[What is new in symptomatic MS treatment: Part 3-bladder dysfunction]. / Neues zur symptomatischen MS-Therapie: Teil 3 ­ Blasenfunktionsstörungen.

The symptomatic treatment of multiple sclerosis (MS) nowadays is of similar importance as immunotherapy within a comprehensive concept of therapy of this chronic disease, since it contributes considerably to the reduction of disabilities in activities of daily living as well as social and occupational life. Moreover, symptomatic treatment is of great importance for amelioration of quality of life. Since our last survey of symptomatic MS treatment in 2004 and publication of the guidelines of the German Neurological Society and the Klinisches Kompetenznetz Multiple Sklerose (KKNMS) in 2014 several developments within the topics of mobility, bladder and sexual function, vision, fatigue, cognition and rehabilitation took place. These new findings together with further aspects of disease measures and overall treatment strategies of the respective symptoms, as well as treatment goals are introduced in a series of six individual contributions. Here, the symptoms of bladder dysfunction will be discussed.

[New aspects of symptomatic MS treatment: Part 4-sexual dysfunction and eye movement disorders]. / Neues zur symptomatischen MS-Therapie: Teil 4 ­ Störungen der Sexualfunktion und der Augenbewegungen.

The symptomatic treatment of multiple sclerosis (MS) is nowadays of similar importance as immunotherapy within a comprehensive treatment concept of this chronic disease. It makes a considerable contribution to the reduction of disabilities in activities of daily living as well as social and occupational life. Moreover, symptomatic treatment is of great importance for amelioration of the quality of life. Since our last survey of symptomatic MS treatment in 2004 and publication of the guidelines of the German Neurological Society and the Clinical Competence Network Multiple Sclerosis (Klinisches Kompetenznetz Multiple Sklerose, KKNMS) in 2014, several developments within the topics of mobility, bladder and sexual function, vision, fatigue, cognition and rehabilitation have taken place. These new findings together with further aspects of disease measurement methods and overall treatment strategies of the respective symptoms as well as treatment goals are introduced in several individual contributions. In this article the symptoms of sexual dysfunction and eye movement disorders are discussed.

[New aspects of symptomatic MS treatment: Part 6 - cognitive dysfunction and rehabilitation]. / Neues zur symptomatischen MS-Therapie: Teil 6 ­ kognitive Störungen und Rehabilitation.

The symptomatic treatment of multiple sclerosis (MS) is nowadays of similar importance as immunotherapy within a comprehensive treatment concept of this chronic disease. It makes a considerable contribution to the reduction of disabilities in activities of daily living as well as social and occupational life. Moreover, symptomatic treatment is of great importance for amelioration of the quality of life. Since our last survey of symptomatic MS treatment in 2004 and publication of the guidelines of the German Neurological Society and the Clinical Competence Network Multiple Sclerosis ("Klinisches Kompetenznetz Multiple Sklerose", KKN-MS) in 2014 several developments within the topics of mobility, bladder and sexual function, vision, fatigue, cognition and rehabilitation have taken place. These new findings together with further aspects of disease measurement methods and overall treatment strategies of the respective symptoms, as well as treatment goals are introduced in several individual contributions. In this article the symptoms of cognitive disorders and the growing impact of rehabilitation are discussed.

[New aspects of symptomatic MS treatment: Part 5 - fatigue]. / Neues zur symptomatischen MS-Therapie: Teil 5 ­ Fatigue.

The symptomatic treatment of multiple sclerosis (MS) is nowadays of similar importance as immunotherapy within a comprehensive treatment concept of this chronic disease. It makes a considerable contribution to the reduction of disabilities in activities of daily living as well as social and occupational life. Moreover, symptomatic treatment is of great importance for amelioration of the quality of life. Since our last survey of symptomatic MS treatment in 2004 and publication of the guidelines of the German Neurological Society and the Clinical Competence Network Multiple Sclerosis (Klinisches Kompetenznetz Multiple Sklerose, KKN-MS) in 2014 several developments within the topics of mobility, bladder and sexual function, vision, fatigue, cognition and rehabilitation have taken place. These new findings together with further aspects of disease measurement methods and overall treatment strategies of the respective symptoms as well as treatment goals are introduced in a series of 6 individual contributions. In this article the symptom of fatigue is discussed.

