Publications by authors named "Masoud Majed"

19 Publications

  • Page 1 of 1

Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial.

Lancet 2019 08;394(10199):672-683

Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Digestive Oncology Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Liver and Pancreaticobiliary Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Background: A fixed-dose combination therapy (polypill strategy) has been proposed as an approach to reduce the burden of cardiovascular disease, especially in low-income and middle-income countries (LMICs). The PolyIran study aimed to assess the effectiveness and safety of a four-component polypill including aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan for primary and secondary prevention of cardiovascular disease.

Methods: The PolyIran study was a two-group, pragmatic, cluster-randomised trial nested within the Golestan Cohort Study (GCS), a cohort study with 50 045 participants aged 40-75 years from the Golestan province in Iran. Clusters (villages) were randomly allocated (1:1) to either a package of non-pharmacological preventive interventions alone (minimal care group) or together with a once-daily polypill tablet (polypill group). Randomisation was stratified by three districts (Gonbad, Aq-Qala, and Kalaleh), with the village as the unit of randomisation. We used a balanced randomisation algorithm, considering block sizes of 20 and balancing for cluster size or natural log of the cluster size (depending on the skewness within strata). Randomisation was done at a fixed point in time (Jan 18, 2011) by statisticians at the University of Birmingham (Birmingham, UK), independent of the local study team. The non-pharmacological preventive interventions (including educational training about healthy lifestyle-eg, healthy diet with low salt, sugar, and fat content, exercise, weight control, and abstinence from smoking and opium) were delivered by the PolyIran field visit team at months 3 and 6, and then every 6 months thereafter. Two formulations of polypill tablet were used in this study. Participants were first prescribed polypill one (hydrochlorothiazide 12·5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg). Participants who developed cough during follow-up were switched by a trained study physician to polypill two, which included valsartan 40 mg instead of enalapril 5 mg. Participants were followed up for 60 months. The primary outcome-occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke)-was centrally assessed by the GCS follow-up team, who were masked to allocation status. We did intention-to-treat analyses by including all participants who met eligibility criteria in the two study groups. The trial was registered with ClinicalTrials.gov, number NCT01271985.

Findings: Between Feb 22, 2011, and April 15, 2013, we enrolled 6838 individuals into the study-3417 (in 116 clusters) in the minimal care group and 3421 (in 120 clusters) in the polypill group. 1761 (51·5%) of 3421 participants in the polypill group were women, as were 1679 (49·1%) of 3417 participants in the minimal care group. Median adherence to polypill tablets was 80·5% (IQR 48·5-92·2). During follow-up, 301 (8·8%) of 3417 participants in the minimal care group had major cardiovascular events compared with 202 (5·9%) of 3421 participants in the polypill group (adjusted hazard ratio [HR] 0·66, 95% CI 0·55-0·80). We found no statistically significant interaction with the presence (HR 0·61, 95% CI 0·49-0·75) or absence of pre-existing cardiovascular disease (0·80; 0·51-1·12; p=0·19). When restricted to participants in the polypill group with high adherence, the reduction in the risk of major cardiovascular events was even greater compared with the minimal care group (adjusted HR 0·43, 95% CI 0·33-0·55). The frequency of adverse events was similar between the two study groups. 21 intracranial haemorrhages were reported during the 5 years of follow-up-ten participants in the polypill group and 11 participants in the minimal care group. There were 13 physician-confirmed diagnoses of upper gastrointestinal bleeding in the polypill group and nine in the minimal care group.

Interpretation: Use of polypill was effective in preventing major cardiovascular events. Medication adherence was high and adverse event numbers were low. The polypill strategy could be considered as an additional effective component in controlling cardiovascular diseases, especially in LMICs.

Funding: Tehran University of Medical Sciences, Barakat Foundation, and Alborz Darou.
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http://dx.doi.org/10.1016/S0140-6736(19)31791-XDOI Listing
August 2019

Seroprevalence and clinical phenotype of MOG-IgG-associated disorders in Sri Lanka.

J Neurol Neurosurg Psychiatry 2019 12 6;90(12):1381-1383. Epub 2019 Aug 6.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

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http://dx.doi.org/10.1136/jnnp-2018-320243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902071PMC
December 2019

Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders.

Brain 2019 05;142(5):1310-1323

Department of Neurology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, Minnesota, USA.

