Chronic inflammatory demyelinating polyradiculoneuropathy: can a diagnosis be made in patients not fulfilling electrodiagnostic criteria?

BACKGROUND AND PURPOSE: The aim was to identify the clinical and diagnostic investigations that may help to support a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients not fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria. METHODS: The data from patients with a clinical diagnosis of CIDP included in a national database were retrospectively reviewed. RESULTS: In all, 535 patients with a diagnosis of CIDP were included. This diagnosis fulfilled the EFNS/PNS criteria in 468 patients (87.2%) (definite in 430, probable in 33, possible in three, while two had chronic immune sensory polyradiculopathy). Sixty-seven patients had a medical history and clinical signs compatible with CIDP but electrodiagnostic studies did not fulfill the EFNS/PNS criteria for CIDP. These patients had similar clinical features and frequency of abnormal supportive criteria for the diagnosis of CIDP compared to patients fulfilling EFNS/PNS criteria. Two or more abnormal supportive criteria were present in 40 (61.2%) patients rising to 54 (80.6%) if a history of a relapsing course as a possible supportive criterion was also included. Increased cerebrospinal fluid proteins and response to immune therapy most frequently helped in supporting the diagnosis of CIDP. Response to therapy was similarly frequent in patients fulfilling or not EFNS/PNS criteria (87.3% vs. 85.9%). CONCLUSIONS: Patients with a clinical diagnosis of CIDP had similar clinical findings, frequency of abnormal supportive criteria and response to therapy compared to patients fulfilling EFNS/PNS criteria. The presence of abnormal supportive criteria may help in supporting the diagnosis of CIDP in patients with a medical history and clinical signs compatible with this diagnosis but non-diagnostic nerve conduction studies.

Risk factors for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): antecedent events, lifestyle and dietary habits. Data from the Italian CIDP Database.

BACKGROUND AND PURPOSE: The role of lifestyle and dietary habits and antecedent events has not been clearly identified in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: Information was collected about modifiable environmental factors and antecedent infections and vaccinations in patients with CIDP included in an Italian CIDP Database. Only patients who reported not having changed their diet or the lifestyle habits investigated in the study after the appearance of CIDP were included. The partners of patients with CIDP were chosen as controls. Gender-matched analysis was performed with randomly selected controls with a 1:1 ratio of patients and controls. RESULTS: Dietary and lifestyle data of 323 patients and 266 controls were available. A total of 195 cases and 195 sex-matched controls were used in the analysis. Patients eating rice at least three times per week or eating fish at least once per week appeared to be at decreased risk of acquiring CIDP. Data on antecedent events were collected in 411 patients. Antecedent events within 1-42 days before CIDP onset were reported by 15.5% of the patients, including infections in 12% and vaccinations in 1.5%. Patients with CIDP and antecedent infections more often had an acute onset of CIDP and cranial nerve involvement than those without these antecedent events. CONCLUSIONS: The results of this preliminary study seem to indicate that some dietary habits may influence the risk of CIDP and that antecedent infections may have an impact on the onset and clinical presentation of the disease.

Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study.

Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-ß) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-ß treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-ß-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 10-6) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10-5) and near ZNF697 (combined P-value 8.15 × 10-5).

Pharmacogenetic study of long-term response to interferon-ß treatment in multiple sclerosis.

The aim of the study is the identification of genetic factors that influence the long-term response to interferon-ß (IFNß) (4-year follow-up). We performed a genome-wide association study in 337 IFNß-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNß-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P<10-4, and two of them (rs7298096 and rs4726460) pointed to two genes, NINJ2 and TBXAS1, that were significantly downregulated after IFNß stimulation in HC (P=3.1 × 10-9 and 5.6 × 10-10). We also observed an eQTL effect for the allele associated with favorable treatment response (rs4726460A); moreover, TBXAS1 appeared downregulated upon IFNß administration (ß=-0.39; P=0.02). Finally, we found an enrichment of pathways related to inflammatory processes and presynaptic membrane, the latter with involvement of genes related to glutamatergic system (GRM3 and GRIK2), confirming its potential role in the response to IFNß.

A monolateral TMJ replacement under intraoral endoscopic assistance for jaw osteomielitis: a modified approach.

Alloplastic replacement has become a valid treatment for TMJ endstage disease. The Alkayat and Bramley pre-auricular approach combined with the submandibular incision are the current surgical approaches for TMJ surgery. The present study shows a modified approach using intraoral endoscopic assistance. A female patient affected by jaw osteomielitis with condylar detachment was treated with total left TMJ alloplastic replacement combined with a right TMJ arthroplasty. No subamandibular incision was performed and, subsequently, the risks for permanent or temporary damage to the marginalis mandibulae nerve and surgical submandibular scar were avoided. Postoperative CT-Scan evidenced a good prosthesis position. No complications occurred after two years of follow-up.