[What is new in symptomatic MS treatment: Part 2-gait disorder and spasticity]. / Neues zur symptomatischen MS­Therapie: Teil 2 ­ Gangstörung und Spastik.

The symptomatic treatment of multiple sclerosis (MS) nowadays is of similar importance as immunotherapy within a comprehensive concept of therapy of this chronic disease, since it contributes considerably to the reduction of disabilities in activities of daily living as well as social and occupational life. Moreover, symptomatic treatment is of great importance for amelioration of quality of life. Since our last survey of symptomatic MS treatment in 2004 and publication of the guidelines of the German Neurological Society and the Klinisches Kompetenznetz Multiple Sklerose (KKN­MS) in 2014 several developments within the topics of mobility, bladder and sexual function, vision, fatigue, cognition and rehabilitation took place. These new findings together with further aspects of disease measures and overall treatment strategies of the respective symptoms, as well as treatment goals are introduced in a series of six individual contributions. Here, the symptoms of gait disorders and spasticity will be discussed.

[What is new in symptomatic MS treatment: Part 1-introduction and methodical approach, ataxia and tremor]. / Neues zur symptomatischen MS­Therapie: Teil 1 ­ Einleitung und methodisches Vorgehen, Ataxie und Tremor.

The symptomatic treatment of multiple sclerosis (MS) nowadays is of similar importance as immunotherapy within a comprehensive concept of therapy of this chronic disease, since it contributes considerably to the reduction of disabilities in activities of daily living as well as social and occupational life. Moreover, symptomatic treatment is of great importance for amelioration of quality of life. Since our last survey of symptomatic MS treatment in 2004 and publication of the guidelines of the German Neurological Society and the Klinisches Kompetenznetz Multiple Sklerose (KKN­MS) in 2014 several developments within the topics of mobility, bladder and sexual function, vision, fatigue, cognition and rehabilitation took place. These new findings together with further aspects of disease measures and overall treatment strategies of the respective symptoms, as well as treatment goals are introduced in a series of six individual contributions. Here, the topic will be introduced, the methodical approach will be explained, and the treatment of ataxia and tremor will be discussed.

Vascular events are risk factors for anal incontinence in systemic sclerosis: a study of morphology and functional properties measured by anal endosonography and manometry.

OBJECTIVES: To study anal sphincter morphology, anal sphincter pressure, and rectoanal inhibitory reflex (RAIR) in patients with systemic sclerosis (SSc) complicated by anal incontinence (AI) and to investigate possible risk factors for AI in SSc. METHOD: Nineteen SSc patients with severe AI were investigated using anal endosonography, anal manometry, and rectal manovolumetry. To determine risk factors for AI, disease characteristics of SSc patients with AI were compared with those of 95 SSc patients without AI; there were five matched SSc patients without AI for each SSc patient with AI. RESULTS: The mean (SD) internal sphincter thickness was 1.3 (0.46) mm in patients with AI, which was thinner (p < 0.001) than reference data from healthy individuals whose internal sphincter measured 2.2 (0.45) mm, whereas the external sphincter thickness did not differ. The mean (SD) resting pressure in AI patients was lower than the reference data from healthy individuals [60 (22) vs. 94 (29) mmHg, p < 0.002] whereas the squeeze pressure did not differ. Centromeric antibodies and features of vascular disease [i.e. the presence of pulmonary arterial hypertension (PAH), digital ulcers, pitting scars, or the need for iloprost infusions] were associated with AI whereas fibrotic manifestations [i.e. modified Rodnan skin score (mRss), the diffuse cutaneous SSc (dcSSc) subset, or low vital capacity (VC)] were not. CONCLUSIONS: SSc patients with AI have a thin internal anal sphincter and a low resting pressure. Risk factors for AI among SSc patients are centromeric antibodies and vascular disease, which supports the hypothesis that gastrointestinal involvement in SSc is in part a vascular manifestation of the disease.

A unique 3D endoanal ultrasound feature of perianal Crohn's fistula: the 'Crohn ultrasound fistula sign'.