Pathogenic antibodies targeting the aquaporin-4 water channel on astrocytes are associated with relapsing inflammatory neuromyelitis optica spectrum disorders. The clinical phenotype is characterized by recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, area postrema attacks and less common brainstem and cerebral events. Patients often develop major residual disability from these attacks, so early diagnosis and initiation of attackpreventing medications is important. Accurate prediction of relapse would assist physicians in counselling patients, planning treatment and designing clinical trials. We used a large multicentre dataset of 441 patients from the UK, USA, Japan and Martinique who collectively experienced 1976 attacks, and applied sophisticated mathematical modelling to predict likelihood of relapse and disability at different time points. We found that Japanese patients had a lower risk of subsequent attacks except for brainstem and cerebral events, with an overall relative relapse risk of 0.681 (P = 0.001) compared to Caucasians and African patients, who had a higher likelihood of cerebral attacks, with a relative relapse risk of 3.309 (P = 0.009) compared to Caucasians. Female patients had a higher chance of relapse than male patients (P = 0.009), and patients with younger age of onset were more likely to have optic neuritis relapses (P < 0.001). Immunosuppressant drugs reduced and multiple sclerosis disease-modifying agents increased the likelihood of relapse (P < 0.001). Patients with optic neuritis at onset were more likely to develop blindness (P < 0.001), and those with older age of onset were more likely to develop ambulatory disability. Only 25% of long-term disability was related to initial onset attack, indicating the importance of early attack prevention. With respect to selection of patients for clinical trial design, there would be no gain in power by selecting recent onset patients and only a small gain by selecting patients with recent high disease activity. We provide risk estimates of relapse and disability for patients diagnosed and treated with immunosuppressive treatments over the subsequent 2, 3, 5 and 10 years according to type of attack at onset or the first 2-year course, ethnicity, sex and onset age. This study supports significant effects of onset age, onset phenotype and ethnicity on neuromyelitis optica spectrum disorders outcomes. Our results suggest that powering clinical treatment trials based upon relapse activity in the preceding 2 years may offer little benefit in the way of attack risk yet severely hamper clinical trial success.
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http://dx.doi.org/10.1093/brain/awz054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487334PMC
May 2019

Paraneoplastic autoimmunity and small-cell lung cancer: Neurological and serological accompaniments.

Thorac Cancer 2019 04 27;10(4):1001-1004. Epub 2019 Feb 27.

Department of Neurology, Mayo Clinic, Rochester, USA.

Paraneoplastic neurological autoimmunity is often associated with small-cell lung cancer (SCLC), a highly malignant neuroendocrine tumor. Paraneoplastic autoimmunity often correlates with longer survival. We describe the paraneoplastic neurological manifestations of patients with SCLC with and without SCLC-predictive autoantibodies and the correlation between autoimmunity and survival. We reviewed the records of 116 patients (51% male) from the Mayo Clinic with histopathologically confirmed SCLC for whom stored serum was available for neural autoantibody testing. Cancer was limited stage in 41%; the median age at diagnosis was 64 years. Paraneoplastic neurological manifestations were recorded in 61% (decreasing frequency: peripheral neuropathy, dysautonomia, cognitive decline, cerebellar ataxia, neuromuscular junction disorder, seizures, cranial neuropathy, movement disorder, brainstem disorder, or myelopathy). Neural autoantibodies, some with pathogenic potential, were detected in the sera of SCLC patients with and without neurological autoimmunity. The most frequent among patients with neurological manifestations were: anti-neuronal nuclear antibody-type 1, voltage-gated calcium channel (VGCC)-N-type, VGCC-P/Q-type, glutamic acid decarboxylase 65 (GAD65), SOX1, and muscle acetylcholine receptor (AChR); while the most common in patients without neurological manifestations were: GAD65, muscle-AChR, and VGCC-P/Q-type. Neither cancer stage at diagnosis nor survival correlated with neurological manifestations or autoantibody-positivity, except for shorter survival in patients with myelopathy. The only predictor of longer survival was limited-stage disease at diagnosis.
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http://dx.doi.org/10.1111/1759-7714.13009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449272PMC
April 2019

A multicenter comparison of MOG-IgG cell-based assays.

Neurology 2019 03 6;92(11):e1250-e1255. Epub 2019 Feb 6.

From the Oxford Autoimmune Neurology Group (P.J.W., M.W., S.R.I.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., S.L.), Affiliated to Euroimmun AG, Luebeck, Germany; and Departments of Neurology (M.M., E.P.F., A.C.K., A.M., S.J.P.) and Laboratory Medicine and Pathology (J.F., J.M., E.P.F., A.C.K., A.M., S.J.P.), Mayo Clinic, College of Medicine, Rochester, MN.

Objectives: To compares 3 different myelin oligodendrocyte glycoprotein-immunoglobulin G (IgG) cell-based assays (CBAs) from 3 international centers.

Methods: Serum samples from 394 patients were as follows: acute disseminated encephalomyelitis (28), seronegative neuromyelitis optica (27), optic neuritis (21 single, 2 relapsing), and longitudinally extensive (10 single, 3 recurrent). The control samples were from patients with multiple sclerosis (244), hypergammaglobulinemia (42), and other (17). Seropositivity was determined by visual observation on a fluorescence microscope (Euroimmun fixed CBA, Oxford live cell CBA) or flow cytometry (Mayo live cell fluorescence-activated cell sorting assay).