Analysis of genes, pathways and networks involved in disease severity and age at onset in primary-progressive multiple sclerosis.

BACKGROUND: The role of genetic factors in influencing the clinical expression of multiple sclerosis (MS) is unclear. OBJECTIVE: The objective of this paper is to identify genes, pathways and networks implicated in age at onset (AAO) and severity, measured using the Multiple Sclerosis Severity Score (MSSS), of primary-progressive MS (PPMS). METHODS: We conducted a genome-wide association study (GWAS) of 470 PPMS patients of Italian origin:. Allelic association of 296,589 SNPs with AAO and MSSS was calculated. Pathway and network analyses were also conducted using different tools. RESULTS: No single association signal exceeded genome-wide significance in AAO and MSSS analyses. Nominally associated genes to AAO and MSSS were enriched in both traits for 10 pathways, including: "oxidative phosphorylation" (FDRAAO=9*10(-4); FDRMSSS=3.0*10(-2)), "citrate (TCA) cycle" (FDRAAO=1.6*10(-2); FDRMSSS=3.2*10(-3)), and "B cell receptor signaling" (FDRAAO=3.1*10(-2); FDRMSSS=2.2*10(-3)). In addition, an enrichment of "chemokine signaling pathway" (FDR=9*10(-4)) for AAO and of "leukocyte transendothelial migration" (FDR=2.4*10(-3)) for MSSS trait was observed, among others. Network analysis revealed that p53 and CREB1 were central hubs for AAO and MSSS traits, respectively. CONCLUSIONS: Despite the fact that no major effect signals emerged in the present GWAS, our data suggest that genetic variants acting in the context of oxidative stress and immune dysfunction could modulate the onset and severity of PPMS.

Predictors of effectiveness of multidisciplinary rehabilitation treatment on motor dysfunction in multiple sclerosis.

OBJECTIVES: To identify clinical predictors of effectiveness of a motor rehabilitation treatment in a cohort of multiple sclerosis (MS) patients. MATERIALS AND METHODS: We analysed 212 consecutive patients who underwent a short-term (3-7 weeks) intensive (two hours per day, five days per week), individualised, goal-oriented inpatient rehabilitation program. Activity limitation and impairment were measured on admission and discharge of the rehabilitation trial using the motor sub-items of the Functional Independence Measure (mFIM) and the Expanded Disability Status Scale (EDSS) score. Multivariate logistic regression models have been tested to evaluate the role of clinical baseline features on rehabilitation effectiveness. RESULTS: According to pre-defined outcome measures, 75.1% of MS patients improved in either activity limitation (≥5 points delta mFIM) or impairment (≥1.0 delta EDSS score if baseline EDSS was ≤5.5, or ≥0.5 if baseline EDSS was >5.5), and 35.4% of MS patients improved in both outcomes. A relapsing-remitting course of disease, a more severe baseline impairment and activity limitation level, a shorter disease duration and a less severe balance dysfunction were predictive of the effectiveness of rehabilitation. DISCUSSION: These data confirm that an intensive inpatient rehabilitation program is able to produce a short-term relevant improvement on clinical and functional outcome measures and suggest some clinical features which can be considered as potential predictors of the outcome of rehabilitative intervention.

Circumscribed myositis ossificans of the masseter muscle: report of a case.

Myositis Ossificans (MO) is an unusual pathological entity still largely unknown, characterized by dystrophic calcification leading to heterotopic ossification of intramuscular connective tissue. The masticatory muscles are exceptionally involved. Four distinct types of myositis ossificans have been described: MO Progressiva, which is a genetic disorder involving several muscular groups; MO Circumscripta, limited to a single muscle and generally due to calcification of an intramuscular haematoma following severe trauma and progressive ossification; MO Pseudo-malignant limited to soft tissue and not associated to any trauma; MO associated to paraplegia. A case of circumscribed myositis ossificans of the masseter muscle in a 62 years-old woman is reported.

Correlation between genetic HLA class I and II polymorphisms and anthropological aspects in the Chaouya population from Morocco (Arabic speaking).

