EAN consensus statement for management of patients with neurological diseases during the COVID-19 pandemic.

BACKGROUND AND PURPOSE: The recent SARS-CoV-2 pandemic has posed multiple challenges to the practice of clinical neurology including recognition of emerging neurological complications and management of coexistent neurological diseases. In a fast-evolving pandemic, evidence-based studies are lacking in many areas. This paper presents European Academy of Neurology (EAN) expert consensus statements to guide neurologists caring for patients with COVID-19. METHODS: A refined Delphi methodology was applied. In round 1, statements were provided by EAN scientific panels (SPs). In round 2, these statements were circulated to SP members not involved in writing them, asking for agreement/disagreement. Items with agreement >70% were retained for round 3, in which SP co-chairs rated importance on a five-point Likert scale. Results were graded by importance and reported as consensus statements. RESULTS: In round one, 70 statements were provided by 23 SPs. In round two, 259/1061 SP member responses were received. Fifty-nine statements obtained >70% agreement and were retained. In round three, responses were received from 55 co-chairs of 29 SPs. Whilst general recommendations related to prevention of COVID-19 transmission had high levels of agreement and importance, opinion was more varied concerning statements related to therapy. CONCLUSION: This is the first structured consensus statement on good clinical practice in patients with neurological disease during the COVID-19 pandemic that provides immediate guidance for neurologists. In this fast-evolving pandemic, a rapid response using refined Delphi methodology is possible, but guidance may be subject to change as further evidence emerges.

The international European Academy of Neurology survey on neurological symptoms in patients with COVID-19 infection.

BACKGROUND AND PURPOSE: Although the main clinical features of COVID-19 infection are pulmonary, several associated neurological signs, symptoms and diseases are emerging. The incidence and characteristics of neurological complications are unclear. For this reason, the European Academy of Neurology (EAN) core COVID-19 Task Force initiated a survey on neurological symptoms observed in patients with COVID-19 infection. METHODS: A 17-question online survey was made available on the EAN website and distributed to EAN members and other worldwide physicians starting on 9 April 2020. RESULTS: By 27 April 2020, proper data were collected from 2343 responders (out of 4199), of whom 82.0% were neurologists, mostly from Europe. Most responders (74.7%) consulted patients with COVID-19 mainly in emergency rooms and in COVID-19 units. The majority (67.0%) had evaluated fewer than 10 patients with neurological manifestations of COVID-19 (neuro COVID-19). The most frequently reported neurological findings were headache (61.9%), myalgia (50.4%), anosmia (49.2%), ageusia (39.8%), impaired consciousness (29.3%) and psychomotor agitation (26.7%). Encephalopathy and acute cerebrovascular disorders were reported at 21.0%. Neurological manifestations were generally interpreted as being possibly related to COVID-19; they were most commonly recognized in patients with multiple general symptoms and occurred at any time during infection. CONCLUSION: Neurologists are currently and actively involved in the management of neurological issues related to the COVID-19 pandemic. This survey justifies setting up a prospective registry to better capture the prevalence of patients with neuro COVID-19, neurological disease characteristics and the contribution of neurological manifestations to outcome.

Demand for neurological services in Central Eastern Europe: a 10-year national survey in Hungary.

BACKGROUND AND PURPOSE: In order to plan neurological capacities at a national level for the next decade, the current use of neurological services should be evaluated. We analyzed the utilization of neurological services in Hungary, a country with a single-payer health insurance system covering the whole population. METHODS: We created a database from medical reports submitted to the National Health Insurance Fund from all hospitals and outpatient services between 2004 and 2013. The number of subjects presenting to the neurological healthcare system and their major diagnoses by 10th International Classification of Diseases categories were analyzed. The overall healthcare service utilization of these patients was also estimated. RESULTS: Of the 10 million inhabitants, 2.9 million people used an inpatient or outpatient neurological service at least once over the 10-year period. Annually, 1% of the population was admitted to neurological inpatient wards and 6% of the population used some neurological outpatient service. Major reasons for using neurological services were: cerebrovascular diseases (I60-I69; 1.2 million patients), episodic and paroxysmal disorders (G40-G47; 1.3 million patients) and general symptoms and signs (R50-R56; 1.3 million patients). The 2.9 million people had 12.7 million hospital admissions to any ward and 365.7 million outpatient visits to any specialist during the 10 years. CONCLUSIONS: The demand for neurological services is high in Hungary; close to 30% of the population used an inpatient or outpatient neurological service at least once during this 10-year period. Results from this project provide data for international comparisons and help to ensure better informed and more focused resource allocation.