Results: Of 25 samples positive by any methodology, 21 were concordant on all 3 assays, 2 were positive at Oxford and Euroimmun, and 2 were positive only at Oxford. Euroimmun, Mayo, and Oxford results were as follows: clinical specificity 98.1%, 99.6%, and 100%; positive predictive values (PPVs) 82.1%, 95.5%, and 100%; and negative predictive values 79.0%, 78.8%, and 79.8%. Of 5 false-positives, 1 was positive at both Euroimmun and Mayo and 4 were positive at Euroimmun alone.

Conclusions: Overall, a high degree of agreement was observed across 3 different MOG-IgG CBAs. Both live cell-based methodologies had superior PPVs to the fixed cell assays, indicating that positive results in these assays are more reliable indicators of MOG autoimmune spectrum disorders.
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http://dx.doi.org/10.1212/WNL.0000000000007096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511109PMC
March 2019

Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive NMOSD.

Neurology 2018 10 26;91(17):e1642-e1651. Epub 2018 Sep 26.

From the Departments of Neurology (E.S., D.D., M.M., E.F., A.G., B.W., S.J.P.), Laboratory Medicine and Pathology (M.M., E.F., A.G., S.J.P.), and Clinical Research Unit (C.H., J.S.), Mayo Clinic College of Medicine, Rochester, MN; Nuffield Department of Clinical Neurosciences (J.P., M.I.L., S.M.), Oxford; The Walton Centre (A.J., D.W., L.E.), NHS Foundation Trust, Liverpool, UK; Department of Neurology (I.N., K.F., T.T., T.M., Y.T.), Tohoku University Graduate School of Medicine, Sendai; Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine and Multiple Sclerosis and Neuromyelitis Optica Center, Southern Tohoku Research Institute for NeuroScience, Koriyama, Japan; Department of Neurology (M.L., A.B.), Johns Hopkins University, Baltimore, MD; Departments of Neurology and Neurotherapeutics (B.M.G.), UT Southwestern Medical Center, Dallas, TX; Department of Neurology (T.T.), Yonezawa National Hospital; and Department of Neurology (I.N.), Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Objective: To define the frequency, duration, and severity of intractable nausea, vomiting, or hiccups in aquaporin-4-immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and propose diagnostic criteria and a severity scale for area postrema syndrome (APS).

Methods: An International NMOSD database was interrogated for frequency of APS. Patients with AQP4-IgG-positive NMOSD completed an APS symptom questionnaire. Nausea and vomiting severity was derived from the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score. The diagnostic criteria, severity scale, and immunotherapy response was applied to a prospective validation cohort of patients from multiple centers.

Results: Analysis of an international database for AQP4-IgG-seropositive NMOSD (n = 430) revealed a high prevalence of isolated APS attacks (onset 7.1%-10.3%; subsequent 9.4%-14.5%) across continents. For 100 patients with 157 episodes of APS, nausea (n = 127, 81%) lasted for a median of 14 days (range 2-365), vomiting (113, 72%) with a median of 5 episodes/d (2-40) lasted 1-20 minutes, and hiccups (102, 65%) lasted a median of 14 days (2-365). Symptoms consistently and completely resolved following immunotherapy. Data were used to propose APS diagnostic criteria and repurpose PUQE score (hiccups severity grade based on symptom duration). The clinical utility was demonstrated in a prospective validation cohort.

Conclusion: Isolated APS attacks are frequently encountered both at onset and during the NMOSD course. The diagnostic criteria proposed here will assist clinicians in recognizing APS. Diagnosis of an APS attack earlier than 48 hours is possible if a dorsal medulla lesion is detected. Accurate diagnosis and evaluation of APS attack severity will assist in outcome measurement in NMOSD clinical trials.
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http://dx.doi.org/10.1212/WNL.0000000000006392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205685PMC
October 2018

Association of MOG-IgG Serostatus With Relapse After Acute Disseminated Encephalomyelitis and Proposed Diagnostic Criteria for MOG-IgG-Associated Disorders.

JAMA Neurol 2018 11;75(11):1355-1363

Department of Neurology, Mayo Clinic, Rochester, Minnesota.

Importance: Recent studies have reported a higher relapse rate following an initial inflammatory demyelinating disorder in pediatric patients with persistent seropositivity of antibodies targeting myelin oligodendrocyte glycoprotein (MOG-IgG1). To date, the clinical implications of longitudinal MOG-IgG1 seropositivity using live cell assays with IgG1 secondary antibodies in adults after acute disseminated encephalomyelitis (ADEM) are unknown.

Objective: To determine whether MOG-IgG1 serostatus (transient vs persistent) and titer change over time provide clinical utility in predicting the likelihood of relapse after ADEM.

