren’s syndrome and systemic lupus erythematosus. The most common manifestation was optic neuritis-transverse myelitis (42.5%). A relapsing course was described in 72.3% of cases. EDSS scores of 0–3.5 were reported in 57.2% of cases and higher than 7.0 in 14.5%. Positive anti-AQP4-IgG antibody occurred in 59.8% and anti-MOG-IgG antibody in 11.5% of individuals. Antibody testing was lacking for 13.4% of patients. The estimated crude prevalence of NMOSD from Panama and the Dominican Republic was 1.62/100,000 (incidence of 0.08–0.41) and 0.73/100,000 (incidence 0.02–0.14), respectively. This multinational study contributes additional insights and data on the understanding of NMOSD in this Latin American region. Full article

The brand interchangeability of antiepileptic drugs (AEDs) is a topic of debate, especially regarding their therapeutic equivalence. This study evaluates the efficacy and tolerability of generic levetiracetam compared to the brand-name equivalent in a routine clinical setting. We conducted a retrospective study, examining patients with stable seizure frequency who received generic levetiracetam after the brand-name drug. During the six-month substitution period, changes in seizure frequency, hospitalization due to seizure exacerbation, adverse events, composite outcomes related to adjusting the AED dosage, and switching back to original levetiracetam were analyzed. Seventy-five patients were enrolled; the majority (85.3%) had focal onset seizures, and almost half (49.3%) had refractory epilepsy. Six months after the substitution, the mean seizure frequency per month was not significantly different (3.15 ± 14.47 vs. 2.77 ± 11.41; p = 0.970). In patients with controlled seizures before the change, the seizure frequency increased significantly (0.56 ± 1.83 vs. 0.03 ± 0.16; p = 0.012). Adverse events occurred in six patients. We have observed recurrent seizures or adverse events from 14 days after the transition. The original drug return rates due to recurrent seizures and adverse events were 5.3% and 1.3%, respectively. Generic levetiracetam might not show therapeutic equivalence to the original molecule, especially in patients adequately controlled by the brand-name drug. Full article

Background: Infantile spasms are an age-specific epileptic disorder. They occur in infancy and early childhood. They can be caused by multiple etiologies. Structural abnormalities represent an important cause of infantile spasms. Brain magnetic resonance imaging (MRI) is one of the integral modalities in the evaluation of this condition. Purpose: The aim of this study is to review and analyze the clinical characteristics and brain MRI findings in a cohort of children diagnosed with infantile spasms. Material and Methods: A cohort of fifty-six children diagnosed with infantile spasms in infancy and early childhood was included. All of them underwent brain MRI for evaluation. The study was conducted in the period from January 2016 to January 2020. Results: Females comprised 57% of the cohort. The mean age for seizure onset was 5.9 months (SD 2.7). Forty-one patients (73%) had active epilepsy, and 51% were diagnosed with global developmental delay. Consanguinity was present in 59% of the cohort. Most of the follow-up MRIs showed structural abnormalities (84%). Hypoxia was reported in 17% of MRIs. Malformations of cortical development were seen in five patients. Brain MRI findings were normal in 16% of patients, and delayed myelination was seen in nineteen patients. Most of the children with active epilepsy (64%) and developmental delay (82%) had an abnormal brain MRI. It was noticed that abnormal second brain MRIs were more likely to be associated with active epilepsy and developmental delay (p = 0.05). Conclusions: Brain MRI is an integral part of infantile spasms’ clinical evaluation. Infantile spasms and abnormal brain MRI can be associated with active epilepsy and global developmental delay. Full article