The aim of this study was to provide genetic and anthropological information on the Chaouya (CH), an Arabic-speaking population living in West Morocco, Atlantic coast (Settat). In 98 unrelated healthy CH volunteers, we first investigated the human leukocyte antigen (HLA) class I and II allele polymorphisms using a sequence-based typing method and examined haplotypes and relatedness of this group to other African and Mediterranean populations. The study showed the close relatedness with Tunisian population and other North Africans, together with a strong influence of various immigrations, mainly Spaniards, French, and Portuguese, as expected. Nevertheless, analysis of class II allele frequencies (afs) showed that Oromo and Amhara Ethiopian groups cluster together with the Berbers and other North Africans, confirming the relationship between these populations (Afro-Asiatic linguistic group, Hamites). South and sub-Saharan Africans cluster separately at a great distance from CH, except the sub-Saharan Bantu population from Congo Kinshasa, which shows a relatively close genetic relationship ascribable to the effect of a diversifying selection. On the other hand, considering HLA class I afs analyses, it was noteworthy that CH grouped together with sub-Saharans, showing a close genetic distance mainly with Ugandas and Kenians Luo.

Prevention of surgery in children with adenoidal hypertrophy treated with intranasal flunisolide: a 12-month follow-up.

Adenoidal hypertrophy (AH) represents one of the most frequent indications for surgery in children. Recently, treatment with intranasal corticosteroids has been suggested to decrease the size of AH. The aim of the study is to evaluate the long-term effect of intranasal flunisolide on AH during a 12-month follow-up. One hundred seventy-eight children with a grade III or IV AH at baseline endoscopic examination were enrolled in this randomised and controlled study. Children were treated with intranasal flunisolide or isotonic saline solution for 8 weeks. Subsequent assessment, including history and fiberoptic endoscopy, was made at 8 weeks, and 6 and 12 months after treatment suspension. Flunisolide treatment was initially associated with significant (p<0.01) reduction of the degree of AH. However, during follow-up all but one of the non-allergic children relapsed, whereas most allergic children maintained AH size reduction (p<0.05). No clinically important adverse events were reported. In conclusion, this preliminary study demonstrates that an 8-week treatment with intranasal flunisolide is significantly associated with reduction of AH, however, the adenoidectomy avoidance was warranted only for allergic children.

HLA-G 14-bp insertion/deletion polymorphism in kidney transplant patients with metabolic complications.

HLA-G, a nonclassical HLA molecule with limited polymorphism has immunomodulating/tolerogenic properties. The most common polymorphism of HLA-G is a deletion/insertion of 14 bp, located at the 3'UTR region of the gene (exon 8). This polymorphism is associated with modifications of mRNA stability that can lead to variations of membrane versus soluble HLA-G expression. HLA-G may be involved in the clinical outcomes of transplantation, as evidenced by studies in hematopoietic cell transplantation. We evaluated the possible prognostic importance of 14-bp polymorphisms of HLA-G among kidney transplantation patients. Using polymerase chain reaction amplification we genotyped 124 patients (mean organ survival: 878.95 +/- 595.12 days; range = 1-2565) and 98 control individuals representative of the Italian population. Products were visualized by electrophoresis on agarose gels. The results showed no differences between patients and controls. Twenty-nine patients with acute or chronic rejection or in whom clinical conditions required the use of steroid bolus treatments also showed no association with HLA-G 14-bp genotypes or alleles. The subset of patients with dyslipidemia during follow-up showed a significant decrease among the HLA-G-14/-14 genotype, compared with heterozygous (+14/-14) and nondeleted homozygous (+14/+14) genotype patients (P(c) = .03). These preliminary data showed that HLA-G 14-bp genotypes, although not predictive of rejection, may be useful to identify individuals at risk for the development of posttransplant complications.

Identification of the novel HLA-A*9250 allele by sequence-based typing in a Caucasian bone marrow donor from Italy.

HLA-A*9250 allele was identified by SBT in a Caucasian bone marrow donor. It differs from the closest A*020101 by only one nucleotide (A-->G) at position 124 in exon 2 (Arg to Gly at codon 18); this is an uncommon variation at a highly conserved nucleotide position, located on the loop between S1-S2 beta-sheets in alpha1 domain.

Identification of the very uncommon allele HLA-Cw*0716 in a Caucasian renal transplant recipient: extension of the exon 4 sequence.

This report describes the unknown exon 4 sequence of the rare human leukocyte antigen-Cw*0716 allele, identified in a Caucasian renal transplant recipient from Italy. This sequence is identical to the Cw*070101 allele, and this result allowed us to confirm the hypothesis of the generation of Cw*0716 allele by an interallelic recombination event between Cw*0701/0706/0718 and Cw*020202 allele.

