Ridha Mrissa

Cerebral Venous Thrombosis: Clinical Features, Risk Factors, and Long-term Outcome in a Tunisian Cohort

BACKGROUND Data from African countries regarding diagnosis, prognosis, management, and outcome of patients with cerebral venous thrombosis (CVT) are limited. The aim of the present study is to characterize clinical presentation, predisposing factors, neuroimaging findings, and outcomes of the disease in the Tunisian population. METHODS This is a prospective study including patients referred to the Neurology Department of the Military Hospital of Tunis between January 2009 and December 2012. The diagnosis of CVT was confirmed in all patients using magnetic resonance imaging and magnetic resonance venography. The demographic, clinical, radiological, and outcome data were recorded and analyzed. Median follow-up was 16 months (range 6 months to 4 years). Primary outcome was death or dependency as assessed by modified Rankin score more than 2 at the end of follow-up. RESULTS This study included 41 patients with CVT. Mean age was 41.24 years, predominantly women (68%). The mode of onset was acute in 10 patients (24%), subacute in 26 (64%), and chronic in 5 (12%). The most common presenting features were headache, observed in 83% of the patients, followed by seizures, focal motor deficits, papilledema, and mental status changes. Lateral (56%) and superior longitudinal (51%) sinuses were the most commonly involved. Multiple sinuses were involved in 46% of cases. Nineteen patients (46%) had a D-dimer level more than 500 ng/mL. Major causes of CVT were thrombophilia (56%), either genetic or acquired, obstetric and gynecological (50%), and septic (34%). Outcome was favorable in 83% of patients. At the end of follow-up, 32 patients (78%) had complete recovery (modified Rankin Scale [mRs] score 0-1), 2 (5%) had partial recovery (mRs score 2), and 4 (10%) were dependent (mRs score 3-5). One patient (2.5%) had a recurrent sinus thrombosis. CONCLUSIONS Our Tunisian population presented distinct risk factors profile with high frequency of thrombophilia, infections, and postpartum state. Oral contraceptive use is not a major risk factor in our population. The overall prognosis was good.

Methylenetetrahydrofolate reductase (C677T and A1298C) polymorphisms, hyperhomocysteinemia, and ischemic stroke in Tunisian patients.

OBJECTIVE The present study evaluated the role of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C gene polymorphisms and correlated these results with plasma homocysteine (Hcy) levels in Tunisian ischemic stroke (IS) patients. METHODS Overall, 84 patients with IS were included and compared with 100 healthy controls. The most common stroke risk factors were investigated. Fasting plasma Hcy levels were measured. Genotyping of the MTHFR C677T and A1298 polymorphisms was studied by polymerase chain reaction. RESULTS Aside from tobacco and alcohol use, the other studied factors were significant risk factors for IS. Mean plasma Hcy levels were significantly higher in IS patients than in controls (16.1 ± 8.28 μmol/L versus 8.76 ± 3.48 μmol/L, P < 10(-3)). Significant associations were found with both the MTHFR 677(CT + TT) and 1298 (AC + CC) genotypes in comparison with controls (P < 10(-3)). A significant synergistic interaction was also found with the double heterozygote MTHFR 677CT/1298AC (P < 10(-3)). Homocysteine levels were significantly higher in IS patients with the MTHFR C677T variant (CT and TT genotypes) (P < 10(-3)); however, the difference was not significant with the MTHFR A1298C variant (AC and CC genotypes) (P = .31). CONCLUSION The MTHFR C677T and A1298 polymorphisms (individually or in concert) and hyperhomocysteinemia represent important risk factors for IS. Elevated Hcy levels were found to be associated with the MTHFR C677T variant; however, no significant association was found with the MTHFR A1298C variant.

Association of methylenetetrahydrofolate reductase polymorphisms with susceptibility to Alzheimer's disease

BACKGROUND Genetic risk factors play an important role in the pathogenesis of Alzheimers disease (AD). In this case-control study, we examined the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and their correlation with this pathology. OBJECTIVE To verify the association between MTHFR C677T and A1298C polymorphisms and Alzheimers disease. METHOD This work was conducted as a case-control study. Cases consisted of thirty-eight patients and 100 individuals without dementia constituted the control group. Genotyping of MTHFR polymorphisms was performed on patients and controls. RESULT Genetic analyses did not indicate a significant association between the MTHFR C677T mutation and AD (C/T: 63.15% versus 39%, p=0.087). However, the genotype prevalence of the missense variant MTHFR A1298C was significantly different between patients and controls (A/C: 55% versus 7%, p<10(-3)). Our data suggest an association between the MTHFR A1298C mutation and AD; however, the MTHFR C677T mutation did not contribute to susceptibility for AD. CONCLUSION The MTHFR A1298C polymorphism is a possible risk factor for Alzheimers disease.

