Guillain-Barre Syndrome Followed by Covid-19 Infection, Vaccination and Other Precipitating Factors during the Pandemic.

Background and Aims: Guillain-Barré syndrome (GBS) is usually triggered by an infection. Vaccination is mentioned as a possible trigger in a small number of GBS cases. The aim of this study was to notice GBS distinctness provoked by various triggers during the COVID-19 pandemic. Material and Methods: A total of 109 GBS patients were divided into three groups, respectively: COVID-19 infection associated (19 patients), COVID-19 vaccination associated (16 patients) and precipitated by some other factors (74 patients). We compared the clinical, neurophysiological and laboratory characteristics of these three groups. Results: Neither were differences recorded in the age of the patients of these three groups at the time of illness, nor in the number of days from the precipitating factor to the onset of symptoms. There were no clinical differences between groups related to severity of the disease or patients' recovery. The only clinical difference was observed in relation to facial nerve bilateral affection because it was significantly higher in the post-vaccination group. According to neurophysiological findings, demyelinating form dominated in all three groups. Conclusion: Clinical characteristics, electrophysiological findings and laboratory characteristics did not differ significantly in Guillain-Barre syndrome followed by COVID-19 infection, vaccination and other precipitating factors during the pandemic. The bilateral involvement of facial nerves was significantly higher in the post-vaccination group. Most of these cases had a mild form of the disorder-distal paresthesias GBS variant.

Artery of Percheron infarction associated with COVID-19 in the young adult.

The artery of Percheron is a small vessel whose occlusion causes bilateral paramedian thalamic and rostral midbrain stroke. COVID-19 is an independent risk factor for acute small vessel ischemic stroke. We presented the case of a young adult patient with infarction in the artery of Percheron territory as a presenting feature of COVID-19. Artery of Percheron infarction is a neurodiagnostic challenge in emergency during COVID-19 pandemic.

Association of circadian rhythm genes ARNTL/BMAL1 and CLOCK with multiple sclerosis.

Prevalence of multiple sclerosis varies with geographic latitude. We hypothesized that this fact might be partially associated with the influence of latitude on circadian rhythm and consequently that genetic variability of key circadian rhythm regulators, ARNTL and CLOCK genes, might contribute to the risk for multiple sclerosis. Our aim was to analyse selected polymorphisms of ARNTL and CLOCK, and their association with multiple sclerosis. A total of 900 Caucasian patients and 1024 healthy controls were compared for genetic signature at 8 SNPs, 4 for each of both genes. We found a statistically significant difference in genotype (ARNTL rs3789327, P = 7.5·10-5; CLOCK rs6811520 P = 0.02) distributions in patients and controls. The ARNTL rs3789327 CC genotype was associated with higher risk for multiple sclerosis at an OR of 1.67 (95% CI 1.35-2.07, P = 0.0001) and the CLOCK rs6811520 genotype CC at an OR of 1.40 (95% CI 1.13-1.73, P = 0.002). The results of this study suggest that genetic variability in the ARNTL and CLOCK genes might be associated with risk for multiple sclerosis.

The impact of betaplus program on patient treatment satisfaction with interferon beta-1b in multiple sclerosis: Multicentric cross-sectional survey in the western Balkan countries.

BACKGROUND: Long-term treatment adherence to disease-modifying drugs (DMDs) may have significant impact on clinical outcomes in multiple sclerosis (MS). It has been recently emphasized that low treatment satisfaction (TS) may be an important factor for achieving high rates of treatment adherence. Interferon (IFN) beta-1b was the first DMD approved for the treatment of MS. The aims of our study were to assess TS in subjects with relapsing-remitting (RR) MS treated with IFN beta-1b in Serbia, Montenegro and the Republika Srpska, Bosnia and Herzegovina (B&H), and additionally, to evaluate the impact of patient support program on TS and adherence. METHODS: This is a cross-sectional survey performed in order to examine TS and adherence with IFN beta-1b in seven MS centers across three countries (Serbia, Montenegro and B&H). Included in the study were 296 adult patients with RRMS treated with IFN beta-1b for at least 6 months. They were invited to complete the Treatment Satisfaction Questionnaire for Medication (TSQM). Additional two treatment adherence questions were also asked. Patient support program (Betaplus®) was available exclusively for patients in Serbia and not for those in Montenegro and the Republika Srpska, B&H. In order to assess the potential impact of this program on TSQM, we combined two groups of patients from Montenegro and B&H and compared their results with those from patients in Serbia. Statistical analysis includes multivariable linear regression analysis in order to assess the differences between three MS patients groups in terms of the TSQM scores, adjusted for potential confounders. For the evaluation of the effects of Betaplus® program, multivariable logistic regression was used, controlling for the same confounding factors. RESULTS: Each of the TSQM summary scores in all three countries implicated high level of patients' satisfaction. There was statistically significant group difference on the Effectiveness summary score (p=0.001) and the Side effects summary score (p=0.006) between the group of subjects from Serbia and the combined group of subjects from Montenegro and B&H, in favor of the former cohort. There was statistically significant group difference neither on the Convenience summary score nor on the Overall satisfaction summary score. Results of adjusted logistic regression analysis based on the availability of patient support program (dependent variable) implicate that it had the most significant impact on the Effectiveness summary score (p=0.008). According to the correlation coefficients in the total patient cohort, all TSMQ summary scores except Effectiveness significantly correlated with the decreased adherence (Side effects: p=0.037; Convenience: p=0.016; Overall satisfaction: p=0.046). CONCLUSION: TS with IFN beta-1b was high in our MS patients. Additionally, these results have demonstrated that patient support program have significant impact on TS with IFN beta-1b in the Balkan cohort of RRMS patients.