Design, Setting, And Participants: This cohort study identified patients with an initial diagnosis of ADEM evaluated at a single referral center between January 1, 1990, and October 1, 2017. Fifty-one patients were included, including 31 children and 20 adults. Longitudinal serologic testing was performed detecting autoantibodies targeting aquaporin 4 (AQP4-IgG) and MOG-IgG1 with clinically validated fluorescence-activated cell sorting assays. Patients were divided into 3 cohorts: persistent seropositivity, transient seropositivity, and seronegativity.

Main Outcomes And Measures: Clinical demographic characteristics, longitudinal AQP4-IgG and MOG-IgG1 serostatus, titers, relapses, use of immunotherapy, and Expanded Disability Status Scale score at follow-up.

Results: Of 51 patients presenting with an initial diagnosis of ADEM, 20 (39%) were adult, 24 (47%) were female, and ages ranged from 12 months to 57 years. Seventeen patients fulfilled criteria for persistent seropositivity; of those, 8 of 9 children (89%) and 7 of 8 adults (88%) had at least 1 relapse after median (range) follow-up periods of 75 (15-236) months and 39 (9-161) months, respectively. Eight patients (16%), including 4 adults, fulfilled criteria for transient seropositivity; of those, no children and 1 of 4 adults (25%) relapsed after median (range) follow-up periods of 32 (24-114) months and 16 (13-27) months, respectively. Of 24 patients with AQP4-IgG and MOG-IgG seronegativity, 6 of 17 children (35%) and 2 of 7 adults (29%) had at least 1 relapse after median (range) follow-up periods of 36 (3-203) months and 34 (15-217) months, respectively. There were only 2 patients, including 1 adult, with AQP4-IgG seropositivity, and both relapsed. The hazard ratio for relapses in those with persistent MOG-IgG1 positivity compared with AQP4-IgG and MOG-IgG1 seronegativity was 3.1 (95% CI, 1.1-8.9; P = .04) in children and 5.5 (95% CI, 1.4-22.5; P = .02) in adults. Immunotherapy was used in 5 of 9 children (56%) and 6 of 8 adults (75%) with persistent seropositivity and in 3 of 17 children (18%) and 1 of 7 adults (14%) with AQP4-IgG and MOG-IgG seronegativity.

Conclusions And Relevance: Relapse occurred in 15 of 17 patients (88%) with persistent MOG-IgG1 seropositivity after ADEM; only 1 patient with transient seropositivity experienced relapse. Our data extend the clinical utility of MOG-IgG1 serological testing to adult patients and highlights that longitudinal serologic evaluation of MOG-IgG1 could help predict disease course and consideration of immunotherapy.
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http://dx.doi.org/10.1001/jamaneurol.2018.1814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248120PMC
November 2018

Elevated LGI1-IgG CSF index predicts worse neurological outcome.

Ann Clin Transl Neurol 2018 May 2;5(5):646-650. Epub 2018 Apr 2.

Department of Neurology Mayo Clinic Rochester Minnesota.

To determine whether CSF leucine-rich glioma-inactivated 1(LGI1)-IgG titer, index or IgG subclass has prognostic significance, we tested serum and CSF specimens collected concomitantly from 39 seropositive patients. LGI1-IgG index was elevated (>1) in 21 patients (54%), suggesting intrathecal synthesis. Patients with worse outcome at last follow-up (modified Rankin Scale >2) had significantly higher index (median 6.57 vs. 0.5,  = 0.048) compared to those with better outcome. Higher CSF LGI1-IgG4 subclass-specific titer and index correlated with worse outcome ( < 0.005 for both). These data suggest that evidence of intrathecal LGI1-IgG synthesis may correlate with neuronal injury and warrant consideration of aggressive immunotherapy.
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http://dx.doi.org/10.1002/acn3.561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945965PMC
May 2018

Prevalence of Myelin Oligodendrocyte Glycoprotein and Aquaporin-4-IgG in Patients in the Optic Neuritis Treatment Trial.

JAMA Ophthalmol 2018 04;136(4):419-422

Department of Neurology, Mayo Clinic, Rochester, Minnesota.

Importance: Autoantibodies to aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) are recently established biomarkers of autoimmune optic neuritis whose frequency and accompanying phenotype, especially for MOG-IgG, are still being characterized. The Optic Neuritis Treatment Trial (ONTT) was a well-known randomized clinical trial in optic neuritis; therefore, knowledge of the serostatus and accompanying phenotype of these patients would be useful to determine the frequency of these antibodies in patients presenting with typical monocular optic neuritis and their outcomes.

Objectives: To determine the AQP4-IgG and MOG-IgG serostatus of patients within the ONTT and describe the clinical features of seropositive patients.

