The COVID-19 pandemic, an environmental neurology perspective.

Neurologists have a particular interest in SARS-CoV-2 because the nervous system is a major participant in COVID-19, both in its acute phase and in its persistent post-COVID phase. The global spread of SARS-CoV-2 infection has revealed most of the challenges and risk factors that humanity will face in the future. We review from an environmental neurology perspective some characteristics that have underpinned the pandemic. We consider the agent, SARS-CoV-2, the spread of SARS-CoV-2 as influenced by environmental factors, its impact on the brain and some containment measures on brain health. Several questions remain, including the differential clinical impact of variants, the impact of SARS-CoV-2 on sleep and wakefulness, and the neurological components of Long-COVID syndrome. We touch on the role of national leaders and public health policies that have underpinned management of the COVID-19 pandemic. Increased awareness, anticipation and preparedness are needed to address comparable future challenges.

Medical management, prevention and mitigation of environmental risks factors in Neurology.

The human environment and exposures arising therefrom are major contributors to neurological disorders ranging from stroke to neurodegenerative diseases. Reduction of exposure to environmental risk factors, with the goal of disease prevention or control, is addressed at the individual as well as the societal level and in recognition of differential subject vulnerability. We examine some practical solutions in high-income countries that may allow a better adaptation to environmental risks and reduce their adverse impact on the nervous system. We consider the citizen's role in reducing unhealthy exposures and explore new approaches to treatment.

The World Federation of Neurology and the challenges in Environment Neurology.

Since its establishment the World Federation of Neurology (WFN) has manifested a keen interest in the environment and its relation to neurological diseases. Thus, in 2007 the WFN renamed the "Neurotoxicological Research Group" to "Environmental Neurology Research Group". In this short article, we review some recent events which illustrate the WFN involvement in Environmental Neurology as well its concerns about global health matters involving environmental issues.

Mediterranean diet: The role of long-chain ω-3 fatty acids in fish; polyphenols in fruits, vegetables, cereals, coffee, tea, cacao and wine; probiotics and vitamins in prevention of stroke, age-related cognitive decline, and Alzheimer disease.

The mechanisms of action of the dietary components of the Mediterranean diet are reviewed in prevention of cardiovascular disease, stroke, age-associated cognitive decline and Alzheimer disease. A companion article provides a comprehensive review of extra-virgin olive oil. The benefits of consumption of long-chain ω-3 fatty acids are described. Fresh fish provides eicosapentaenoic acid while α-linolenic acid is found in canola and soybean oils, purslane and nuts. These ω-3 fatty acids interact metabolically with ω-6 fatty acids mainly linoleic acid from corn oil, sunflower oil and peanut oil. Diets rich in ω-6 fatty acids inhibit the formation of healthier ω-3 fatty acids. The deleterious effects on lipid metabolism of excessive intake of carbohydrates, in particular high-fructose corn syrup and artificial sweeteners, are explained. The critical role of the ω-3 fatty acid docosahexaenoic acid in the developing and aging brain and in Alzheimer disease is addressed. Nutritional epidemiology studies, prospective population-based surveys, and clinical trials confirm the salutary effects of fish consumption on prevention of coronary artery disease, stroke and dementia. Recent recommendations on fish consumption by pregnant women and potential mercury toxicity are reviewed. The polyphenols and flavonoids of plant origin play a critical role in the Mediterranean diet, because of their antioxidant and anti-inflammatory properties of benefit in type-2 diabetes mellitus, cardiovascular disease, stroke and cancer prevention. Polyphenols from fruits and vegetables modulate tau hyperphosphorylation and beta amyloid aggregation in animal models of Alzheimer disease. From the public health viewpoint worldwide the daily consumption of fruits and vegetables has become the main tool for prevention of cardiovascular disease and stroke. We review the important dietary role of cereal grains in prevention of coronary disease and stroke. Polyphenols from grapes, wine and alcoholic beverages are discussed, in particular their effects on coagulation. The mechanisms of action of probiotics and vitamins are also included.

Extra-virgin olive oil for potential prevention of Alzheimer disease.