Urgent carotid stenting before cardiac surgery in a young male patient with acute ischemic stroke caused by aortic and carotid dissection.

Introduction: Acute aortic dissection (AD) is the most common life-threatening disorder affecting the aorta. Neurological symptoms are present in 17-40% of cases. The management of these patients is controversial. Case report: We presented a 37-year-old man admitted for complaining of left-sided weak-ness. Symptoms appeared two hours before admission. The patient had no headache, neither thoracic pain. Neurological examination showed mild confusion, left-sided hemiplegia, National Institutes of Health Stroke Scale (NIHSS) score was 10. Ischemic stroke was suspected, brain multislice computed tomography (MSCT) and angiography were performed and right intrapetrous internal carotid artery dissection noted. Subsequent color Doppler ultrasound of the carotid arteries showed dissection of the right common carotid artery (CCA). The patient underwent thoracic and abdominal MSCT aortography which showed ascending aortic dissection from the aortic root, propagating in the brachiocephalic artery and the right CCA. Digital subtraction angiography was performed subsequently and two stents were successfully implanted in the brachiocephalic artery and the right CCA prior to cardiac surgery, only 6 hours after admission. The ascending aorta was reconstructed with graft interposition and the aortic valve re-suspended. The patient was hemodynamically stable and with no neurologic deficit after surgery. Unfortinately, at the operative day 6, mediastinitis developed and after intensive treatment the patients died 35 days after admission. Conclusion: In young patients with suspected stroke and oscillatory neurological impairment urgent MSCT angiography of the brain and neck and/or Doppler sonography of the carotid and vertebral artery are mandatory to exclude carotid and aortic dissection. The prompt diagnosis permits urgent carotid stenting and cardiosurgery. To the best of our knowledge, this is the first published case of immediate carotid stenting in acute ischemic stroke after the diagnosis of carotid and aortic dissection and prior to cardiac surgery

Importance of angle correction in transcranial color-coded duplex insonation of arteries at the base of the brain.

BACKGROUND/AIM: Transcranial color-coded duplex (TCCD) sonography allows visualization of the vessels being examined and measurement of the angle of insonation. The published literature suggests that blood vessels are insonated at the angle lower than 30 degrees, hence no correction for the angle is necessary. The aim of this study was to determine the availability of intracranial blood vessels for insonation, and the percentage of arteries and their segments which can be insonated at the angles lower than 30 degrees. METHODS: The study included 120 patients (mean age 51). For each of the segments the angle of insonation was registered based on TCCD vizualization, and hemodynamic parameters were measured. The angle of insonation was measured using combined B-mode and color Doppler vizualization, as the angle between the direction of the ultrasound beam and the axis of the shown arterial segment. RESULTS: The total success rate of insonation was 86.33% (1,554 out of 1,800). The mean angle of insonation value in all the examined arterial segments was 42 degrees. The insonation angle was higher than 30 degrees in about three quarters of the examined segments, especially in the A2 segment of the anterior cerebral artery (98%), the P1 segmet of the posterior cerebral artery (87%) and in the terminal internal carotid artery (83%). The A1 segment of the anterior cerebral artery showed the best insonation conditions with the angle of insonation lower than 30 degrees in 53% of the cases. CONCLUSION: The presented results of angles of insonation measurements for the anterior, middle and posterior cerebral arteries and their segments, as well as the terminal portion of the internal carotid artery clearly indicate that their average values in tested segments were very often higher than 30 degrees, which can cause an error in blood flow velocity measurement that cannot be ignored. The results confirm the necessity of correcting flow velocity values on the basis of the angle of insonation in TCCD sonography.