Design, Setting, And Participants: In this follow-up study of the randomized clinical trial, ONTT, conducted between July 1, 1988, and June 30, 1991, analysis of serum for AQP4-IgG and MOG-IgG was performed from January 1 to April 30, 2017. A total of 177 patients from the ONTT with acute optic neuritis and serum available for analysis were enrolled from 13 academic referral centers.

Interventions: Analysis of serum for AQP4-IgG and MOG-IgG was performed at Mayo Clinic Neuroimmunology Laboratory in 2017 with a flow cytometry, live cell, AQP4- and MOG-transfected cell-based assay.

Main Outcomes And Measures: Aquaporin-4-IgG and MOG-IgG serostatus.

Results: Of the 177 patients in the study (135 women and 42 men; mean [SD] age, 32.8 [6.9] years), 3 were positive for MOG-IgG (1.7%) and none were positive for AQP4-IgG. All 3 patients positive for MOG-IgG had disc edema at presentation. Two patients later had a single episode of recurrent optic neuritis. All 3 patients had complete recovery of visual acuity, and none were corticosteroid dependent, although peripheral visual field loss persisted in 1 patient. None of the 3 patients positive for MOG-IgG had demyelinating lesions on magnetic resonance imaging scans, and none had developed multiple sclerosis at the 15-year follow-up.

Conclusions And Relevance: Frequency of MOG-IgG was rare in the ONTT, and AQP4-IgG was not found in patients in the ONTT. Characteristics of patients positive for MOG-IgG in the ONTT support the previously described phenotype of MOG-IgG optic neuritis. Myelin oligodendrocyte glycoprotein-related disease appears to be a different entity than multiple sclerosis. Overall, AQP4-IgG and MOG-IgG may be less common in isolated optic neuritis than previously reported.
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http://dx.doi.org/10.1001/jamaophthalmol.2017.6757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876803PMC
April 2018

Prevalence of multiple sclerosis in Iranian emigrants: review of the evidence.

Neurol Sci 2016 Nov 28;37(11):1759-1763. Epub 2016 Jun 28.

Isfahan Research Committee of Multiple Sclerosis, Isfahan University of Medical Sciences, Isfahan, Iran.

Iran has the highest prevalence of multiple sclerosis (MS) in the Middle East and Asia. Rate of emigration has been significantly raised among Iranians and though, multiple studies have been published on prevalence of MS among Iranian emigrants. Here we systematically reviewed these publications. We performed a comprehensive literature search was performed on April 30, 2015 in data bases of MEDLINE, EMBASE, Scopus and Google Scholar for the terms 'multiple sclerosis', 'incidence', 'prevalence', 'epidemiology', 'migration', 'emigrant', 'immigrant', 'Iran', 'Parsis' and 'Persian'. Study location, prevalence day or period, and age of at disease onset were recorded for all the included publications. Nine publications from Sweden, Canada, Norway, UK, and India were included. Only three reported age-adjusted prevalence and six reported age of disease onset. MS prevalence among Iranian emigrants varied from 21 per 100,000 people in Bombay, India in 1985 to 433 per 100,000 people in British Columbia, Canada in 2012. Five studies reported the prevalence in the region of interest, ranging from 1.33 in Bombay, India to 240 in British Columbia, Canada. Five studies also reported the prevalence of MS in the population of the destination country, and in all of them, the prevalence of MS was higher in Iranian immigrants compared to native people. Prevalence studies performed in Iran and also on Iranian emigrants indicate roles for both genetic and environmental factors in MS susceptibility. Data might indicate that living in a high-risk area increases the susceptibility to MS.
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http://dx.doi.org/10.1007/s10072-016-2641-7DOI Listing
November 2016

CSF herpes virus and autoantibody profiles in the evaluation of encephalitis.

Neurol Neuroimmunol Neuroinflamm 2016 Aug 1;3(4):e245. Epub 2016 Jun 1.

Departments of Neurology (J.J.L., C.J.K., A.M.), and Laboratory Medicine and Pathology (M.J.B., M.M., C.J.K., A.M.), College of Medicine, Mayo Clinic, Rochester, MN.

Objective: To report the frequency of coexisting herpes viruses (herpes simplex virus 1 [HSV-1] or HSV-2, varicella zoster virus, Epstein-Barr virus [EBV], cytomegalovirus, or human herpes virus 6 [HHV-6]) and autoantibodies in patients with encephalitis (herpes or autoimmune) in clinical laboratory service.

Methods: Three groups were evaluated for herpes viruses and antibodies: group 1-patients whose CSF was positive for a herpes virus by real-time PCR over a period of 6 months; group 2-patients whose CSF was positive for an autoimmune encephalitis-associated antibody over 5 years (e.g., NMDA receptor [NMDA-R] antibody), and the same number of controls without autoimmune/infectious disease; and group 3-incidental autoimmune parainfectious encephalitis cases encountered over 1 year.