Comparing ischaemic stroke in six European countries. The EuroHOPE register study.

BACKGROUND AND PURPOSE: The incidence of hospitalizations, treatment and case fatality of ischaemic stroke were assessed utilizing a comprehensive multinational database to attempt to compare the healthcare systems in six European countries, aiming also to identify the limitations and make suggestions for future improvements in the between-country comparisons. METHODS: National registers of hospital discharges for ischaemic stroke identified by International Classification of Diseases codes 433-434 (ICD-9) and code I63 (ICD-10), medication purchases and mortality were linked at the patient level in each of the participating countries and regions: Finland, Hungary, Italy, the Netherlands, Scotland and Sweden. Patients with an index admission in 2007 were followed for 1 year. RESULTS: In all, 64,170 patients with a disease code for ischaemic stroke were identified. The number of patients registered per 100,000 European standard population ranged from 77 in Scotland to 407 in Hungary. Large differences were observed in medication use. The age- and sex-adjusted all-cause case fatality amongst hospitalized patients at 1 year from stroke was highest in Hungary at 31.0% (95% confidence interval 30.5-31.5). Regional differences in age- and sex-adjusted 1-year case fatality within countries were largest in Hungary (range 23.6%-37.6%) and smallest in the Netherlands (20.5%-27.3%). CONCLUSIONS: It is feasible to link population-wide register data amongst European countries to describe incidence of hospitalizations, treatment patterns and case fatality of ischaemic stroke on a national level. However, the coverage and validity of administrative register data for ischaemic stroke should be developed further, and population-based and clinical stroke registers should be created to allow better control of case mix.

High-resolution ultrasonography of peripheral nerves: measurements on 14 nerve segments in 56 healthy subjects and reliability assessments.

PURPOSE: The aim of this study was to assess different aspects of reliability in high-resolution ultrasonography (HRUS) of the peripheral nerves and to establish reference values for the most frequently examined nerve segments. MATERIALS AND METHODS: A nerve size parameter, the cross-sectional area (CSA) of the C5, C6 and C7 cervical roots, the median, ulnar, radial, superficial radial, peroneal, tibial, and the sural nerves was measured using HRUS at a total of 14 predefined anatomical sites in two different cohorts of healthy subjects (n = 56), and the inter-rater, intra-rater and inter-equipment reliability of measurements was assessed. RESULTS: The mean CSA of the 14 nerve segments ranged from 2 to 10 mm(2). The intra-rater, inter-rater and inter-equipment reliability was high with intraclass correlation coefficients of 0.93, 0.98, and 0.86, respectively. The CSA values showed no consistent correlation with age, height, and body weight, but males had significantly larger values than females for nerve segments on the arm after correcting for age, weight and height in multivariate analysis. CSA values did not differ when two independent cohorts were compared. CONCLUSION: Peripheral nerve ultrasonography is a reliable and reproducible diagnostic method in the hands of experienced examiners. Normal values for several upper and lower extremity nerves are provided by our study.

Etiology of first-ever ischaemic stroke in European young adults: the 15 cities young stroke study.

BACKGROUND AND PURPOSE: Risk factors for IS in young adults differ between genders and evolve with age, but data on the age- and gender-specific differences by stroke etiology are scare. These features were compared based on individual patient data from 15 European stroke centers. METHODS: Stroke etiology was reported in detail for 3331 patients aged 15-49 years with first-ever IS according to Trial of Org in Acute Stroke Treatment (TOAST) criteria: large-artery atherosclerosis (LAA), cardioembolism (CE), small-vessel occlusion (SVO), other determined etiology, or undetermined etiology. CE was categorized into low- and high-risk sources. Other determined group was divided into dissection and other non-dissection causes. Comparisons were done using logistic regression, adjusting for age, gender, and center heterogeneity. RESULTS: Etiology remained undetermined in 39.6%. Other determined etiology was found in 21.6%, CE in 17.3%, SVO in 12.2%, and LAA in 9.3%. Other determined etiology was more common in females and younger patients, with cervical artery dissection being the single most common etiology (12.8%). CE was more common in younger patients. Within CE, the most frequent high-risk sources were atrial fibrillation/flutter (15.1%) and cardiomyopathy (11.5%). LAA, high-risk sources of CE, and SVO were more common in males. LAA and SVO showed an increasing frequency with age. No significant etiologic distribution differences were found amongst southern, central, or northern Europe. CONCLUSIONS: The etiology of IS in young adults has clear gender-specific patterns that change with age. A notable portion of these patients remains without an evident stroke mechanism according to TOAST criteria.

Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings.

Miller Fisher syndrome (MFS), a variant of the Guillain-Barré syndrome (GBS), is characterized by ophthalmoplegia, ataxia, and areflexia. The annual incidence is around one patient per one million population. The antiganglioside anti-GQ1b IgG antibody has a role in the pathogenesis of the syndrome, especially of ophthalmoplegia. The presence of this antibody in the serum can be identified in over 80% of the patients, peaking in the first week, whereas albuminocytological dissociation in the cerebrospinal fluid (CSF) appears later. The most consistent electrophysiological findings in MFS are reduced sensory nerve action potentials and absent H reflexes. More variability is seen with F waves and various investigations involving cranial structures. Although there are usually no abnormalities in MFS by routine neuroimaging, in a few cases, contrast enhancement of nerve roots and signs of central nervous system involvement were described supporting the hypothesis of an anti-GQ1b-syndrome, a continuum involving GBS, MFS, and Bickerstaff's brainstem encephalitis. Owing to the lack of randomized trials, treatments used for GBS (intravenous immunoglobulin and plasmapheresis) are usually applied, although from retrospective analyses, the outcome was similar between treated and untreated subjects. The outcome of MFS is usually good with case fatality of < 5%. In the few autopsy cases, macroscopic abnormalities were generally not seen in the nervous system. Microscopic examination of the peripheral nervous system (including cranial nerves) showed segmental demyelination with minimal perivascular infiltration with normal spinal cord and brain stem.

Preserved structural and functional characteristics of common carotid artery in properly treated normoglycemic women with gestational diabetes mellitus.

Women with gestational diabetes mellitus (GDM) are at high risk of subsequently developing type 2 diabetes mellitus which is an important cardiovascular risk factor. We have evaluated whether preclinical morphological and functional arterial changes are present in GDM. Diameter, intima-media thickness (IMT), intima-media cross-section area (IMCSA) and elasticity features (compliance, distensibility coefficient, circumferential strain, stiffness index (SI) α and ß, incremental elastic modulus) of the common carotid arteries (CCA) were studied in the 3rd trimester in 25 women with GDM, and 17 normal pregnant women matched for age and body mass index using an ultrasonographic vessel wall-movement tracking system and applanation tonometry. Mean IMT, IMCSA and SI α tended to be larger, whereas compliance was smaller in women with GDM but none of these differences were significant. Serum glucose (4.99 ± 0.51 vs. 4.79 ± 0.61 mmol/L, p=0.37) and HbA1c (5.33 ± 0.27 vs. 5.36 ± 0.47 mmol/L, p=0.85) proved normoglycemia in both groups. In conclusion, by the combination of methods we applied in this case control study, neither morphological nor functional characteristics of large elastic arteries differ significantly between well-treated normoglycemic women with GDM and non-diabetic pregnant women in the 3rd trimester.

The Debrecen Stroke Database: demographic characteristics, risk factors, stroke severity and outcome in 8088 consecutive hospitalised patients with acute cerebrovascular disease.