AIM: Using a high-resolution 3D endoanal ultrasound, we have observed that some perianal fistulas show a hypoechogenic fistula tract surrounded by a well-defined hyperechogenic area with a thin hypoechogenic edge in patients with Crohn's disease ['Crohn's Ultrasound Fistula Sign' (CUFS)], unlike conventional fistula tracks. The study aimed to determine the prevalence of CUFS in a consecutive series of patients with anal fistula. METHOD: Of 157 patients (median age 45, range 14-86 years, 100 males) with perianal fistula were examined with 3D endoanal ultrasound. All 3D volumes were stored and analysed retrospectively by two independent observers blinded to the clinical information of the patients. RESULTS: There were 29 patients with Crohn's disease of whom 20 (69%) showed CUFS. CUFS was absent in 125 (98%) of 128 patients without Crohn's disease. The positive and negative predictive value of CUFS for Crohn's disease was 87% and 93%, respectively. The kappa value of the two independent observers was 0.77, indicating a substantial interobserver agreement. CONCLUSION: This study provides a new 3D endoanal ultrasound criterion, CUFS, of perianal fistula in patients with Crohn's disease. The sign can be used to discriminate a Crohn's from other types of fistula, which may be useful in the management of patients with anal fistula.

Defects on endoanal ultrasound and anal incontinence after primary repair of fourth-degree anal sphincter rupture: a study of the anal sphincter complex and puborectal muscle.

OBJECTIVES: To perform three-dimensional endoanal ultrasound (EAUS) after primary repair of fourth-degree anal sphincter rupture (ASR) and correlate the sonographic defects with anal incontinence (AI); to measure the axial and sagittal thickness and angle of the puborectal muscle (PRM) as well as the length of the anal canal, and then correlate these measures with AI; and to assess the interobserver measurement agreement between an inexperienced and an experienced sonologist. METHODS: EAUS was offered to 84 consecutive women, who were asked to answer a validated questionnaire after fourth-degree ASR. AI was graded according to the Wexner score and EAUS defects were graded according to the Starck score. RESULTS: Sixty-one women (73%) answered the questionnaire. The median (range) follow-up time was 5.1 (1.3-8.7) years. Thirty-three (54%) of these women underwent EAUS and were included in the study. There was no difference in the incontinence scores between women who underwent EAUS and those who did not. Eleven of the women who underwent EAUS (33%) were continent, 22 women (67%) had flatus incontinence at least once a month, of whom 12 also had incontinence for liquid stool and two had incontinence for solid stool. The median Wexner score was 2 (range, 0-12). Five of the patients (15%) had no ultrasound defects. All of the patients with Wexner scores > or = 4 had a Starck score of > or = 10. No association between ultrasound defects and AI was demonstrated, however, the angle of the PRM and parity were associated with Starck score. No clear association between the measurements of the PRM and AI was shown. The experienced observer detected more of the small defects than did the inexperienced observer. CONCLUSION: In a 1-9-year follow-up period after primary suture of fourth-degree ASR, the frequency of AI was high, at 67%. No clear association was seen between AI and sphincter defects detected on ultrasonography. There was an association between the angle of the PRM and the extent of ultrasound defects.

ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis.