Association of HLA-DR/DQ polymorphism with myasthenia gravis in Tunisian patients.

BACKGROUND AND OBJECTIVE Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction. MG has been shown to be associated with many human leukocyte antigens (HLA) in different populations. The aim of this study was to investigate the probable association between HLA-DR/DQ alleles and MG in Tunisian patients. PATIENTS AND METHODS HLA DR/DQ genotyping was performed using polymerase chain reaction sequence-specific primers (PCR-SSP) with 48 MG patients and 100 healthy individuals serving as the control group. RESULTS Myasthenia gravis in Tunisian patients was found to be associated with the following alleles (p(c) denotes Bonferroni corrected probability values): HLA-DRB1*03 (p(c)<10(-3)), DRB1*04 (p(c)=0.005), DQB1*02 (p(c)=0.002) and, DQB1*03 (p(c)=0.007). CONCLUSION Our data demonstrated a new HLA-MG predisposition with DRB1*04. The DRB1*03, DRB1*04, DQB1*02, and DQB1*03 alleles also could be predisposing genetic factors for MG in the Tunisian population.

Association of methylenetetrahydrofolate reductase A1298C polymorphism but not of C677T with multiple sclerosis in Tunisian patients

BACKGROUND AND OBJECTIVE Multiple sclerosis (MS) is a chronic neurological disease characterized by central nervous system (CNS) inflammation and demyelination of nerve axons. The aim of this study was to investigate a possible association between the methylenetetrahydrofolate reductase (MTHFR) gene and multiple sclerosis in Tunisian patients. PATIENTS AND METHODS The genotyping of two missense variants of the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C was performed in 80 multiple sclerosis patients and 200 healthy controls. RESULTS No significant differences were found in the frequency of the MTHFR C677T polymorphism between MS patients and healthy controls. However, the genotype prevalence of the missense variant MTHFR A1298C was significantly different between patients and controls (A/C: 55% versus 7%, p<10(-3); C/C: 13.75% versus 0%, p<10(-3), respectively). CONCLUSION Although our preliminary findings suggest no association between the MTHFR C677T variants and MS, there is evidence to suggest a significant association between the MTHFR A1298C polymorphisms and MS.

Association of HLA-DR/DQ Polymorphism With Alzheimer’s Disease

Background:Alzheimers disease (AD) is a complex disorder, resulting from an interaction between environmental and genetic factors. Several studies have addressed the association of AD with major histocompatibility complex (MHC) polymorphisms without arriving at any definite conclusions. The human leukocyte antigen (HLA) region is the key susceptibility locus in many immunological diseases. The aim of this study was to investigate the probable association between HLA-DR/DQ alleles and AD in Tunisian patients. Methods:HLA-DR/DQ genotyping was performed using polymerase chain reaction sequence-specific primers with 55 AD patients and 100 healthy individuals serving as the control group. Results:AD in Tunisian patients was found to be associated with the following alleles (Pc denotes Bonferroni corrected probability values): HLA-DRB1*15 (Pc < 10–3), DRB1*04 (Pc = 0.03) and DQB1*06 (Pc < 10–3). Two haplotypes found to be associated with the disease were DRB1*1501/DQB1*0602 (Pc < 10–3) and DRB1*0402/DQB1*0302 (Pc = 0.02). Conclusions:The authors believe this to be the first research linking the haplotypes DRB1*1501/DQB1*0602 and DRB1*04/DQB1*0302 with AD. Larger studies in other populations will be important to support the present findings of the possible susceptible risk of HLA-DR/DQ in AD.

Clinical features and disability progression in multiple sclerosis in Tunisia: Do we really have a more aggressive disease course?