BACKGROUND: High stroke mortality in central-eastern European countries might be due to higher stroke incidence, more severe strokes or less effective acute care than in countries with lower mortality rate. Hospital databases usually yield more detailed information on risk factors, stroke severity and short-term outcome than population-based registries. PATIENTS AND METHODS: The Debrecen Stroke Database, data of 8088 consecutively hospitalised patients with acute cerebrovascular disease in a single stroke centre in East Hungary between October 1994 and December 2006, is analysed. Risk factors were recorded and stroke severity on admission was scored by the Mathew stroke scale. The modified Glasgow outcome scale was used to describe patient condition at discharge. RESULTS: Mean age was 68+/-13 years, 11.4% had haemorrhagic stroke. The rate of hypertension on admission was 79% in men, and 84% in women, 40.3% of men and 19.8% of women were smokers, and 34% of all patients had a previous cerebrovascular disease in their history. Case fatality was 14.9%, and 43% had some disability at discharge. Outcome at discharge was worse with higher age, higher glucose, higher blood pressure, higher white cell count and erythrocyte sedimentation rate and more severe clinical signs on admission. In multivariate analysis admission blood pressure lost its significance in predicting outcome. CONCLUSIONS: In this large Hungarian stroke unit database hypertension on admission, smoking and previous cerebrovascular disease were more frequent than in most western databases. These findings indicate major opportunities for more efficient stroke prevention in this and probably other eastern European countries.

Vinpocetine for acute ischaemic stroke.

BACKGROUND: Vasoactive and neuroprotective drugs such as vinpocetine are used to treat stroke in some countries. OBJECTIVES: To assess the effect of vinpocetine in acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched February 2007), MEDLINE (1966 to February 2007) and Scopus (1960 to February 2007). We also searched the Internet Stroke Center Stroke Trials Registry, Google Scholar, the science-specific search engine Scirus and Wanfang Data, the leading information provider in China. We contacted researchers in the field and four pharmaceutical companies that manufacture vinpocetine. Searches were complete to February 2007. SELECTION CRITERIA: Unconfounded randomised trials of vinpocetine compared with placebo, or any other reference treatment, in people with acute ischaemic stroke. We included trials if treatment started no later than 14 days after stroke onset. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria. One review author extracted the data, which was then checked by the second review author. We assessed trial quality. The primary outcome measure was death or dependency. MAIN RESULTS: We included two trials, involving a total of 70 participants. Data for 63 participants were reported in the two trials combined. The rate of death or dependency did not differ between the treatment and placebo groups at one and three months. The 95% confidence intervals for the outcome measures were wide and included the possibility of both significant benefit and significant harm. No adverse effects were reported. AUTHORS' CONCLUSIONS: There is not enough evidence to evaluate the effect of vinpocetine on survival or dependency in patients with acute ischaemic stroke.

Mannitol for acute stroke.

BACKGROUND: Mannitol is an osmotic agent and a free radical scavenger which might decrease oedema and tissue damage in stroke. OBJECTIVES: To test whether treatment with mannitol reduces short and long-term case fatality and dependency after acute ischaemic stroke or intracerebral haemorrhage (ICH). SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (searched December 2006), MEDLINE (1966 to January 2007), the Chinese Stroke Trials Register (searched November 2006), the China Biological Medicine Database (searched December 2006) and the Latin-American database LILACS (1982 to December 2006). We also searched the database of Masters and PhD degree theses at Sao Paulo University (searched January 2007), and neurology and neurosurgery conference proceedings in Brazil from 1965 to 2006. In an effort to identify further published, ongoing and unpublished studies we searched reference lists and contacted authors of published trials. SELECTION CRITERIA: We included randomised controlled trials comparing mannitol with placebo or open control in patients with acute ischaemic stroke or non-traumatic intracerebral haemorrhage. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed quality, extracted data, and performed the data analysis. MAIN RESULTS: Three small trials, involving 226 participants, were included. One trial included patients with presumed ischaemic stroke without computerised tomography (CT) verification, and the other two trials included patients with CT-verified ICH. Data on the primary outcome measure (death and dependency) were not available in any of the trials. Death and disability could be calculated in the larger ICH trial without differences between the mannitol and control groups. Case fatality was not reported in the trial of ischaemic stroke. Case fatality did not differ between the mannitol and control groups in the ICH trials. Adverse events were either not found or not reported. The change in clinical condition was reported in two trials, and the proportion of those with worsening or not improving condition did not differ significantly between mannitol-treated patients and controls. Based on these three trials neither beneficial nor harmful effects of mannitol could be proved. Although no statistically significant differences were found between the mannitol-treated and control groups, the confidence intervals for the treatment effect estimates were wide and included both clinically significant benefits and clinically significant harms as possibilities. AUTHORS' CONCLUSIONS: There is currently not enough evidence to support the routine use of mannitol in acute stroke patients. Further trials are needed to confirm or refute whether mannitol is beneficial in acute stroke.