Small internal jugular veins with restricted outflow are associated with severe multiple sclerosis: a sonographer-blinded, case-control ultrasound study.

BACKGROUND: Recent evidence has indicated an association between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis. Small internal jugular veins (IJVs) (with a cross-sectional area of less than 0.4 cm²) have been previously described as difficult to catheterize, and their presence may potentially affect cerebrospinal venous drainage. In this blinded extracranial color-Doppler study we had two principal aims: first, to assess prevalence of CCSVI among Serbian MS patients compared to healthy controls; and second, to assess prevalence of small IJVs (with a CSA ≤ 0.4 cm²) among MS patients and controls. METHODS: The sixty seven unrelated patients with clinical isolated syndrome (CIS), relapsing-remitting (RR), secondary progressive (SP) and primary progressive (PP) multiple sclerosis and 21 healthy controls were examined by high-resolution color-Doppler. RESULTS: The ultrasonographic criteria of CCSVI (according to Zamboni) were positive in 11.9% of the patients and in none of the control subjects. The CCSVI-positive patients had significantly longer disease durations and were significantly more disabled (measured by their Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) scores), but after adjustment for gender and disease duration, CCSVI was not an independent risk factor for multiple sclerosis severity. The small IJVs were found in 28.4% of the patients and 28.6% of the controls. The patients with small IJVs were associated with decreased venous outflow from the brain and presented with longer disease durations and significantly higher EDSS and MSSS scores compared to patients without small IJVs. A multivariate logistic regression analysis adjusted for gender and disease duration showed that small IJV is an independent factor associated with multiple sclerosis severity (EDSS ≥6) (adjusted OR = 8.9, 95% CI: 1.8-45.6, p = 0.007). Among patients with small IJVs the 36.84% were also CCSVI positive. CONCLUSIONS: Both, CCSVI and small IJVs seem to influence or follow MS severity, but only small IJVs turned out to be an independent factor in this study. Thus, small IJVs with restricted outflow, which might be aspects of CCSVI different from the criteria originally described by Zamboni, emerge as a cofactor in the multifactorial pathophysiology of multiple sclerosis.

[Intimomedial thickness of the vertebral arteries complex: a new useful parameter for the assessment of atheroclerotic process?].

BACKGROUND/AIM: An integral part of Doppler ultrasound examination of cervical blood vessels is determination of intimomedial thicknes (IMT) of the common carotid. The aim of the study was to estimate the relations between IMT of the common carotid and vertebral arteries in order to determine if the value of IMT obtained on the vertebral artery could be applied in clinical practice. METHODS: We measured IMT in a randomized, prospective and cross-sectional study, performed on 50 persons both sexes (29 men and 21 women), at the age from 18 to 79 years (mean age 52.4 +/- 17.63 years). All the persons were healthy, what was confirmed with clinical examination and laboratory analyses. Measurements were perfomed from January 2006 until September 2008. Intimomedial thickness was recorded by two dimensional ultrasonography in B-mode on both common carotid arteries: one value was obtained as average of three successeful measurements (measurements were perform on different places). We measured IMT on the first segment of both vertebral arteries, 1.5 cm proximal from the connection of the first and second segments (we got results of the measurement of IMT on the vertebral arteries in the same way: mean value from the three records). RESULTS: The measured value of IMT on the common carotid arteries (IMT = 0.782 +/- 0.248 mm), obtained from 50 healthy persons, was higher than that measured on the vertabral artery on the first segment (IMT = 0.585 +/- 0.134 mm). The values of IMT after measurement on two different places were statistically highly different (t = 7.03, SD = 0.028, p < 0.01). Coefficient of variability of IMT values in carotid circulation (CV = 34.4%) was higher than that in vertebral circulation (22.9%). Values of IMT on vertebral arteries were in statistically significant correlation with those in carotid circulation (r = 0.24 and t- = 2.48; p < 0.02). There were no statistically significant difference between IMT measurement on the right and the left side so they were analysed as the same set. CONCLUSION: Values of IMT on the vertebral arteries are one more undependent parameter of Doppler-sonographic examination of cervical vessels, which significantly correlates with IMT values on common carotid artery. Variability of this parameter is lower, and absolute values lower than the same in the common carotid artery. Therefore, this parameter is probably not so sensitive. On the other hand, lower variability of IMT values on the vertebral artery might be of higher specificity for prediction of atherosclerotic progress by the increased values of this parameter than based on IMT values obtained on the common carotid arteries.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

