Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives.

Voltage-gated calcium channels (VGCCs) are widely expressed in the brain, heart and vessels, smooth and skeletal muscle, as well as in endocrine cells. VGCCs mediate gene transcription, synaptic and neuronal structural plasticity, muscle contraction, the release of hormones and neurotransmitters, and membrane excitability. Therefore, it is not surprising that VGCC dysfunction results in severe pathologies, such as cardiovascular conditions, neurological and psychiatric disorders, altered glycemic levels, and abnormal smooth muscle tone. The latest research findings and clinical evidence increasingly show the critical role played by VGCCs in autism spectrum disorders, Parkinson's disease, drug addiction, pain, and epilepsy. These findings outline the importance of developing selective calcium channel inhibitors and modulators to treat such prevailing conditions of the central nervous system. Several small molecules inhibiting calcium channels are currently used in clinical practice to successfully treat pain and cardiovascular conditions. However, the limited palette of molecules available and the emerging extent of VGCC pathophysiology require the development of additional drugs targeting these channels. Here, we provide an overview of the role of calcium channels in neurological disorders and discuss possible strategies to generate novel therapeutics.

A Review of the Health Protective Effects of Phenolic Acids against a Range of Severe Pathologic Conditions (Including Coronavirus-Based Infections).

Phenolic acids comprise a class of phytochemical compounds that can be extracted from various plant sources and are well known for their antioxidant and anti-inflammatory properties. A few of the most common naturally occurring phenolic acids (i.e., caffeic, carnosic, ferulic, gallic, p-coumaric, rosmarinic, vanillic) have been identified as ingredients of edible botanicals (thyme, oregano, rosemary, sage, mint, etc.). Over the last decade, clinical research has focused on a number of in vitro (in human cells) and in vivo (animal) studies aimed at exploring the health protective effects of phenolic acids against the most severe human diseases. In this review paper, the authors first report on the main structural features of phenolic acids, their most important natural sources and their extraction techniques. Subsequently, the main target of this analysis is to provide an overview of the most recent clinical studies on phenolic acids that investigate their health effects against a range of severe pathologic conditions (e.g., cancer, cardiovascular diseases, hepatotoxicity, neurotoxicity, and viral infections-including coronaviruses-based ones).

Suggestibility in functional neurological disorder: a meta-analysis.

OBJECTIVE: Responsiveness to direct verbal suggestions (suggestibility) has long been hypothesised to represent a predisposing factor for functional neurological disorder (FND) but previous research has yielded conflicting results. The aim of this study was to quantitatively evaluate whether patients with FND display elevated suggestibility relative to controls via meta-analysis. METHODS: Four electronic databases were searched in November 2019, with the search updated in April 2020, for original studies assessing suggestibility using standardised behavioural scales or suggestive symptom induction protocols in patients with FND (including somatisation disorder) and controls. The meta-analysis followed Cochrane, Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines. Data extraction and study quality coding were performed by two independent reviewers. Standardised suggestibility scores and responsiveness to symptom induction protocols were used to calculate standardised mean differences (SMDs) between groups. RESULTS: Of 26 643 search results, 19 articles presenting 11 standardised suggestibility data sets (FND: n=316; control: n=360) and 11 symptom suggestibility data sets (FND: n=1285; control: n=1409) were included in random-effect meta-analyses. Meta-analyses revealed that patients with FND displayed greater suggestibility than controls on standardised behavioural scales (SMD, 0.48 (95% C, 0.15 to 0.81)) and greater responsiveness to suggestive symptom induction (SMD, 1.39 (95% CI 0.92 to 1.86)). Moderation analyses presented mixed evidence regarding the extent to which effect sizes covaried with methodological differences across studies. No evidence of publication bias was found. CONCLUSIONS: These results corroborate the hypothesis that FND is characterised by heightened responsiveness to verbal suggestion. Atypical suggestibility may confer risk for FND and be a cognitive marker that can inform diagnosis and treatment of this condition.