Factors influencing hemorrhagic transformation in ischemic stroke: a clinicopathological comparison.

As hemorrhagic transformation (HTr) is a frequent complication and can worsen the outcome of acute ischemic stroke, our aim was to assess the risk factors of HTr. Using the database of our neuropathological laboratory, 245 consecutive acute ischemic stroke patients were analyzed. An exploratory logistic regression procedure was carried out to find the best multiple model identifying the factors associated with HTr. The autopsy revealed ischemic infarct in 175 (71%) and ischemic infarct with HTr in 70 (29%) patients. Mean age was 71.5 +/- 11.4 years (mean +/- SD) and 74.8 +/- 10.2 years (mean +/- SD), respectively. The multiple model confirmed age in case of embolic stroke, and diabetes mellitus and infarct size as independent risk factors of HTr. It seems that not serum glucose level but diabetes mellitus in the case history is an independent predictor of HTr.

Disability is the major determinant of the severity of depressive symptoms in primary headaches but not in low back pain.

Pain syndromes are often associated with depression. In a prospective study we analysed if determinants of depression differ among patients with different primary headaches and between headaches and non-headache pain. During a 2-year period between 1 February 2002 and 31 January 2004, 635 subjects (migraine n = 231; tension-type headache n = 176; cluster headache n = 11; patients with low back pain n = 103; and healthy subjects n = 114) seen by two neurologists filled in a questionnaire on pain characteristics, the MIDAS questionnaire and the Beck Depression Inventory. A multivariate general regression model was used to identify independent predictors of the severity of depressive symptoms. Pain was most frequent in chronic tension-type headache and most intense in the cluster subgroup (P < 0.001, Kruskal-Wallis ANOVA). In univariate tests gender, age, pain frequency, pain intensity and disability were all significantly associated with the severity of depressive symptoms. In the multivariate model disability was the most important independent determinant of the severity of depressive symptoms in the pooled headache group as well as in the migraine and tension-type headache subgroups. In contrast to patients with headache, pain frequency and pain intensity were the significant independent predictors of the severity of depressive symptoms in patients with low back pain. In a multivariate model, after controlling for other factors, determinants of the severity of depressive symptoms were different in headache and non-headache pain subjects, suggesting a different mechanism for developing depression in primary headaches and in other pain syndromes.

Primary headaches in an outpatient neurology headache clinic in East Hungary.

The majority of patients with primary headache do not seek medical help. In the present study we analyse the characteristics of those patients with primary headaches who consulted a single headache outpatient service in East Hungary. All consecutive patients with primary headaches referred to the headache center between February 2002 and April 2003 were asked to fill in a questionnaire on headache characteristics and the migraine disability score (MIDAS) form. A total of 327 patients had some form of primary headache: 42% migraine, 31% tension-type headache, 1% cluster headache and 26% had combination headache. Of the patients 95% were younger than 60 years of age. Only 16% of the patients were male. Chronic daily headache was found in 41% of patients. Although headache was the least severe in tension-type headache, reported disability occurred on much more days in this group than in migraine patients. The majority of patients with primary headache were in the active age group. Patients with tension-type headache need more attention, as disability is more severe in this patient group than generally assumed. More attention to the headaches of men and the elderly could improve the quality of life in these groups of the Hungarian population.

The Mures-Uzhgorod-Debrecen study: a comparison of hospital stroke services in Central-Eastern Europe.

Stroke mortality is extremely high in Central-Eastern European countries. The high rate of risk factors and differences in health care services might be among the factors resulting in high stroke morbidity and mortality in this region. As only few prospectively collected information are available from this region, we decided to evaluate some characteristics of stroke services in neurological departments of a Romanian, a Ukrainian and a Hungarian city in the framework of the Mures-Uzhgorod-Debrecen comparative epidemiological study. We registered demographic data, the absence or presence of the most important risk factors, and clinical signs on admission and at discharge. We recorded the application of various diagnostic methods, stroke treatment and recommendations for secondary prevention. Follow-up is planned after 30 days and after 1 year. The paper summarizes the methodology of this prospective epidemiological study of stroke patients hospitalized in neurological departments in Târgu Mures, Uzhgorod and Debrecen, three Central-Eastern European cities in Romania, Ukraine and Hungary, respectively.

