Personalizing ocrelizumab treatment in Multiple Sclerosis: What can we learn from Sars-Cov2 pandemic?

During SARS-CoV-2 pandemic, we adopted a personalized delayed protocol for ocrelizumab infusions in Relapsing Remitting Multiple Sclerosis (RRMS) patients according to the national recommendations. Out of the 83 RRMS patients whose infusion was scheduled between March and December 2020, 56 patients experienced a delay in treatment based on MS severity and SARS-CoV2 infection risk profile. In most cases, the immunophenotype was performed monthly to guide re-infusions. Specifically, B CD19 + cells repopulation rate was monitored. Mean infusion delay was 103,1 [SD 40,6] days, and none of the patients presented relapses or active disease at MRI at the end of the observation period. Treatment naïve status and the interval between immunophenotyping and the last ocrelizumab infusion were predictors of earlier B CD19 + cells repopulation. Two patients contracted SARS-CoV2 with complete recovery. Definitive data about Sars-Cov2 vaccine efficacy in patients treated with ocrelizumab are still lacking. Our findings suggest that a personalized treatment with a delayed infusion schedule does not compromise ocrelizumab short-term efficacy and may help to lengthen the therapeutic window for an effective response to SARS-CoV2 vaccine.

Assessing upper limb function in multiple sclerosis using an engineered glove.

BACKGROUND AND PURPOSE: The importance of upper limb function in multiple sclerosis (MS) is increasingly recognized, especially for the evaluation of patients with progressive MS with reduced mobility. Two sensor-engineered gloves, able to measure quantitatively the timing of finger opposition movements, were previously used to assess upper limb disability in MS. The aims of the present study were: (1) to confirm the association between glove-derived variables and standard measures of MS disability in a larger cohort; (2) to assess the correlation with quantitative magnetic resonance imaging (MRI) and quality of life (QoL) measures; and (3) to determine if the glove-derived variables offer advantages over the standard measure for assessing upper limb function in MS, namely, the Nine-Hole Peg Test (9HPT). METHODS: Sixty-five patients with MS, stable on disease-modifying treatment, were evaluated at baseline using the glove, and through clinical examination (Expanded Disability Status Scale, Symbol Digit Modalities Test, Timed 25-Foot Walk Test and 9HPT), MRI evaluation and QoL questionnaires. Correlations between the glove-derived variables and clinical, MRI and QoL variables were assessed using Spearman's rank correlation coefficient analysis. RESULTS: Glove-derived variables significantly differed between patients with relapsing-remitting and those with progressive MS, with similar or slightly higher correlations of the 9HPT with clinical variables. We found greater correlations of the QoL physical component with glove-derived variables than with the 9HPT, and a significant correlation of its mental component with the glove-derived variables but not with the 9HPT. CONCLUSION: The study results, confirming previous findings and showing advantages over the 9HPT, encourage the investigation of sensitivity to change in glove-derived variables in a longitudinal setting.

Tocilizumab in MOG-antibody spectrum disorder: a case report.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-related spectrum disorders (MOG-SD) are a heterogeneous group of inflammatory demyelinating diseases of the central nervous system, usually responsive to conventional immunosuppressive therapies. However, knowledge about treatment of non-responder patients is scarce. METHODS: We report on a 20-year-old MOG-SD patient who experienced clinical deterioration despite rituximab-induced B-cell depletion. RESULTS: Rescue therapy with tocilizumab (TCZ) prevented further relapses, with reduction of spinal-cord load on MRI, and a remarkable reduction of disability at the two-year follow-up. CONCLUSION: Our observations suggest that TCZ could induce clinico-radiologic improvements, which make it as an option for the treatment of MOG-SD.

Analysis of the role of the pyruvate decarboxylase gene family in Arabidopsis thaliana under low-oxygen conditions.

Plants under low-oxygen conditions adapt their metabolism by inducing the fermentative pathway, with ethanol as the predominant end product. Activities of pyruvate decarboxylase (PDC) and alcohol dehydrogenase (ADH) are required for this pathway. While a single gene encodes ADH in Arabidopsis, a family of four genes codes PDC. The availability of microarray data sets enabled the relative importance of the four PDC genes under low oxygen to be assessed, and revealed that, contrary to previous published evidence, not only PDC1 but also PDC2 plays a role under hypoxic conditions. We observed a high level of expression, both at transcript and protein levels of PDCs, even under aerobic conditions when ADH is almost absent. This suggests that PDC has a role under aerobic conditions, which is not coupled to fermentative metabolism. The expression of both PDC1 and PDC2 is strongly up-regulated under low oxygen. PDC1 is predominantly present in roots, while PDC2 appears to be leaf-specific. We showed that mutations in both PDC1 and PDC2 result in lower tolerance to submergence.

Sacral nerve stimulation in patients with severe constipation.