Psychedelic-assisted therapy for functional neurological disorders: A theoretical framework and review of prior reports.

Functional neurological disorders (FNDs), which are sometimes also referred to as psychogenic neurological disorders or conversion disorder, are common disabling neuropsychiatric disorders with limited treatment options. FNDs can present with sensory and/or motor symptoms, and, though they may mimic other neurological conditions, they are thought to occur via mechanisms other than those related to identifiable structural neuropathology and, in many cases, appear to be triggered and sustained by recognizable psychological factors. There is intriguing preliminary evidence to support the use of psychedelic-assisted therapy in a growing number of psychiatric illnesses, including FNDs. We review the theoretical arguments for and against exploring psychedelic-assisted therapy as a treatment for FNDs. We also provide an in-depth discussion of prior published cases detailing the use of psychedelics for psychosomatic conditions, analyzing therapeutic outcomes from a contemporary neuroscientific vantage as informed by several recent neuroimaging studies on psychedelics and FNDs.

Gitelman syndrome associated with chondrocalcinosis and severe neuropathy: a novel heterozygous mutation in SLC12A3 gene.

Gitelman syndrome (GS) is an inherited salt-wasting tubulopathy characterized by hypocalciuria, hypokalemia, hypomagnesemia and metabolic alkalosis, due to inactivating mutations in the SLC12A3 gene. Symptoms may be systemic, neurological, cardiovascular, ophthalmological or musculoskeletal. We describe a 70 year-old patient affected by recurrent arthralgias, hypoesthesia and hyposthenia in all 4 limbs and severe hypokalemia, complicated by atrial flutter. Moreover, our patient reported eating large amounts of licorice, and was treated with medium-high dosages of furosemide, thus making diagnosis very challenging. Genetic analysis demonstrated a novel heterozygous mutation in the SLC12A3 gene; therefore, we diagnosed GS and started potassium and magnesium replacement. GS combined with chondrocalcinosis and neurological involvement is quite common, but this is the first case of an EMG-proven severe neuropathy associated with GS. Herein, we underline the close correlation between hypomagnesemia, chondrocalcinosis and neurological involvement. Moreover, we report a new heterozygous mutation in exon 23 (2738G>A), supporting evidence of a large genetic heterogeneity in this late-onset congenital tubulopathy.

[Restless legs syndrome]. / Le syndrome des jambes sans repos.

Restless legs syndrome, also called Willis-Ekbom disease, is a frequent sensorimotor disease, more often encountered in women than men. It is characterized by an urge to move legs, during the evening or the beginning of the night, increased by rest and relieved by movement. Two forms are classically distinguished: primary restless legs syndrome occurring in young adults with family history and secondary forms occurring in older adults with comorbidities such as iron deficiency, chronic renal failure or neurological diseases (affecting central or peripheral nervous system). The clinical impact of the urge to move the legs may be major, including in particular sleep disorders which can profoundly alter the quality of life. Pathophysiology of restless legs syndrome still remains partially understood and probably relies on dopamine metabolism abnormality secondary to cerebral iron deficiency in genetically susceptible patients. That's why, besides nutritional and sleep hygiene advices, treatment of restless legs syndrome includes iron supplementation if there is an iron deficiency. Pharmacological treatment, for severe to very severe forms, includes use of dopamine agonists, antiepileptic drugs or opioids. These medications have numerous side effects and each prescription has to be individually customized for each patient.

Neurology of Nutritional Deficiencies.

PURPOSE OF REVIEW: The goal of this chapter is to educate clinicians on the neurologic manifestations of certain nutritional deficiencies in order to promptly identify and appropriately treat these patients. RECENT FINDINGS: Many vitamin and nutritional deficiencies have been described dating back to the early days of neurology and medicine. Some are very rare and thus, there are no randomized controlled studies to assess supplementation or dosage; however, there are reviews of case reports that can assist clinicians in choosing treatments. While endemic vitamin and nutritional deficiencies may be rarely encountered in many countries, vulnerable populations continue to be at risk for developing neurologic complications. These populations include those with diseases causing malabsorption, the elderly, chronic alcohol users, as well as pregnant mothers with hyperemesis gravidarum to name a few. It is important to recognize syndromes associated with these nutritional deficiencies, as prompt identification and treatment may prevent permanent neurologic damage.