Observational epidemiological studies provide valuable information regarding naturally occurring protective factors observed in populations with very low prevalences of vascular disease. Between 1935 and 1965, the Italian-American inhabitants of Roseto (Pennsylvania, USA) observed a traditional Italian diet and maintained half the mortality rates from myocardial infarction compared with neighboring cities. In the Seven Countries Study, during 40years (1960-2000) Crete maintained the lowest overall mortality rates and coronary heart disease fatalities, which was attributed to strict adherence to the Mediterranean diet. In the French Three-City Study, a ten-year follow-up (2000-2010) showed that higher consumption of olive oil was associated with lower risk of death, as well as protection from cognitive decline and stroke. A large number of population-based studies and intervention trials have demonstrated that the Mediterranean diet is associated with lower prevalence of vascular disease, obesity, arthritis, cancer, and age-associated cognitive decline. Many of these effects are the result of consumption of fruits, seeds, legumes and vegetables but olive oil is the chief dietary fat in Mediterranean countries and the main source of monounsaturated fatty acids, as well as an important source of beneficial polyphenols and other antioxidants. Considering the critical role of vascular factors in the pathogenesis of late-onset Alzheimer disease it seems appropriate to focus on disease modification through proven dietary therapy. The authors base their hypothesis on meta-analyses of epidemiological data, numerous experimental studies, and a comprehensive review of the mechanisms of action of extra-virgin olive oil and its components in the prevention of vascular disease. In addition, extra-virgin olive oil has had positive effects on experimental animal models of Alzheimer disease. We therefore propose that extra-virgin olive oil is a promising tool for mitigating the effects of adverse vascular factors and may be utilized for potential prevention of late-onset Alzheimer disease.

Environmental neurology in the tropics.

We address the impact of the tropical environment on the human nervous system using the multifaceted approach characteristic of environmental neurology. First, environmental factors are examined according to their nature (physical, chemical and biological) and in relation to human activity and behavior. Some factors are specific to the tropics (climate and infections), while others are non-specific (chemicals, human communities and their way of life). Second, we examine the major role of human adaptation to the success of Homo sapiens, with emphasis on the linkage between thermoregulation and sleep-wake regulation. Third, we examine the performance of environmental neurology as a clinical discipline in tropical climates, with focus on the diagnostic and therapeutic challenges posed by human African trypanosomiasis. Finally, the prevention, early detection and monitoring of environmental neurological diseases is examined, as well as links with political and economic factors. In conclusion, practitioners of environmental neurology seek a global, multidisciplinary and holistic approach to understanding, preventing and treating neurological disorders within their purview. Environmental neurology integrates an expanded One Health concept by linking health and wellness to the interaction of plants, animals, humans and the ecosystem. Recent epidemics and the current COVID-19 pandemic exemplify the need for worldwide action to protect human health and biodiversity.

Consistency of clinical diagnosis of dementia in NEDICES: A population-based longitudinal study in Spain.

BACKGROUND: Few longitudinal studies have verified the clinical diagnosis of dementia based on clinical examinations. We evaluated the consistency of the clinical diagnosis of dementia over a period of 3 years of follow-up in a population-based, cohort study of older people in central Spain. METHODS: Individuals (N = 5278) were evaluated at baseline (1994-1995) and at follow-up (1997-1998). The evaluation included a screening questionnaire for dementia and a neurological assessment. RESULTS: Dementia screening consisted of a 37-item version of the Mini-Mental State Examination (MMSE) and the Pfeffer Functional Activities Questionnaire (FAQ). Study neurologists investigated those participants who screened positively (N = 713) as well as 843 who had screened negatively to test the sensitivity of the screening instruments or because they had a positive screening for other chronic neurological diseases. We detected 295 patients among those who screened positive and 13 among those who screened negatively. Three years follow-up evaluation demonstrated 14 diagnostic errors at baseline (4.5%) leading to a final number of 306 patients with dementia. The corrected prevalence of dementia was 5.8% (95% confidence interval [CI] 5.2-6.5). CONCLUSIONS: The diagnosis of dementia was highly accurate in this population-based, Spanish cohort study, and our prevalence figures agree with other European surveys. Given the high cost and difficulties of population rescreening and its relatively low yield, we conclude that a single 2-phase investigation (screening followed by clinical examination) provides accurate information for most population-based prevalence studies of dementia.

Incidence and subtypes of dementia in three elderly populations of central Spain.