INTRODUCTION: Fast and precise diagnostics of the disease from the large group of adult leukoencephalopathy is difficult but responsible job, because the outcome of the disease is very often determined by its name. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by the mutation of Notch 3 gene on chromosome locus 19p13. Beside the brain arterioles being the main disease targets, extracerebral small blood vessels are affected by the pathological process. Clinically present signs are recurrent ischemic strokes and vascular dementia. CADASIL in its progressive form shows a distinctive pattern of pathological changes on MRI of endocranium. The diagnosis is confirmed by the presence of granular osmiophilic material (GOM) in histopathological skin biopsies. CASE REPORTS: Two young adult patients manifested ischemic strokes of unknown etiology, cognitive deterioration, migraine and psychopathological phenomenology. MRI of endocranium pointed on CADASIL. Ultrastructural examination of skin biopsy proved the presence of GOM in the basal lamina and near smooth muscle cells of arteriole dermis leading to CADASIL diagnosis. The presence of GOM in histopathological preparation is 100% specific for CADASIL. The patients were not searched for mutation in Notch 3 gene on chromosome 19, because some other leukoencephalopathy was disregarded. CONCLUSION: Suggestive clinical picture, distinctive finding of endocranium MRI, the presence of GOM by ultrastructural examination of histopathological skin biopsies are sufficient to confirm CADASIL diagnosis.

Interleukin 7 receptor alpha polymorphism rs6897932 and susceptibility to multiple sclerosis in the Western Balkans.

The interleukin 7 receptor alpha single nucleotide polymorphism rs6897932 was identified as a multiple sclerosis susceptibility-modifying polymorphism in genome-wide and gene scan studies, mainly in populations in western countries. The aim of this study was to investigate the association of interleukin 7 receptor alpha rs6897932 with multiple sclerosis in populations from the Western Balkans: Serbia, Croatia, and Slovenia. A total of 678 unrelated white patients and 597 unrelated, ethnically matched healthy controls were included in the study. Genotyping was performed by real-time polymerase chain reaction. We found no significant difference in genotype or allele frequencies between controls and patients with multiple sclerosis either separately in Serbian, Croatian, and Slovenian populations or in the whole sample from the Western Balkans. The odds ratio for multiple sclerosis in this study was 1.04 (0.86-1.25) for the C allele. It is known that demographic as well as environmental factors have a substantial role in multiple sclerosis development, as well as population genetic background. The results of this study indicate that other types of genome variants should be required for the development and/or progression of multiple sclerosis, which may vary among populations.

Temporal patterns of soluble adhesion molecules in cerebrospinal fluid and plasma in patients with the acute brain infraction.

The aim of this study was to define concentration changes of soluble adhesion molecules (sICAM-1, sVCAM-1 and sE-Selectin) in cerebrospinal fluid and plasma, as well as, number of peripheral blood leukocytes and the albumin coefficient in the patients with the acute brain infarction. We also, analyzed the correlation between the measured levels, the infarct volume and the degree of neurological and the functional deficit. The study included 50 patients with the acute cerebral infarction and the control group consisted of 16 patients, age and sex matched. Obtained results showed significant increase in number of leukocytes, the albumin coefficient and the level of soluble adhesion molecules within the first seven days in patients. The highest values of measured parameters were noted within the third and the fourth day after the insult, which is the suggested period of maximal intensity of inflammatory reactions. Significant correlation was found between measured parameters and the infarct volume, the degree of neurological and the functional deficit. The results suggest that investigated parameters in CSF and blood represent a dynamic index of inflammatory events as one of the fundametal mechanisms responsible for neuron damage during acute phase of brain infarction.

The tag SNP for HLA-DRB1*1501, rs3135388, is significantly associated with multiple sclerosis susceptibility: cost-effective high-throughput detection by real-time PCR.

BACKGROUND: Recently a high-resolution HLA and SNP map was defined and the analysis provided informative tag SNPs that capture much of the common variation in the MHC region. This concept enables detection of smaller number of SNPs, making it "surrogate" markers for haplotype associated with certain disease. The SNP rs3135388 was proposed as a tagging SNP for DRB1*1501/DQB10602 alleles, associated with MS. The aim of the study was to investigate the HLA rs3135388 genotypes in association with MS in patients from Serbia. METHODS: Two hundred sixty nine consecutive patients from Serbia with relapse-remitting and secondary progressive MS were recruited for the study. Genomic DNA was isolated from peripheral blood cells. We designed the TaqMan assay for high-throughput genotyping of HLA rs3135388 on 7500 Real-Time PCR System. RESULTS: We found significantly higher frequency of rs3135388 A allele carriers in MS patients compared to controls (p<0.001, chi(2)). In our population the carriers of one A allele had adjusted OR 2.09 (95% CI 1.41-3.09, p<0.001) for MS susceptibility. CONCLUSION: We assessed significant association of rs3135388 A allele carriership with MS in patients from Serbia. This HLA-DRB1*1501 "surrogate" marker is useful in association studies in MS.