Background: Cerebral small vessels disease (cSVD) is an age-related disorder and risk factor for stroke and cognitive/motor impairments. Neurological complications (NCs) are among the causes of adverse outcomes in older liver transplant recipients. This study sought to determine whether cSVD predicts acute NCs in over 65-year-old liver transplant patients. Methods: Data were collected, from a retrospective medical chart review, of 22 deceased donor liver transplant recipients aged 65 years or older with a pre-operative brain magnetic resonance imaging (MRI). We used the Fazekas score (0–3) as a quantitative measurement of the vascular lesion load seen in the MRI. We analyzed all post-operative acute NCs occurring during the hospital stay and any other non-NC. Results: cSVD was recognized in all patients. Neurological complications (NCs) occurred in 18.1% of patients with toxic-metabolic encephalopathy the most frequent diagnosis (13.64%). More severe cSVD was associated with seizures (p = 0.0362), longer hospital stay (p 0.0299), and disability (p 0.0134). In our elderly cohort, hepatic encephalopathy (HE) (p 0.0287) and ascites (p 0.0270) were predictors of NCs after liver transplantation. Ascites and/or variceal bleeding and severity of liver disease were associated with adverse post-operative outcomes. The small sample size limited the statistical analysis power. Conclusions: We present the preliminary data of a single-center retrospective study aimed at understanding the cSVD role on NCs and non-NCs after a liver transplantation in elderly patients. This would encourage a more appropriate multicenter prospective study that will definitely confirm if a neurological screening in old age liver transplant candidates is appropriate. Full article

POLR3B and POLR3A are the major subunits of RNA polymerase III, which synthesizes non-coding RNAs such as tRNAs and rRNAs. Nucleotide mutations of the RNA polymerase 3 subunit b (polr3b) gene are responsible for hypomyelinating leukodystrophy 8 (HLD8), which is an autosomal recessive oligodendroglial cell disease. Despite the important association between POLR3B mutation and HLD8, it remains unclear how mutated POLR3B proteins cause oligodendroglial cell abnormalities. Herein, we show that a severe HLD8-associated nonsense mutation (Arg550-to-Ter (R550X)) primarily localizes POLR3B proteins as protein aggregates into lysosomes in the FBD-102b cell line as an oligodendroglial precursor cell model. Conversely, wild type POLR3B proteins were not localized in lysosomes. Additionally, the expression of proteins with the R550X mutation in cells decreased lysosome-related signaling through the mechanistic target of rapamycin (mTOR). Cells harboring the mutant constructs did not exhibit oligodendroglial cell differentiated phenotypes, which have widespread membranes that extend from their cell body. However, cells harboring the wild type constructs exhibited differentiated phenotypes. Ibuprofen, which is a non-steroidal anti-inflammatory drug (NSAID), improved the defects in their differentiation phenotypes and signaling through mTOR. These results indicate that the HLD8-associated POLR3B proteins with the R550X mutation are localized in lysosomes, decrease mTOR signaling, and inhibit oligodendroglial cell morphological differentiation, and ibuprofen improves these cellular pathological effects. These findings may reveal some of the molecular and cellular pathological mechanisms underlying HLD8 and their amelioration. Full article

We report the clinical and genetic analysis of a patient with a rare form of an autosomal recessive genetic neuropathy, Charcot Marie Tooth (CMT) disease type 4J. She presented at age 62 years with signs and symptoms consistent with a mild neuropathy. The onset of symptoms began approximately ten years earlier. Electrophysiological testing confirmed a demyelinating neuropathy and a comprehensive neuropathy screening for common causes of neuropathy was unrevealing. She underwent commercial whole exome sequencing, analyzing more than eighty genes known to cause neuropathy. Two mutations were detected, c.122T > C, p.Ile41Thr and c.2247dupC, p.Ser750GlnX10 in the FIG4 gene. The p.Ile41Thr mutation, which is paternally inherited, is a recurrent mutation reported in a number of unrelated families of European descent. The patient’s father, also of European descent, provides further evidence supporting a founder effect for this mutation. In most patients carrying the p.Ile41Thr mutation, the neuropathy, unlike our patient, is often severe with early onset. The second mutation, c.2247dupC, p.Ser750GlnX10 is maternally inherited and not previously reported. Furthermore, based upon our protein modeling analysis, c.2247dupC is disease producing, representing a novel pathogenic mutation. Our study of this patient expands the clinical and genetic spectrum of patients with CMT 4J. Full article