BACKGROUND Few epidemiological data are available on multiple sclerosis (MS) patients in North Africa (NA). Studies of immigrants from NA showed a more aggressive course compared to European patients. OBJECTIVE The aim of this study is to describe clinical and long term course characteristics of MS in Tunisia and to compare it to European cohorts. METHOD A total of 437 MS patients from three hospital based cohorts in Tunisia and having prospective follow up between 2010 and 2012 were analyzed. We considered as endpoints the time to reach EDSS scores of 3, 4 and 6 in the different clinical forms of MS and the beginning of a secondary progressive (SP) phase. RESULTS Sex ratio was 2.34. Mean age of onset was 30.3 years. The course was relapsing-remitting (RR) in 91% of patients and primary progressive (PP) in 9%. The most frequent isolated onset symptoms were respectively motor (28%), optic neuritis (20%) and sensory (16%) dysfunction. Median time to SP onset was 19.1 years. Median times from onset of multiple sclerosis to assignment of a score of 3, 4 and 6 were 8, 10.7 and 15 years respectively. Benign form of MS represented 31.5%. Median interval from the onset of the disease to EDSS score of 3, 4 and 6 was shorter in PP-MS than in RR-MS. However, there was no difference between these two groups for the median time from the assignment of EDSS 4 to the assignment EDSS 6. CONCLUSIONS Our study shows that Tunisian MS patients have a quite similar clinical feature to European patients. Still, larger MS multicenter cohort studies in NA with longer follow-up duration could clearly respond to the issue.

Thrombophilic polymorphisms – factor V Leiden G1691A, prothrombin G20210A and MTHFR C677T – in Tunisian patients with cerebral venous thrombosis

Cerebral venous thrombosis (CVT) has been associated with thrombophilic defects. We performed a study to evaluate the role of three single nucleotide polymorphisms (SNP), factor V Leiden G1691A (FVL), prothrombin gene mutation G20210A (FII-G20210A) and methylenotetrahydrofolate reductase variant C677T (MTHFR-C677T), as risk factors for CVT in Tunisian patients. A single center case-control study (26 patients with CVT and 197 controls) was performed. Genomic DNA was tested for the three SNP. The principle finding was the association between FVL and CVT (p<0.001, Odds ratio=6.1, 95% confidence interval=2.3-16.5). However, neither the FII-G20210 (p=0.536) nor the homozygous MTHFR-C677T genotype (p=0.325) variant contributed to the risk of CVT in these Tunisian patients.

Association of HLA-DR/DQ polymorphism with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in Tunisian patients.

BACKGROUND AND OBJECTIVE Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated disorder of the peripheral nervous system (PNS). The aim of this study was to investigate associations between HLA-DR/DQ alleles and CIDP in Tunisian patients. PATIENTS AND METHODS HLA DR/DQ genotyping was performed using polymerase chain reaction sequence-specific primers (PCR-SSP) with 36 CIDP patients and 100 healthy individuals serving as the control group. RESULTS CIDP in Tunisian patients was found to be associated with the HLA-DRB1*13 allele (pc=0.03) (where pc denotes the Bonferroni corrected probability value). Moreover, the two haplotypes, DRB1*13/DQB1*06 (22.22% of patients vs. 8.5% of controls, pc=0.017) and DRB1*07/DQB1*03 (13.88% of patients vs. 3% of controls, pc=0.005), were found to confer a susceptibility to CIDP. CONCLUSION To our knowledge, this is the first study performed to analyze the association of HLA-DRB1/DQB1 alleles on CIDP susceptibility in a Tunisian population.

Limbic encephalitis associated with leucine-rich glioma-inactivated 1 antibodies.

We describe the case of a patient with confirmed limbic encephalitis associated with leucine-rich glioma-inactivated 1 (LGI1) antibodies. A 59-year-old man presented to the Department of Neurology with bizarre behavior, memory loss, cognitive impairment, visual hallucinations, and myoclonus and faciobrachial dystonic seizures. A brain magnetic resonance imaging (MRI) revealed no hippocampal lesions. Blood tests showed hyponatremia. An electroencephalogram showed disorganization and slowing of background activity. Antiepileptic drugs were ineffective. The patient exhibited considerable improvement following immunotherapy. The diagnosis of limbic encephalitis associated with LGI1 antibodies should be considered in patients with clinical manifestations mimicking psychiatric disorders and in cases of refractory epilepsy especially with faciobrachial dystonic seizures. There is frequently hyponatremia, and cerebral MRI may be normal. Full recovery can be expected with early diagnosis and prompt treatment.