Identification of a novel HLA-B allele, HLA-B*3580, with possible implication in transplantation and CTL response.

A new human leukocyte antigen (HLA)-B allele, named B*3580, with an amino acid substitution at residue 156, has been identified during the sequence-based typing of a patient waiting for a hematopoietic cell transplantation.

Identification of the uncommon allele HLA-A*7403 in a Caucasian renal transplant cadaveric donor: extension of the exon 4 sequence.

This report describes the unknown exon 4 sequence of the rare A*7403 allele, identified in a Caucasian renal transplant cadaveric donor from Italy. This sequence is identical to that of the only known A*7401 exon 4, and this result allowed us to confirm the hypothesis of the generation of A*7403 allele from the ancestor A*7402 by point mutation in exon 2.

Sequence-based typing characterization of the novel HLA-Cw*1609 allele in the Moroccan Chaouya group.

The novel human leukocyte antigen (HLA)-Cw*1609 allele was identified by sequence-based typing in a Moroccan Chaouya donor. It differs from the closest Cw*1602 by only one nucleotide (C --> G) at position 244 in exon 2 (Glu to Gln at codon 58 in alpha1 domain).

Identification of a novel HLA-A*02 allele, A*027401*.

A novel HLA-A*02 allele was detected in a Caucasian patient from central Italy, requiring a hematopoietic cell transplantation. Direct sequencing identified a variation in one nucleotide position, which was confirmed by cloning. The name A*027401 was officially assigned by the WHO Nomenclature Committee in November 2004. A*027401 differs from A*02010101 by a single G to A substitution at nucleotide position 595 in exon 3. The new variant would lead to a nonsynonymous nucleotide change (GGG to AGG) at codon 175, resulting in a basic Arg in the alpha-helix of the alpha2-domain, in place of a non-polar Gly. The presence of an uncommon variation at a highly conserved nucleotide position could have implications in unrelated hematopoietic cell transplantation.

Characterization of a novel HLA-Cw*02 variant, Cw*0208, in a Caucasian individual.

We describe an additional HLA-Cw*02 variant, HLA-Cw*0208, which has been identified in a renal transplant recipient of Caucasian origin (Italy). After performing preliminary serological typing, we analyzed exons 2 and 3 of the HLA-C locus polymorphism by cloning the amplified DNA and using a sequence-based typing method. The new allele differs from Cw*020202 by one nucleotide substitution at nucleotide 61 (G-->A) of exon 2, which translates to a difference of one amino acid at residue 21 (His-->Arg) of the HLA-C heavy chain. We propose that Cw*0208 was generated by a random point mutation in codon 21 from the Cw*020202 allele, or through gene conversion of Cw*020202 with another allele, probably the Cw*1205 and Cw*1602 alleles.

Human leukocyte antigen-A, -B, and -Cw polymorphism in a Berber population from North Morocco using sequence-based typing.

Class I human leukocyte antigen (HLA) polymorphism was examined in a Berber population from North Morocco, named Metalsa (ME). All data were obtained at high-resolution level, using sequence-based typing. The most frequent alleles were: HLA-A*0201 and A*0101; HLA-B*44 (B*4403 and B*4402); B*0801 and the B*50 allele group (B*5001 and B*5002); HLA-Cw*0602; and Cw*07 group (Cw*070101, Cw*070102, Cw*0702, Cw*0704, and Cw*0706), and Cw*040101. The novel HLA-B*570302 allele was identified. It differs at position 486 and position 855 from B*570301, resulting in synonymous Thr and Val. The analysis also evidenced some alleles common in Africans (A*3402, A*6802, A*7401, B*1503, B*4102, B*4202, B*7801, B*5802, Cw*1701, and Cw*1703) and some uncommon alleles (A*3004, B*2702, B*2703, B*5001,02, B*3503, and Cw*0706). The predominant HLA-A-Cw-B-DRB1-extended haplotypes in ME population were A*0101-Cw*0501-B*4402-DRB1*0402, A*240201-Cw*0701-B*0801-DRB1*030101, A*2301-Cw*040101-B*4403-DRB1*040501, A*0201-Cw*040101-B*4403-DRB1*1302, and A*3002-Cw*0602-B*5002-DRB1*0406. This study demonstrates a strong relatedness of ME to other Moroccan and North African populations, some characteristics of sub-Saharan Africans and evidenced the influence of various immigrations during centuries. Nevertheless, this study highlights some unique genetic traits of the ME population compared to other ethnic groups within Morocco, which could be of great interest for clinical aims, transplantation, and diseases.