Natural coagulation inhibitor proteins in young patients with cerebral ischemia.

Disturbances of coagulation and fibrinolytic pathways were studied in 53 young patients with cerebral ischemia. Upon admission 26 of 53 patients had abnormality in at least one of the antithrombin-III, protein C, protein S activities or in activated protein C (APC) ratios. Three months after the first examination the majority of the previously detected abnormalities returned to normal values and the most frequent alterations were decrease in protein S activity (3 patients) and APC resistance (3 patients). Conditions resulting in impaired fibrinolysis were frequently detected upon admission. Elevation of plasminogen activator inhibitor-1, lipoprotein (a), and alpha-2-antiplasmin was present in 23, 10, and 4 cases, respectively. It is concluded that abnormalities of coagulation as well as of the fibrinolytic systems are prevalent in the acute phase of cerebral ischemia, however, the results may be significantly influenced by the disease process or the acute phase effect.

Transcranial Doppler monitoring in hypertensive patients during physical exercise.

PURPOSE: To evaluate the diagnostic value of a combined method, i.e. ergometer cycling with continuous bilateral transcranial Doppler monitoring (TCD) to detect cerebral hemodynamic abnormalities in recently diagnosed hypertensive patients. METHODS: 30 neurologically symptom-free, nontreated patients with essential hypertension and 30 age- and sex-matched controls were studied. Carotid ultrasound, resting ECG and blood parameters were investigated. Cycling ergometry was performed according to the WHO protocol. Blood pressure, heart rate, end-tidal CO2 (etCO2) and bilateral middle cerebral artery (MCA) blood flow velocity (MV) were monitored. RESULTS: At rest, MV in the MCA did not differ significantly between controls and hypertensive subjects. MV continuously increased in controls until the end of loading whereas a plateau was reached at 4 min in hypertensive subjects. During 6 min of cycling, the time course of absolute values of MV in the MCA and that of the changes in the ratio of mean velocity/end-tidal CO2 (DeltaMV/DeltaetCO2) differed significantly between hypertensive subjects and controls (p = 0.03 and p = 0.02, respectively). CONCLUSION: Ergometer cycling combined with TCD revealed altered vasoreactivity, therefore this may be a sensitive method for the detection of early hemodynamic impairment in nontreated hypertensive subjects.

A population study of stroke in West Ukraine: incidence, stroke services, and 30-day case fatality.

BACKGROUND AND PURPOSE: According to World Health Organization statistics, Ukraine has extremely high stroke mortality. No population-based prospective studies of stroke incidence have been performed yet in this European country with approximately 50 million inhabitants. High reported rates of stroke mortality in official statistics conflict with some locally published incidence data in Ukraine. To obtain accurate data, we evaluated stroke incidence and 30-day case fatality in a prospective population study in the West Ukrainian city of Uzhgorod with a population of 126 000 inhabitants. METHODS: Case certification by neurologists and follow-up at 30 days after stroke for all patients identified by any level of the health service system were performed for a 12-month period. RESULTS: We identified 352 stroke cases. The age-standardized incidence was 341 and 238 of 100 000 and mortality was 83 and 69 of 100 000 with the use of the European or world standard population for standardization. Mean age of stroke patients was 63.4+/-12.5 years. Rate of hospitalization was 66%. Hospitalized patients were >10 years younger than those treated in their homes. The 30-day case fatality rates were 15.4% among hospitalized patients and 36.8% among those treated at home. Overall 30-day case fatality was 23.3%. CONCLUSIONS: Stroke incidence and 30-day case fatality in this West Ukrainian city were similar to those of some West European countries and were much lower than what could be expected from World Health Organization statistics. The relatively low incidence rate seems accurate; because of the organization of local stroke services, it is not probable that a considerable proportion of patients with acute stroke could bypass all levels of the acute care health system. Local health statistics reported a much lower number of stroke cases and stroke deaths than found in our survey; thus, further study is needed to clarify the reason for the discrepancy between local data and the high reported stroke mortality in Ukraine.