Results: In group 1, antibodies were detected in 27 of 100 herpes PCR-positive CSF specimens (CSFs), either unclassified neural or nonneural in all but one patient with NMDA-R antibody detected after EBV infection. Antibodies were also detected in 3 of 7 CSFs submitted for repeat PCR testing (unclassified, 2; AMPA receptor, 1). In group 2, herpes viruses were detected in 1 of 77 controls (HHV-6) and 4 of 77 patients with autoimmune encephalitis (EBV, 2; HHV-6, 2); autoantibodies targeted NMDA-R in 3/4 and GABAB-R in 1/4. In group 3, NMDA-R antibody was detected in 7 patients post-HSV-1 encephalitis. Of the remaining 3 patients, 2 had unclassified neural antibodies detected, and one had GABAB-R autoimmunity. Concomitant neoplasms were discovered in 2 patients each from groups 2 and 3.

Conclusions: Autoantibodies and herpes virus DNA frequently coexist in encephalitic CSF. Some patients develop parainfectious autoimmunity following viral CNS infection (usually HSV-1 encephalitis). The significance of detecting herpes nucleic acids in others remains unclear.
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http://dx.doi.org/10.1212/NXI.0000000000000245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897981PMC
August 2016

Clinical utility of testing AQP4-IgG in CSF: Guidance for physicians.

Neurol Neuroimmunol Neuroinflamm 2016 Jun 20;3(3):e231. Epub 2016 Apr 20.

Departments of Laboratory Medicine and Pathology (M.M., J.P.F., A.M., V.A.L., S.J.P.), Neurology (A.M., V.A.L., S.J.P.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN.

Objective: To define, using assays of optimized sensitivity and specificity, the most informative specimen type for aquaporin-4 immunoglobulin G (AQP4-IgG) detection.

Methods: Results were reviewed from longitudinal service testing for AQP4-IgG among specimens submitted to the Mayo Clinic Neuroimmunology Laboratory from 101,065 individual patients. Paired samples of serum/CSF were tested from 616 patients, using M1-AQP4-transfected cell-based assays (both fixed AQP4-CBA Euroimmun kit [commercial CBA] and live in-house flow cytometry [FACS]). Sensitivities were compared for 58 time-matched paired specimens (drawn ≤30 days apart) from patients with neuromyelitis optica (NMO) or high-risk patients.

Results: The frequency of CSF submission as sole initial specimen was 1 in 50 in 2007 and 1 in 5 in 2015. In no case among 616 paired specimens was CSF positive and serum negative. In 58 time-matched paired specimens, AQP4-IgG was detected by FACS or by commercial CBA more sensitively in serum than in CSF (respectively, p = 0.06 and p < 0.001). A serum titer >1:100 predicted CSF positivity (p < 0.001). The probability of CSF positivity was greater around attack time (p = 0.03). No control specimen from 128 neurologic patients was positive by either assay.

Conclusions: FACS and commercial CBA detection of AQP4-IgG is less sensitive in CSF than in serum. The data suggest that most AQP4-IgG is produced in peripheral lymphoid tissues and that a critical serum/CSF gradient is required for IgG to penetrate the CNS in pathogenic quantity. Serum is the optimal and most cost-effective specimen for AQP4-IgG testing.

Classification Of Evidence: This study provides Class IV evidence that for patients with NMO or NMOSD, CSF is less sensitive than serum for detection of AQP4-IgG.
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http://dx.doi.org/10.1212/NXI.0000000000000231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841640PMC
June 2016

Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum.

Ann Neurol 2016 May 4;79(5):775-783. Epub 2016 Apr 4.

Department of Neurology, Mayo Clinic, Rochester, MN.

Objective: Neuromyelitis optica (NMO) and its spectrum disorders (NMOSD) are inflammatory demyelinating diseases (IDDs) with a specific biomarker, aquaporin-4-immunoglobulin G (AQP4-IgG). Prior NMO/NMOSD epidemiological studies have been limited by lack of AQP4-IgG seroprevalence assessment, absence of population-based USA studies, and under-representation of blacks. To overcome these limitations, we sought to compare NMO/NMOSD seroepidemiology across 2 ethnically divergent populations.

Methods: We performed a population-based comparative study of the incidence (2003-2011) and prevalence (on December 31, 2011) of NMO/NMOSD and AQP4-IgG seroincidence and seroprevalence (sera collected in 80-84% of IDD cases) among patients with IDD diagnosis in Olmsted County, Minnesota (82% white [Caucasian]) and Martinique (90% black [Afro-Caribbean]). AQP4-IgG was measured by M1 isoform fluorescence-activated cell-sorting assays.