Etiology of ischemic stroke among young adults of Serbia.

BACKGROUND/AIM: Etiology of ischemic stroke (IS) among young adults varies among countries. The aim of the study was to investigate the causes and risk factors of IS in the young adults of Serbia. METHODS: A total of 865 patients with IS, aged 15 to 45 years, were treated throughout the period 1989-2005. Etiologic diagnostic tests were performed on the patient by the patient basis and according to their availability at the time of investigation. The most likely cause of stroke was categorized according to the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria. RESULTS: There were 486 men and 379 women, with 19% of the patients < or = 30 years old. Large artery arteriosclerosis and small artery disease were confirmed in 14% of the patients, and embolism and other determined causes in 20%. Undetermined causes made up 32% of the patients, mostly those (26%) with incomplete investigations. Smoking (37%), hypertension (35%) and hyperlipidemia (35%) were the most common risk factors. Rheumatic heart diseases and prosthetic valves were the most common causes of IS. Arterial dissections and coagulation inhibitors deficiency were detected in a small number of patients. CONCLUSION: Etiology of IS among Serbian young adults shares characteristics of those in both western and less developed countries.

Association of MMP-3 5A/6A gene polymorphism with susceptibility to carotid atherosclerosis.

OBJECTIVES: Stromelysin-1 (MMP-3) as a key member of metalloproteinase family could have an important role in atherogenesis. The 5A/6A polymorphism in the promoter of MMP-3 gene affects the level of MMP-3 gene expression. We assessed whether the MMP-3 promoter low- and high-activity genotypes are related to susceptibility for carotid atherosclerosis (CA) in Serbian population. DESIGN AND METHODS: The study group of case-control design consisted of 515 participants. The 265 patients with ultrasonographic evidence of carotid plaque presence were recruited for the study. The 5A/6A polymorphism was typed by RFLP-PCR. RESULTS: There was significantly higher prevalence of genotypes containing 6A allele in the patients with CA compared to controls (p<0.05). The model of inheritance with the dominant effect of 6A allele gave elevated and significant OR for carotid atherosclerosis (adjusted OR 2.35, CI=1.0-5.5, p=0.048). CONCLUSIONS: Subjects carrying genotypes with 6A allele had significantly higher susceptibility to carotid atherosclerosis.

Association of the MMP-3 5A/6A gene polymorphism with multiple sclerosis in patients from Serbia.

Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in remodeling of the extracellular matrix. MMPs are suggested to play a role in the influx of inflammatory cells into the CNS, disruption of the blood brain barrier, and to degrade myelin in vitro. In this study, we have investigated the possible association of MMP-3 5A/6A gene polymorphism with MS susceptibility and/or severity in patients from Serbia. A total of 184 MS patients (150 RR, 34 SP) and 236 controls have been studied. Results show that the distribution of MMP-3 5A/6A genotype frequencies between MS patients and controls were not significantly different. In bout onset patients, carriers of MMP-3 6A/6A genotype had significantly higher mean MSSS values compared to the carriers of 5A allele (6.29+/-1.89 vs. 5.29+/-2.62, respectively, ANCOVA, p=0.01 Scheffe post-hoc test). In conclusion, our results indicate association of MMP-3 6A/6A genotype with significantly higher mean MSSS values. Thus, the obtained results suggest that it should be carefully considered during follow up of patients with MS. Further genetic and functional studies are needed to resolve the complex role of MMPs and their tissue inhibitors in MS pathology and/or regeneration.

Matrix metalloproteinase-9 -1562 C/T gene polymorphism in Serbian patients with multiple sclerosis.

Matrix metalloproteinase-9 (MMP-9) is suggested to play a role in MS by mediating T cell migration across subendothelial basement membrane and by contribution to myelin breakdown. We studied the association of MMP-9 -1562 C/T gene polymorphisms with MS susceptibility and severity in 187 patients from Serbia. The significant decrease in T allele carriership (p = 0.01), was found in female MS patients. In addition, a trend toward lower MSSS in T allele carriers was noticed (CC, mean 5.7 +/- 2.5 vs. CT+TT, mean 4.9 +/- 2.5). Further studies in different populations are needed to resolve the potential influence of MMP-9 gene polymorphism on MS.