Escalation therapy with mitoxantrone (MX) in highly active multiple sclerosis is limited by partially dose-dependent side-effects. Predictors of therapeutic response may result in individualized risk stratification and MX dosing. ATP-binding cassette-transporters ABCB1 and ABCG2 represent multi-drug resistance mechanisms involved in active cellular MX efflux. Here, we investigated the role of ABC-gene single nucleotide polymorphisms (SNPs) for clinical MX response, corroborated by experimental in vitro and in vivo data. Frequencies of ABCB1 2677G>T, 3435C>T and five ABCG2-SNPs were analysed in 832 multiple sclerosis patients (Germany, Spain) and 264 healthy donors. Using a flow-cytometry-based in vitro assay, MX efflux in leukocytes from individuals with variant alleles in both ABC-genes (designated genotype ABCB1/ABCG2-L(ow), 22.2% of patients) was 37.7% lower than from individuals homozygous for common alleles (ABCB1/ABCG2-H(igh), P < 0.05, 14.8% of patients), resulting in genotype-dependent MX accumulation and cell death. Addition of glucocorticosteroids (GCs) inhibited MX efflux in vitro. ABC-transporters were highly expressed in leukocyte subsets, glial and neuronal cells as well as myocardium, i.e. cells/tissues potentially affected by MX therapy. In vivo significance was further corroborated in experimental autoimmune encephalomyelitis in Abcg2(-/-) animals. Using a MX dose titrated to be ineffective in wild-type animals, disease course and histopathology in Abcg2(-/-) mice were strongly ameliorated. Retrospective clinical analysis in MX monotherapy patients (n = 155) used expanded disability status scale, relapse rate and multiple sclerosis functional composite as major outcome parameters. The clinical response rate [overall 121 of 155 patients (78.1%)] increased significantly with genotypes associated with decreasing ABCB1/ABCG2-function [ABCB1/ABCG2-H 15/24 (62.5%) responders, ABCB1/ABCG2-I(ntermediate) 78/98 (79.6%), ABCB1/ABCG2-L 28/33 (84.8%), exact Cochran-Armitage test P = 0.039]. The odds ratio for response was 1.9 (95% CI 1.0-3.5) with each increase in ABCB1/ABCG2 score (from ABCB1/ABCG2-H to -I-, and -I to -L). In 36 patients with severe cardiac or haematological side effects no statistically relevant difference in genotype frequency was observed. However, one patient with biopsy proven cardiomyopathy only after 24 mg/m2 MX exhibited a rare genotype with variant, partly homozygous alleles in 3 ABC-transporter genes. In conclusion, SNPs in ABC-transporter genes may serve as pharmacogenetic markers associated with clinical response to MX therapy in multiple sclerosis. Combined MX/GC-treatment warrants further investigation.

Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity.

B cells are increasingly recognized as major players in multiple sclerosis pathogenesis. The BAFF/APRIL system is crucial for B cell homoeostasis and may drive B cell-dependent autoimmunity. We asked whether this system is affected by Interferon (IFN)-beta therapy. We analysed transcription of the ligands (BAFF, APRIL, TWE-PRIL) and the corresponding receptors (BAFF-R, TACI and BCMA) by TaqMan-PCR ex vivo in whole blood and in immune cell subsets purified from IFN-beta-treated multiple sclerosis patients. Serum BAFF concentrations were determined by ELISA. This cross-sectional study involved 107 donors. IFN-beta therapy strongly induced BAFF transcription proportionally to the IFN-beta biomarker MxA in monocytes and granulocytes in vivo. BAFF serum concentrations were elevated in IFN-beta-treated multiple sclerosis patients to a similar level as observed in SLE patients. In cultured PBMC, neutrophils, fibroblasts and astrocytes, BAFF was induced by IFN-beta concentrations similar to those reached in vivo in treated multiple sclerosis patients. BAFF turned out to be the main regulated element of the BAFF/APRIL system. In untreated multiple sclerosis patients, there was no BAFF increase as compared to healthy controls. Our study reveals a complex situation. We show that IFN-beta therapy induces a potent B cell survival factor, BAFF. However, B cell depletion would be desirable at least in some multiple sclerosis patients. The systemic induction of BAFF by IFN-beta therapy may facilitate the production of various autoantibodies and of IFN-neutralizing antibodies. Individual MS/NMO patients who have major B cell involvement may benefit less than others from IFN-beta therapy, thus explaining interindividual differences of the therapeutic response.

The extent of endosonographic anal sphincter defects after primary repair of obstetric sphincter tears increases over time and is related to anal incontinence.