Results: The age- and sex-adjusted incidence (7.3 vs 0.7/1,000,000 person-years [p < 0.01]) and prevalence (10 vs 3.9/100,000 [p = 0.01]) in Martinique exceeded that in Olmsted County. The AQP4-IgG age- and sex-adjusted seroincidence (6.5 vs 0.7/1,000,000 person-years [p < 0.01]) and seroprevalence (7.9 vs 3.3/100,000 [p = 0.04]) were also higher in Martinique than Olmsted County. The ethnicity-specific prevalence was similar in Martinique and Olmsted County: 11.5 and 13/100,000 in blacks, and 6.1 and 4.0/100,000 in whites, respectively. NMO/NMOSD represented a higher proportion of IDD cases in Martinique than Olmsted County (16% vs 1.4%; p < 0.01). The onset age (median = 35-37 years) and female:male distribution (5-9:1) were similar across both populations; 60% of prevalent cases were either blind in 1 eye, dependent on a gait aid, or both.

Interpretation: This study reports the highest prevalence of NMO/NMOSD in any population (10/100,000 in Martinique), estimates it affects 16,000 to 17,000 in the USA (higher than previous predictions), and demonstrates it disproportionately affects blacks. Ann Neurol 2016;79:775-783.
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http://dx.doi.org/10.1002/ana.24617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988933PMC
May 2016

Polypill for the prevention of cardiovascular disease (PolyIran): study design and rationale for a pragmatic cluster randomized controlled trial.

Eur J Prev Cardiol 2015 Dec 17;22(12):1609-17. Epub 2014 Sep 17.

Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

Background: The complexity of treatment regimens, costs and pill burden decrease the medication adherence and contribute to shortfall in cardiovascular preventive drug coverage. The polypill, a fixed dose combination pill of established drugs, is expected to increase adherence and reduce the costs whilst preventing major cardiovascular events (MCVE).

Design And Methods: The PolyIran trial is a pragmatic cluster randomized trial nested within the Golestan Cohort Study (GCS). Subjects were randomized to either non-pharmacological preventive interventions alone (minimal care arm) or together with a polypill (polypill arm) comprising hydrochlorothiazide, aspirin, atorvastatin and either enalapril or valsartan. This study benefits from the infrastructure of the primary health care system in Iran and the interventions are delivered by the local auxiliary health workers (Behvarz) to the participants. The primary outcome of the study is the occurrence of first MCVE within five years defined as non-fatal and fatal myocardial infarction, unstable angina, sudden death, heart failure, coronary artery revascularization procedures, and non-fatal and fatal stroke.

Trial Status: From February 2011 to April 2013, 8410 individuals (236 clusters) attended the eligibility assessment. Of those, 3421 in the polypill arm and 3417 in the minimal care arm were eligible. The study is ongoing.

Conclusion: The infrastructure of GCS and the primary health care system in Iran enabled the conduct of this pragmatic large-scale trial. If the polypill strategy proves effective, it may be implemented to prevent cardiovascular disease in developing countries.
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http://dx.doi.org/10.1177/2047487314550803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836725PMC
December 2015

Seizure risk factors in shunted hydrocephalic patients.

Pediatr Neurosurg 2012 21;48(5):286-90. Epub 2013 Jun 21.

Department of Neurosurgery, Children's Hospital Medical Center, Tehran University of Medical Science, Tehran, Iran.

Objective: There are controversies about seizure risk factors in shunted hydrocephalic patients which can be due to having merged two different types of seizure (preshunt and postshunt seizures) in previous studies. Also, it is not known whether a considerable change in ventricular size after shunting can be a risk factor of postshunt seizures.

Methods: 150 hydrocephalic patients who underwent shunting from 2006 to 2011 in the Children's Hospital Medical Center in Tehran, Iran, were visited at least 1 year after shunting to assess risk factors of preshunt and postshunt seizures. Ventricular size was assessed by using a radiologic index of bifrontal ratio (BFR).

Results: Preshunt seizures were higher in patients with postinfectious hydrocephalus and intraventricular hemorrhage. Early shunting, history of shunt complications and shunt infection, and a high number of shunt revisions were significant risk factors for developing postshunt seizures. The change in BFR after shunting was not a significant risk factor of postshunt seizures.

Conclusion: The difference between risk factors of preshunt seizures and postshunt seizures shows that they are two different types of seizures with different natures. Preshunt seizures are hard to prevent as they are related to the underlying disease of the brain or the etiology of hydrocephalus. However, postshunt seizures are related to the shunt and might be decreased by preventing shunt complications.
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http://dx.doi.org/10.1159/000351547DOI Listing
April 2014

Isolated vertigo and possibility of brain ischemia.

Arch Iran Med 2012 Aug;15(8):469-71

Department of Neurology, Urmia University of Medical Sciences, Iran.