OBJECTIVE: To assess age-, gender, and subtype-specific incidence rates of dementia in three populations in central Spain using data from the Neurological Disorders in Central Spain (NEDICES), a population-based survey of elderly participants. METHODS: Individuals were evaluated at baseline (1994-1995) and at follow-up (a median of 3.2 years later in 1997-1998). The evaluation included a screening questionnaire for dementia and a neurological assessment, when possible. RESULTS: Of 5278 participants evaluated at baseline, there were 306 prevalent dementia cases. One hundred and sixty-one incident dementia cases were identified among 3,891 individuals assessed at follow-up. The large majority had Alzheimer's disease (AD): 115 (71.4%) AD, 18 (11.2%) vascular dementia (VaD), 11 (6.8%) dementia associated with parkinsonism, 11 (6.8%) undetermined etiology, and 6 (3.7%) secondary dementia. Average annual incidence rates (per 1,000 person-years) in the population aged 65 to 90 and over years, adjusted to the standard European population, were 10.6 (95% CI, 8.9 to 12.3) for dementia, 7.4 (95% CI=6.0 to 8.8) for AD, and 1.4 (95% CI=0.6 to 2.3) for VaD. Age-specific incidence rates of dementia and AD increased exponentially with advancing age. Age, stroke and illiteracy were independent risk factors for dementia and AD. Aggregation of vascular risk factors was related to a higher risk of both VaD and AD. CONCLUSIONS: In the NEDICES study, incidence of dementia increased with age beyond age 85 and AD was the most frequent type of dementia. The risk of AD and VaD increased with the number of vascular risk factors.

Defining dementia: clinical criteria for the diagnosis of vascular dementia.

The recognition of cerebrovascular disease (CVD) as a contributing factor and a cause of dementia has led to the development of clinical criteria for vascular dementia (VaD). Due to high specificity, the consensus criteria developed by the National Institute for Neurological and Communicative Disorders and Stroke (NINDS)-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) have been used in controlled clinical trials to select patients with pure VaD. VaD is predominantly a subcortical frontal form of dementia with prominent executive dysfunction. In contrast, the criteria of the NINCDS-Alzheimer's Disease and Related Disorders Association (ADRDA) emphasize memory loss as the main feature to distinguish Alzheimer's disease (AD) from VaD and from other forms of dementia. Moreover, CVD may precipitate the clinical expression of AD. Although no criteria have been created specifically for patients having AD with CVD, the ischemic score, the Informant Questionnaire on Cognitive Decline in the Elderly and a history of prestroke mild cognitive impairment (MCI) may be useful for identifying patients with this mixed form of dementia.

Cerebral congestion. A vanished disease.

The concept of "cerebral congestion" as a cause of apoplexy was first proposed by Morgagni in 1761, and had a profound influence in the treatment of stroke during the next 150 years. It accounted not only for cerebral hemorrhage, but also for lacunae (Dechambre, 1838), état criblé (Durand-Fardel, 1842), depression, maniac outbursts, headaches, coma, and seizures. According to Hammond (1871, 1878), cerebral congestion was "more common...than any other affection of the nervous system." This notion fell into oblivion when an accurate method for bedside determination of blood pressure became available (Riva-Rocci, 1896; Korotkov, 1905) allowing for better understanding of the neurologic complications of arterial hypertension.

Retrovirus-associated myelopathies.

Human T-lymphotropic virus type I (HTLV-I), the causative agent of adult T-cell leukemia and non-Hodgkin's lymphoma (ATLL)--or a cross-reacting retrovirus--has been associated with tropical spastic paraparesis in Martinique, Jamaica, Colombia, Trinidad and Tobago, the Seychelles, and probably also in Zaire. The Caribbean basin and sub-Saharan Africa are endemic for ATLL. A similar etiology has been invoked in a chronic spastic myelopathy occurring in areas of high ATLL endemicity in Japan. An HTLV-I viral antigen has been demonstrated in cerebrospinal fluid lymphocytes of a Japanese patient with myelopathy. Human T-lymphotropic virus type I antibodies have occurred in patients in Florida and Japan (areas of HTLV-I endemicity) who were diagnosed as having clinically definite multiple sclerosis (MS), but not in patients with MS in other parts of the world. Human T-lymphotropic virus type I, like some lentiviruses--visna and human immunodeficiency virus, in particular--may be both lymphotropic and neurotropic. Tropical spastic paraparesis, the Japanese myelopathy, and, perhaps, an MS-like neurologic syndrome, may represent clinical variants of the same disease, a retroviral myelopathy.

Treatment of myelopathy in Sjögren syndrome with a combination of prednisone and cyclophosphamide.