Functional Neurological Symptom Disorder: A Diagnostic Algorithm.

Functional neurological symptom disorder (FNSD) is a neuropsychiatric disorder characterized by the presence of neurological symptoms in the absence of any neurological abnormality that can be linked to a known pathology. Few studies have taken interest in this subject probably because of the heterogeneity of results. It is most often a diagnosis of exclusion which often means that patients undergo many tests and find themselves erring for a diagnosis with very little satisfaction of the outcomes. A reliable imagery pattern would therefore provide some relief and confirmation for both patients and clinicians. It could also facilitate acceptation of the diagnosis and reduce the societal cost associated with FNSD for the patient. The aim of this present study was to describe a clinicoradiological correspondence algorithm of FNSD using the PET scan and SPECT scan (PoSPs) and grant the clinician with a reliable tool to facilitate the diagnosis of FNSD. A systematic review according to the 2009 PRISMA criteria statement was used to guide the review. Our study included 3 of our own consenting patients who met the Diagnostic and Statistical Manual of Mental Disorders 5th edition criteria as well as 25 other patients from 7 different studies. Our results showed a hypoactivation with poor clinicoradiological correspondence and poor stability in time. This hypoactivation was mostly in the frontal lobe, which could explain some behavioral alterations. These findings oppose the ones found in organic pathologies and therefore should orient towards FNSD. In the light of these findings, we recommend the clinicians to perform two PoSPs, searching for clinicoradiological lack of correspondence and time stability using our algorithm.

Auditory brainstem response.

The auditory brainstem response (ABR), consisting of five to six vertex-positive peaks with separation of about 0.8ms, is very sensitive to factors that affect conduction velocity and hence ABR wave latencies in the brainstem auditory pathways. In addition, disorders causing dissynchronization of neural activity result in an amplitude decrease or disappearance of ABR peaks. The opposite effects occur in the maturation process, which takes about 2 years postterm; here conduction velocity increases quickly to its adult value, but synaptic delays being sensitive to synchronous release of transmitter substance take considerably longer. In neurological disorders, those that cause dissynchrony, such as auditory neuropathy and vestibular schwannoma, Gaucher disease, and Krabbe disease, the (longer latency) ABR peaks are reduced or absent. Effects on neural conduction, resulting in increased ABR interwave latencies, are found in vestibular schwannomas, Bell's palsy, Duane retraction syndrome, Marcus Gunn ptosis, and various encephalomyopathies. These measures allow an assessment of the parts of the brainstem that are involved.

Telemedicine in Neurological Disorders: Opportunities and Challenges.

Introduction: Telemedicine represents an emerging model for the assessment and management of various neurological disorders. Methods: We sought to discuss opportunities and challenges for the integration of telemedicine in the management of common and uncommon neurological disorders by reviewing and appraising studies that evaluate telemedicine as a means to facilitate the access to care, deliver highly specialized visits, diagnostic consultations, rehabilitation, and remote monitoring of neurological disorders. Results: Opportunities for telemedicine in neurological disorders include the replacement of or complement to in-office evaluations, decreased time between follow-up visits, reduction in disparities in access to healthcare, and promotion of education and training through interactions between primary care physicians and tertiary referral centers. Critical challenges include the integration of the systems for data monitoring with an easy-to-use, secure, and cost-effective platform that is both widely adopted by patients and healthcare systems and embraced by international scientific societies. Conclusions: Multiple applications may spawn from a model based on digitalized healthcare services. Integrated efforts from multiple stakeholders will be required to develop an interoperable software platform capable of providing not only a holistic approach to care but also one that reduces disparities in the access to care.