OBJECTIVE: To describe and classify endosonographic obstetric sphincter defects at 1 week, 3 months and 1 year after primary repair, and to relate the endosonographic results to anal sphincter pressure and to symptoms of anal incontinence over time. METHODS: Forty-one women who had suffered a third- or fourth-degree perineal tear at delivery underwent anal endosonography and anal manometry 1 week, 3 months and 1 year after primary suture of the tear. The extent of the endosonographic defects was described using defect scores ranging from 0 (no defect) to 16 (maximal defect), the score taking into account the location and the longitudinal and circumferential extent of the defect. The women answered a questionnaire with regard to bowel function 1 and 4 years after delivery, the degree of incontinence being expressed as a Wexner score. RESULTS: Some 90% (37/41) of the women had endosonographic defects at 1 week, 3 months and 1 year. The endosonographic defect scores increased significantly between the first and second examinations and then remained unchanged. At 1 year there was a negative correlation between endosonographic sphincter defect score and sphincter pressure. At 1 and 4 years, 54% (22/41) and 61% (25/41) of the women, respectively, had a Wexner score >/= 1. There was a positive correlation between the endosonographic sphincter defect score at 1 week, 3 months and 1 year and the Wexner incontinence score at 1 and 4 years. The endosonographic sphincter defect score at 1 week was the variable that was most predictive of the Wexner score at 4 years (r = 0.48, P = 0.002). CONCLUSION: The higher the endosonographic sphincter defect score after primary repair of an obstetric sphincter tear the lower the sphincter pressure and the higher the risk of anal incontinence.

Acquired thrombotic thrombocytopenic purpura as the presenting symptom of systemic lupus erythematosus. Successful treatment with plasma exchange and immunosuppression--report of two cases.

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening syndrome characterized by platelet aggregation causing occlusive microangiopathy. It has been described as a complication in systemic lupus erythematosus (SLE). Recent research indicated that genetic or autoantibody-induced deficiency of the metalloprotease ADAMTS13 plays a key role in the pathogenesis of TTP. Here we report two uncommon cases of TTP as the first presenting symptom of SLE. Both patients were treated with combined plasma exchange and immunosuppressive therapy, and recovered completely. Although TTP and SLE have several clinical findings in common, and both disorders may coexist more frequently than we currently assume, features of one disease should not mislead to reject the alternative disorder.

Endosonography of the anal sphincter in women of different ages and parity.

OBJECTIVES: To obtain reference data representative of normal findings at anal endosonography in pregnant and non-pregnant women. To determine intraobserver and interobserver agreement in the detection of endosonographic anal sphincter defects in asymptomatic women. METHODS: Twenty-five non-pregnant nulliparous women and 25 non-pregnant parous women (age range, 20-67 years) and 47 pregnant women (age range, 21-39 years) underwent anal manometry and anal endosonography. The endosonographic internal and external sphincter thickness and sphincter length were measured online. Endosonographic sphincter defects were measured and classified offline from videotapes by two independent examiners using an endosonographic defect score ranging from 0 (no defect) to 16 (maximal defect), the score taking into account the location and the longitudinal and circumferential extension of the defect. RESULTS: Endosonographic sphincter thickness and length did not differ between non-pregnant nulliparous and parous women and did not change substantially with age. The anal sphincter was thicker and the anal resting pressure area and manometric sphincter length were greater in pregnant than in non-pregnant women of the same age (20-39 years). There was good intra- and interobserver agreement with regard to detection of endosonographic anal sphincter defects (kappa > or = 0.70). Eighteen (19%) women had endosonographic sphincter defects but in only four (4%; 4/97) cases were they moderate or large (defect score, 7-10). Ten (20%) of the non-pregnant women reported minor gas incontinence and one reported minor incontinence for both gas and liquid stool. The frequency of incontinence did not differ between women with and without sphincter defects. CONCLUSIONS: Reference data representative of normal findings at anal endosonography have been established for non-pregnant women and for nulliparous women in the third trimester of pregnancy. Small endosonographic sphincter defects and minor gas incontinence are common in women without known sphincter trauma. They seem to be unrelated to each other and may be regarded as normal variants.

Results of endosonographic imaging of the anal sphincter 2-7 days after primary repair of third- or fourth-degree obstetric sphincter tears.