Background: In cases of isolated vertigo, physicians are unable to definitely distinguish between central or peripheral vertigo by history and physical examination. Some central causes of isolated vertigo such as cerebellar stroke can be life-threatening and require intervention. Brain infarction can be detected shortly after the onset of clinical symptoms by using diffusion-weighted MRI (DWI). We have conducted this study to perform DWI on isolated vertigo patients with a higher probability of brain infarction.

Methods: We enrolled 55 consecutive patients with isolated vertigo who had at least one cardiovascular risk factor. A questionnaire that consisted of cardiovascular risk factors was completed and DWI performed for each patient. We analyzed the association of cardiovascular risk factors with infarction as identified by DWI.

Results: Using DWI, 5 (9.1%) patients had an acute ischemic stroke. Among cardiovascular risk factors, analysis showed a significant relationship between diabetes mellitus (DM) and infarction.

Conclusion: Isolated vertigo may occur due to the occlusion of a small artery in the area of brain circulated by the posterior inferior cerebellar artery. According to our results, DWI may be used in diabetic patients with isolated vertigo to locate a probable infarction.
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http://dx.doi.org/012158/AIM.005DOI Listing
August 2012

Antigliadin antibody in sporadic adult ataxia.

Iran J Neurol 2012 ;11(1):16-20

Department of Radiology, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: The most common neurologic manifestation of gluten sensitivity is ataxia, which accounts for up to 40% of idiopathic sporadic ataxia. Timing of diagnosis of gluten ataxia is vital as it is one of the very few treatable causes of sporadic ataxia and causes irreversible loss of Purkinje cells. Antigliadin antibody (AGA) of the IgG type is the best marker for neurological manifestations of gluten sensitivity. This study was conducted to measure the prevalence of gluten ataxia in a group of Iranian patients with idiopathic ataxia.

Methods: For 30 patients with idiopathic cerebellar ataxia, a questionnaire about clinical and demographic data was completed. Serum AGA (IgA and IgG) and antiendomysial antibody (AEA) were assessed. Gluten ataxic patients underwent duodenal biopsy. Magnetic resonance imaging was done for all patients to see if cerebellar atrophy is present.

Results: Only 2 patients had a positive IgG AGA (6.7%) who both had a positive AEA while none of them showed changes of celiac disease in their duodenal biopsies. Only presence of gastrointestinal symptoms and pursuit eye movement disorders were higher in patients with gluten ataxia.

Conclusion: Prevalence of gluten ataxia in Iranian patients with idiopathic ataxia seems to be lower than most of other regions. This could be explained by small sample size, differences in genetics and nutritional habits and also effect of serologic tests in clinical versus research setting. Further researches with larger sample size are recommended.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829230PMC
November 2013

A pilot double-blind randomised placebo-controlled trial of the effects of fixed-dose combination therapy ('polypill') on cardiovascular risk factors.

Arch Iran Med 2011 Jan;14(1):78-80

Digestive Diseases Research Center, Shariati Hospital, Tehran University of Medical Sciences, Iran.

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http://dx.doi.org/011141/AIM.0020DOI Listing
January 2011

Risk factors for latex sensitization in young children with myelomeningocele. Clinical article.

J Neurosurg Pediatr 2009 Sep;4(3):285-8

Departments of Neurosurgery, Children's Hospital Medical Center, Tehran, Iran.

Object: Patients with myelomeningoceles (MMCs) are at increased risk of latex allergy and sensitization. Number of surgeries and history of atopy are known risk factors. The object of this study was to evaluate the role of diagnostic procedures and nonsurgical treatments in latex sensitization in young patients with MMC.

Methods: Seventy-three children with MMC were included in the study. For each child a questionnaire was administered and serum determination of IgE was performed, and 62 children underwent skin prick tests (SPTs), 60 of which had reliable results. Multivariate logistic regression modeling was performed, using latex sensitization as the dependent variable.

Results: The mean age of the 73 patients was 3.8 years. The SPT results were positive in 30.6%, whereas results of testing for latex-specific IgE were positive in only 8.2%. In univariate analysis, history of untethering, barium enema, and number of clean intermittent catheterizations (CICs) per day were significantly associated with positive results on the SPT. Although the number of surgical procedures was significantly higher in patients who had shunts, no significant relationship between the presence of a shunt and latex sensitization was seen.

Conclusions: The young age of the patients in this study may account for the low prevalence of latex sensitization that was found. In young patients with MMC, the numbers of CICs per day, a history of untethering, circumcision, and a barium enema performed without latex-free equipment could be risk factors for latex sensitization. The use of latex-free gloves in all procedures performed in these cases, nonlatex polyvinyl chloride catheters in CIC, and ordinary nonballoon tips in barium enemas could decrease the risk of sensitization.
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http://dx.doi.org/10.3171/2009.4.PEDS08364DOI Listing
September 2009