Diagnosis and Management of Neuropathic Itch.

Neuropathic pruritus is a challenging condition that can be caused by injury or dysfunction in any part of the nervous system. A vast array of clinical pictures exist, including both localized and generalized pruritus, and their principal entities are described in this article. Diagnosis is often difficult and depends on patient history, imaging, and neurophysiologic studies. Other causes of chronic itch should be excluded. The management of neuropathic itch is demanding and the majority of interventions are not curative. The best treatment options include anticonvulsants, topical anesthetics, and capsaicin.

Miming neurological syndromes improves medical student's long-term retention and delayed recall of neurology.

Basic examination and diagnostic skills in neurology are important for every graduating medical student. However, a majority of medical students consider neurology as complex and difficult to master. We evaluate the impact a learner-friendly, innovative simulation-based training programme has on long-term retention and delayed recall of neurological semiology amongst third-year medical students from the University Pierre et Marie Curie in Paris, France. The 2013 class received standard teaching in neurological semiology. The 2015 class who received the same standard teaching in neurological semiology were also invited to voluntarily participate in The Move, a mime-based role-play training programme of neurological semiology. During the Move, students were trained to simulate a patient with a neurological syndrome or the physician examining the patient. Students were evaluated with an assessment thirty months after their neurological rotation, including 15 questions to evaluate long-term retention of neurological semiology, and 10 to test background knowledge in general semiology. The semiology test was performed by 366/377 students from the 2013 class (standard education group) and by 272/391 students from the 2015 class, among which 186 participated in The Move (The Move group) and 86 did not (standard education group). The mean neurological semiology score was higher in the 2015 class compared to the 2013 class (p = 0.007) and remained so after adjustment for the general semiology performance (p = 0.003). The adjusted mean neurological semiology score was 1.21/15 points higher [95% CI 0.66, 1.75] in The Move group compared to the standard education group, corresponding to a 14% better ranking. The Move programme improves medical student's long-term retention and delayed recall of neurological semiology. This learner-friendly interactive teaching may in turn enhance clinical proficiency of future physicians in neurological semiology.

Tropical diseases in the ICU: A syndromic approach to diagnosis and treatment.

Tropical infections form 20-30% of ICU admissions in tropical countries. Diarrheal diseases, malaria, dengue, typhoid, rickettsial diseases and leptospirosis are common causes of critical illness. Overlapping clinical features makes initial diagnosis challenging. A systematic approach involving (1) history of specific continent or country of travel, (2) exposure to specific environments (forests or farms, water sports, consumption of exotic foods), (3) incubation period, and (4) pattern of organ involvement and subtle differences in manifestations help in differential diagnosis and choice of initial empiric therapy. Fever, rash, hypotension, thrombocytopenia and mild derangement of liver function tests is seen in a majority of patients. Organ failure may lead to shock, respiratory distress, renal failure, hepatitis, coma, seizures, cardiac arrhythmias or hemorrhage. Diagnosis in some conditions is made by peripheral blood smear examination, antigen detection or detection of microbial nucleic acid by PCR. Tests that detect specific IgM antibody become positive only in the second week of illness. Initial therapy is often empiric; a combination of intravenous artesunate, ceftriaxone and either doxycycline or azithromycin would cover a majority of the treatable syndromes. Additional antiviral or antiprotozoal medications are required for some specific syndromes. Involving a physician specializing in tropical or travel medicine is helpful.

Psychiatric and Medical Conditions in Transition-Aged Individuals With ASD.