OBJECTIVES: To describe the endosonographic image of the anal sphincter 2-7 days after delivery in women who had undergone a primary repair of an obstetric sphincter tear. METHODS: Forty-eight women who had suffered a third- or fourth-degree sphincter tear at delivery and had undergone primary sphincter repair were examined with endoanal sonography 2-7 days after delivery. A score from 0 to 16 was used to describe the extent of the endosonographic defects, a score of 0 indicating no defect and a score of 16 a defect > 180 degrees involving the whole length and depth of the sphincter. Clinical information was retrieved from the delivery and operation records after the analysis of the ultrasound images and the classification of the sonographic defects had been completed. RESULTS: Clinically, 34 (71%) women had a partial third-degree tear, 11 (23%) had a total third-degree tear, and three (6%) had a fourth-degree tear. Forty-three (90%; 95% CI, 77-97%) women had sonographic defects, all hypoechoic. Twenty-three (54%) sonographic defects were confined to the proximal part of the anal canal and involved less than half of the length of the anal canal. Thirty (63%) defects were confined to the external sphincter. Five of nine women (56%) with an endosonographic sphincter defect score >/= 8 had undergone primary sphincter repair by a doctor in training vs. 9 of 39 women (23%) with an endosonographic sphincter score < 8 (P = 0.05), despite the fact that 86% (12/14) of the tears sutured by doctors in training were clinically partial third-degree tears vs. 65% (22/34) of those sutured by specialists (P = 0.15). Five (15%) of 34 women with a clinical partial third-degree tear had an endosonographic sphincter score >/= 8 vs. four (29%) of 14 with a clinical total third- or fourth-degree sphincter tear (P = 0.26). CONCLUSIONS: Most women (90%) with a clinical third- or fourth-degree obstetric sphincter tear have endosonographic sphincter defects if they are examined 2-7 days after primary repair. The extent of the endosonographic defects seems to be determined mainly by the surgical experience of the doctor performing the repair, and not by the clinical degree of the tear.

Rectal endosonography can distinguish benign rectal lesions from invasive early rectal cancers.

OBJECTIVE: To determine whether an experienced ultrasound examiner, using good ultrasound equipment with high multifrequency probes, can discriminate between a high grade or low grade dysplastic adenoma (pT0) and very early invasive rectal cancers (pT1). SUBJECTS AND METHODS: Sixty consecutive patients with clinically possibly pT0 or pT1 rectal tumours referred for transanal local excision underwent endorectal ultrasound examination. Lesions where the endorectal ultrasound image showed the mucosal layer to be expanded but the submucosal layer to be intact (uT0) were considered to represent a low grade or high grade dysplasia adenoma (pT0). An irregularity or disruption of the submucosal layer (uT1) was considered to characterize early invasive rectal cancers (pT1). The ultrasound staging was compared with the histological staging made on the basis of the diagnoses in the excised specimens. RESULTS: The histopathological diagnoses were: invasive rectal cancer (n = 18, 10 pT1, 4 pT2, 4 pT3 cancers); high grade dysplastic adenoma (n = 21); low grade dysplastic adenoma (n = 18); non adenomatous benign lesions (n = 3). Endorectal ultrasound incorrectly classified two of the invasive cancers (both pT1 tumours) as noninvasive lesions. Five of 42 pT0 tumours were overstaged as uT1 tumours. Overstaging was more common in patients who had undergone a previous excision and in tumours with peritumoral inflammation and desmoplastic reaction. The sensitivity of endorectal ultrasound with regard to invasive cancer was 89% (16/18), specificity 88% (37/42), positive predictive value 76% (16/21), negative predictive value 95% (37/39), and accuracy 88% (53/60). Among pT0 and pT1 tumours, the corresponding figures were 80% (8/10), 88% (37/42), 62% (8/13), 95% (37/39), and 87% (45/52). CONCLUSION: Endorectal ultrasound can distinguish between noninvasive lesions and invasive rectal cancers clinically of stage pT0 or pT1.

Rhinovirus RNA in the maxillary sinus epithelium of adult patients with acute sinusitis.

We used in situ hybridization for the detection of rhinovirus in maxillary sinus biopsy specimens obtained from 14 adult patients with acute sinusitis. In 7 specimens, rhinovirus RNA could be demonstrated in the maxillary sinus epithelium, thereby confirming the etiology of rhinovirus and the clinical suspicion of acute sinusitis.