BACKGROUND: Peripheral neuropathy is a common complication of primary Sjögren syndrome, but central nervous system involvement also occurs and may be the only extraglandular manifestation. Sicca symptoms may also be minimal. Combinations of lesions along with relapses and remissions can suggest multiple sclerosis in the proper clinical setting, making the correct diagnosis elusive. OBJECTIVES: To report a case of progressive transverse myelopathy with previous optic neuropathy in primary central nervous system Sjögren syndrome (CNS-SS), and to review 17 previously reported cases and the patient's responses to various therapies. DESIGN: Case report and literature review. SETTING: University hospital. PATIENT: A 63-year-old Hispanic woman with a 10-month history of progressive spastic paraparesis associated with optic neuropathy and a T10 sensory level. Magnetic resonance imaging demonstrated multifocal, contrast-enhancing lesions in the spinal cord. The patient was diagnosed as having CNS-SS because of the presence of sicca symptoms, abnormal serological test results, and salivary gland biopsy results, which fulfilled San Diego criteria for "definite" Sjögren syndrome. She responded to treatment with a combination of prednisone and cyclophosphamide. CONCLUSIONS: Diagnosis of primary CNS-SS requires a high index of suspicion and specialized clinical testing. Treatment with pulse doses of corticosteroids alone may be suboptimal, but results of treatment with a combination of corticosteroids and either cyclophosphamide or chlorambucil have been encouraging.

Prolonged serum levodopa levels with controlled-release carbidopa-levodopa in the treatment of Parkinson's disease.

Twenty parkinsonian patients (Hoehn and Yahr scale, I through III) were treated with controlled-release carbidopa-levodopa (CR-2 or CR-3) and standard carbidopa-levodopa (Sinemet, 25 mg/100 mg) in a double-blind, crossover pharmacokinetic and clinical efficacy study. The controlled-release agents had a slower rise to peak plasma values and flatter pharmacokinetic curves than did the standard. The area under the curve for CR-3 was significantly increased by 55.5% as compared with standard agent and by 84.2% as compared with CR-2. No differences in clinical efficacy were found between controlled-release agents and the standard agent for this group of parkinsonian patients with mild to moderate severity. The dissociation between the prolonged serum levodopa levels and unimproved clinical efficacy may have resulted from the absence of patients with prominent motor fluctuations and/or substantial serum levodopa variability that was especially prominent with CR-3.

Treatment of chronic Parkinson's disease with controlled-release carbidopa/levodopa.

Controlled-release carbidopa/levodopa 50/200 (SINEMET CR) and standard carbidopa/levodopa (SINEMET 25/100) were compared in a double-blind, six-month, crossover study involving 21 patients with chronic Parkinson's disease and motor response fluctuations. Daily dosage frequency was significantly reduced with SINEMET CR compared with SINEMET 25/100, while the daily amount of levodopa required with SINEMET CR was significantly greater. No significant differences in disability ratings, motor response fluctuations, or safety were detected during double-blind conditions. In the open-label, dose-finding phase of the study, SINEMET CR was superior to standard SINEMET 25/100 in patient ratings of percent "on" time (good motor function), clinical assessments of motor function, and activities of daily living. This finding resulted from a depreciation of the value of the "old drug" rather than an overestimation of the value of the experimental drug. This double-blind study also suggested that elderly male patients with Parkinson's disease derived the greatest benefit from SINEMET CR.

Human T-lymphotropic virus type I antibodies in the serum of patients with tropical spastic paraparesis in the Seychelles.

Tropical spastic paraparesis (TSP), a chronic myelopathy of unknown etiology, was studied in the Seychelles. Human T-lymphotropic virus type I (HTLV-I) and human immunodeficiency virus antibodies were determined using an enzyme-linked immunosorbent assay and confirmed with an indirect fluorescent antibody test in serum samples of 20 patients with TSP and 16 controls. Test results indicated that 17 patients (85%) and two controls (transverse myelopathy and clinically probable multiple sclerosis) were positive for HTLV-I. Serum samples of nine healthy controls and five with other neurologic diseases were negative for HTLV-I. No serum samples were positive for human immunodeficiency virus. Estimated relative risk for TSP in those subjects whose serum is positive for HTLV-I antibodies is 40. This result is highly statistically significant. Although primarily associated with adult T-cell leukemia and non-Hodgkin's lymphoma, HTLV-I could also be an etiologic agent of TSP.