BACKGROUND AND OBJECTIVES: Children with autism spectrum disorder (ASD) have a variety of medical and psychiatric conditions and an increased use of health care services. There is limited information about the prevalence of psychiatric and medical conditions in adolescents and young adults with ASD. Our objective was to describe the frequency of medical and psychiatric conditions in a large population of diverse, insured transition-aged individuals with ASD. METHODS: Participants included Kaiser Permanente Northern California members who were enrolled from 2013 to 2015 and who were 14 to 25 years old. Individuals with ASD (n = 4123) were compared with peers with attention-deficit/hyperactivity disorder (n = 20 615), diabetes mellitus (n = 2156), and typical controls with neither condition (n = 20 615). RESULTS: Over one-third (34%) of individuals with ASD had a co-occurring psychiatric condition; the most commonly reported medical conditions included infections (42%), obesity (25%), neurologic conditions (18%), allergy and/or immunologic conditions (16%), musculoskeletal conditions (15%), and gastrointestinal (11%) conditions. After controlling for sex, age, race, and duration of Kaiser Permanente Northern California membership, most psychiatric conditions were significantly more common in the ASD group than in each comparison group, and most medical conditions were significantly more common in the ASD group than in the attention-deficit/hyperactivity disorder and typical control groups but were similar to or significantly less common than the diabetes mellitus group. CONCLUSIONS: Although more research is needed to identify factors contributing to this excess burden of disease, there is a pressing need for all clinicians to approach ASD as a chronic health condition requiring regular follow-up and routine screening and treatment of medical and psychiatric issues.

Cheiro-Oral Syndrome.

Cheiro-Oral Syndrome (COS) is a very rare neurological syndrome associated with varied etiology. We report a 53-year-old man presented with left sided perioral and ipsilateral hand/fingers burning sensation for a one-month duration. On examination, he had hypesthesia over left perioral and distal palmar aspect of all five fingers. MRI revealed subacute infarct in the posterior limb of right internal capsule adjacent to and minimally involving thalamus. He was diagnosed as CheiroOral Syndrome as a result of ischemic stroke and managed.

Health Symptoms Associated with Pesticides Exposure among Flower and Onion Pesticide Applicators in Arusha Region.

INTRODUCTION: Pesticides are extensively used in agriculture to control harmful pests and prevent crop yield losses or product damage. In Tanzania several studies have been conducted on health effects of pesticides on agricultural workers. However, there are few studies on neurological health symptoms associated with pesticide exposure in flower and onion farms. OBJECTIVE: The objective of this cross-sectional study was to assess health symptoms associated with pesticide exposure among flower and onion pesticide applicators in the Arusha region, Tanzania. METHODS: Data on demographic variables and health symptoms associated with pesticide exposure were collected from 140 males who were employed in spraying pesticides on flower and onion farms in Arusha, Meru and Karatu districts between April and May 2017. The study participants were interviewed using a structured questionnaire with questions focusing sociodemographic characteristics, occupation, pesticide exposure, common type of pesticide used in the area and neurological symptoms experienced during and after pesticide spraying. To determine the intensity of pesticide exposure, acetylcholinesterase assay was done by using the Test-mate Model 400 device with a photometric sensor. RESULTS: Ninety-five percent of pesticide applicators reported handling organophosphate pesticides. Body weakness was the most frequently reported neurological symptom (57.1%) followed by perspiration and headache (40.7%), poor appetite and depression (29.3%) and irritation (26.4%). About 27% of pesticide applicators had an acetylcholinesterase level below the limit value. CONCLUSION: A high proportion of neurological health symptoms and cholinesterase test depression was noted among pesticide applicators in both farms. There is a need to conduct further studies to ascertain causality for such high instances of neurological symptoms.

AANEM Choosing Wisely - second list.

Choosing Wisely is an initiative of the ABIM Foundation in partnership with Consumer Reports that seeks to advance a national dialogue on avoiding wasteful or unnecessary medical tests, treatments and procedures. The American Association for Neuromuscular & Electrodiagnostic Medicine's (AANEM) Professional Practice Committee (PPC) identified areas in neuromuscular and electrodiagnostic medicine that have the greatest potential for overuse/misuse and provided five recommendations for both patients and physicians to consider before proceeding with the specified test or treatment. This is the second list created by the PPC. The first was published in 2015. A combined list can be found online: http://www.choosingwisely.org/societies/american-association-of-neuromuscular-electrodiagnostic-medicine/. Muscle Nerve 57: 335-336, 2018.

Neurological presentations revealing acquired copper deficiency: diagnosis features, aetiologies and evolution in seven patients.

BACKGROUND: Acquired copper deficiency (ACD) is a rare condition usually diagnosed from haematological changes. AIMS: To characterise the diagnosis features and the evolution of patients with ACD revealed by neurological symptoms. METHODS: Clinical, biological and magnetic resonance imaging (MRI) data were prospectively analysed at diagnosis and during follow up under copper supplementation. RESULTS: Seven patients were studied over a 5-year period. Time to diagnosis ranged from 2.5 to 15 months. Subacute ascending paraesthesias and gait disorder were the first symptoms. All patients had a posterior cord syndrome (PCS) with sensory ataxic gait associated with superficial hypoesthesia of the feet; 50% had also lateral cord signs. Electrodiagnostic tests diagnosed a lower limb sensory neuropathy in four patients. Spinal cord MRI was normal in three of seven patients. Anaemia and lymphopenia were diagnosed in six of seven patients. Serum copper was always low, and urinary copper was low or normal. Serum and urinary zinc were high in four patients. Decreased copper intake (stoma/parenteral nutrition, malnutrition, malabsorption with lack of vitamin supplementation after bariatric or other digestive surgeries) was found in four patients, and the chronic use of denture adhesive paste containing zinc was discovered in four patients. One patient had both the causes recorded. After copper supplementation, copper balance and then haematological disturbances were the first features to normalise gradually in 2 months. Radiological myelitis disappeared in 10 months, whereas neurological symptoms improved in six of seven patients after a mean follow up of 2 years. CONCLUSIONS: Progressive PCS with anaemia and lymphopenia must raise the possibility of an ACD. Early copper supplementation could increase the neurological prognosis.

Active exergames to improve cognitive functioning in neurological disabilities: a systematic review and meta-analysis.

INTRODUCTION: Exergames represent a way to perform physical activity through active video games, serving as potentially useful tool in the field of neurorehabilitation. However, little is known regarding the possible role of exergames in improving cognitive functions in persons suffering from neurological disabilities. EVIDENCE ACQUISITION: A search for relevant articles was carried out on PubMed/Medline, Scopus, PEDro, and Google Scholar. Only randomized controlled studies and non-randomized but controlled studies were retained. The following additional inclusion criteria were applied: studies focused on physical activity interventions carried out by means of exergames; populations targeted were affected by neurological disabilities; and reported results were related to cognitive outcomes. We calculated standardized mean differences (SMD) and pooled results using a random effects meta-analysis. EVIDENCE SYNTHESIS: Of 520 abstracts screened, thirteen studies met the criteria to be included yielding a total of 465 participants, 233 randomized to exergames, and 232 allocated to the alternative or no intervention. The included studies varied in terms of studied populations (e.g., multiple sclerosis, post-stroke hemiparesis, Parkinson's disease, dementia, dyslexia, Down syndrome), type and duration of interventions, and cognitive outcome measures. Exergames significantly improved executive functions (SMD=0.53, P=0.005; 8 studies, N.=380) and visuo-spatial perception (SMD=0.65, P<0.0001; 5 studies, N.=209) when compared to the alternative or no intervention. There were no significant differences for attention (SMD=0.57, P=0.07; 7 studies, N.=250) and global cognition (SMD=0.05, P=0.80; 6 studies, N.=161). CONCLUSIONS: Exergames are a highly-flexible tool for rehabilitation of both cognitive and motor functions in adult populations suffering from various neurological disabilities and developmental neurological disorders. Additional high-quality clinical trials with larger samples and more specific cognitive outcomes are needed to corroborate these preliminary findings. CLINICAL REHABILITATION IMPACT: Exergames could be considered either as a supplemental treatment to conventional rehabilitation, or as strategy to extend benefits of conventional programs at home.