Epidemic neuropathy in Cuba: a plea to end the United States economic embargo on a humanitarian basis.

During 1992-1993, an epidemic of neurologic disease in Cuba affected 50,862 patients with optic neuropathy, sensorineural deafness, predominantly sensory peripheral neuropathy, and dorsolateral myelopathy. The clinical syndromes were identical to those of prisoners of war subjected to nutritional restriction in tropical prison camps during World War II (Strachan's disease). A dietary deficiency of group B vitamins and sulfur-containing amino acids appears to have been the primary cause of the epidemic. This was a consequence of economic and political events in Cuba linked to the collapse of the Soviet Union and socialist countries. The recently toughened 30-year-old US economic embargo on Cuba contributed to these problems and hampered the investigation, treatment, and prevention of the epidemic. A plea is made to the neurologic community to request the lifting of the trade blockade on a humanitarian basis.

Multiple sclerosis or HTLV-I myelitis?

Several authors have demonstrated the presence of antibodies against the HTLV-I retrovirus in patients with MS. Considerable controversy exists regarding the etiologic significance, if any, of this finding, but the presence of these antibodies in the blood or CSF of MS patients has led to reconsideration of that diagnosis in certain cases. It is recommended that, before the diagnosis of MS is changed to that of HTLV-I-associated chronic myelitis, at least 2 of the following abnormalities be present: (1) clinical or electrophysiologic involvement of peripheral nerve or muscle; (2) the presence of oligoclonal bands in the serum; (3) the presence in blood or CSF of lymphocytes with multilobed nuclei; (4) a positive serologic test for syphilis; (5) the presence of a sicca syndrome; and (6) the presence of pulmonary lymphocytic alveolitis.

Tropical myeloneuropathies: the hidden endemias.

Tropical myeloneuropathies include tropical ataxic neuropathy and tropical spastic paraparesis. These disorders occur in geographic isolates in several developing countries and are associated with malnutrition, cyanide intoxication from cassava consumption, tropical malabsorption (TM), vegetarian diets, and lathyrism. TM-malnutrition was a probable cause of myeloneuropathies among Far East prisoners of war in World War II. Clusters of unknown etiology occur in India, Africa, the Seychelles, several Caribbean islands, Jamaica, and Colombia. Treponemal infection (yaws) could be an etiologic factor in the last two. Tropical myeloneuropathies, a serious health problem, are multifactorial conditions that provide unsurpassed opportunities for international cooperation and neurologic research.

Tropical spastic paraparesis in the Seychelles Islands: a clinical and case-control neuroepidemiologic study.

We confirmed the occurrence of endemic tropical spastic paraparesis (TSP) in the Seychelles. Most patients (14/21) were low-income black women. Mean age at onset was 42.8 years (range, 20 to 65). In 62%, onset and progression were slow. Complete paralysis developed in 8/21 (38%) after an evolution of 2 to 15 years. All patients had bilateral pyramidal signs. Loss of vibratory perception occurred in 6/21 (28%). A case-control study of putative risk factors failed to show significant differences. The clinical and epidemiologic features of TSP in the Seychelles appear to be similar to those described in other tropical countries.

Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop.

Criteria for the diagnosis of vascular dementia (VaD) that are reliable, valid, and readily applicable in a variety of settings are urgently needed for both clinical and research purposes. To address this need, the Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke (NINDS) convened an International Workshop with support from the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), resulting in research criteria for the diagnosis of VaD. Compared with other current criteria, these guidelines emphasize (1) the heterogeneity of vascular dementia syndromes and pathologic subtypes including ischemic and hemorrhagic strokes, cerebral hypoxic-ischemic events, and senile leukoencephalopathic lesions; (2) the variability in clinical course, which may be static, remitting, or progressive; (3) specific clinical findings early in the course (eg, gait disorder, incontinence, or mood and personality changes) that support a vascular rather than a degenerative cause; (4) the need to establish a temporal relationship between stroke and dementia onset for a secure diagnosis; (5) the importance of brain imaging to support clinical findings; (6) the value of neuropsychological testing to document impairments in multiple cognitive domains; and (7) a protocol for neuropathologic evaluations and correlative studies of clinical, radiologic, and neuropsychological features. These criteria are intended as a guide for case definition in neuroepidemiologic studies, stratified by levels of certainty (definite, probable, and possible). They await testing and validation and will be revised as more information becomes available.