PURPOSE: Constipation is frequently a multifactorial disease. This study was designed to evaluate the potential effects of sacral nerve stimulation for patients suffering from severe chronic constipation. METHODS: Nineteen patients suffering from pathologic colonic transit time or rectal outlet obstruction were included. Only patients with severe rectal outlet obstruction who needed digital manipulation for defecation or patients suffering from pathologic colonic transit constipation with less than two bowel movements per week were regarded as candidates. A temporary stimulation lead was implanted into the sacral foramen that showed the best muscular response. After an evaluation period, the stimulation electrode was removed. An improvement in constipation (more than 2 bowel movements per week or defecation without digital manipulation, respectively) during the test stimulation, as well as a recurrence of prestimulation constipation symptoms during the following surveillance period of three weeks were prerequisites for implanting the permanent sacral nerve stimulating system. RESULTS: All of the patients showed a positive motor response to acute needle stimulation. After the evaluation period, eight patients (42 percent) reported an improvement of constipation, and permanent systems were implanted successfully. During the median follow-up of 11 (range, 2-20) months, a significant improvement in the Wexner constipation score was observed compared with the preoperative baseline level (baseline: median: 23, range, 18-27; 12 months after implantation: median, 8, range, 4-13). After successful sacral nerve stimulation, patients also showed a significant improvement in their quality of life. CONCLUSIONS: Patients suffering from severe constipation are a new challenge for sacral nerve stimulation but further research on pelvic floor function is needed.

Sacral nerve stimulation for neurogenic faecal incontinence.

BACKGROUND: Sacral nerve stimulation (SNS) has emerged as a promising technique for the treatment of faecal incontinence. This study assessed the outcome of SNS in a cohort of patients with incontinence of neurological aetiology. METHODS: Thirty-six patients were included in a trial of SNS. Twenty-nine subsequently had a permanent implant. Evaluation consisted of a continence diary, anal manometry, saline retention testing and quality of life assessment. RESULTS: After a median follow-up of 35 (range 3-71) months, 28 patients showed a marked improvement in or complete recovery of continence. Incontinence to solid or liquid stool decreased from a median of 7 (range 4-15) to 2 (range 0-5) episodes in 21 days (P = 0.002). Saline retention time increased from a median of 2 (range 0-5) to 7 (range 2-15) min (P = 0.002). Maximum resting and squeeze anal canal pressures increased compared with preoperative values. Quality of life on all scales among patients who received a permanent implant increased at 12 and 24 months after operation. CONCLUSION: SNS is of value in selected patients with neurogenic faecal incontinence.

Long-term results of modified graciloplasty for sphincter replacement after rectal excision.

OBJECTIVE: Restoration of the anal sphincter by means of electrically stimulated (dynamic) graciloplasty is a new therapeutic option for patients with severe faecal incontinence or those having abdomino-perineal resection (APR) of the anorectum. The present study reviews the outcome of total anorectal reconstruction (TAR) after APR for low rectal cancer or recurrent anal cancer. METHODS: From 1992 to 2000, 35 of 64 patients treated with dynamic graciloplasty had a TAR performed either synchronously (n=26) or as a secondary procedure one to five years after rectal excision (n = 9). RESULTS: The most frequent complication was injury or erosion of the neorectum (n = 9) which, was avoided with increasing surgical experience. Defaecation disorders and consequent incontinence were the most common functional problem and had to be treated with periodical enemas. CONCLUSION: Although sphincter replacement by means of TAR after APR led to poorer functional results than those achieved in patients treated with dynamic graciloplasty for faecal incontinence, TAR remains a valid treatment option for patients who do not tolerate a permanent stoma.

Sacral nerve stimulation as a treatment for fecal incontinence.

BACKGROUND & AIMS: Sacral nerve stimulation is a proven therapeutic option for the treatment of some forms of urinary incontinence. Very recently, preliminary reports have given evidence for its efficacy in fecal incontinence (FI) too. METHODS: Since November 1998, 20 patients have been treated for severe FI. The cause of FI was mainly neurologic (n = 15), and was idiopathic in 5 patients. After temporary (subchronic) external stimulation over a period of 10-14 days, patients whose continence status improved underwent implantation of a permanent quadripolar lead and a subcutaneously implanted pulse generator. RESULTS: Acute (needle) testing revealed a positive pelvic floor response in 16 patients who underwent subsequent permanent implantation. The median number of incontinence episodes decreased from 6 episodes (3-15/21 days) to 2 (0-5/21 days). The time period of retention of a volume of saline causing an urge until definitive defecation was 2 minutes (range, 0-5 minutes) preoperatively and increased to 7.5 minutes (2-15 minutes) postoperatively. Results of preoperative and postoperative (3 months) anal manometry showed a statistically significant increase in maximal resting and squeeze pressures. CONCLUSIONS: Sacral nerve stimulation seems to be a new and promising modality for patients with certain types of FI in whom conventional treatment options have failed to achieve an improvement.

Quality of life after surgery for rectal cancer: do we still need a permanent colostomy?

INTRODUCTION: A permanent colostomy is a serious limitation of the quality of life. Besides cure of cancer, preservation of sphincter function is an important goal of surgery for rectal cancer. METHODS: In a prospective study a concept offering every patient with rectal cancer either sphincter salvage or a "neosphincter" was investigated, and the impact of this strategy on oncologic results, sphincter function, and quality of life was analyzed. RESULTS: From 1992 to 1997, 276 patients were accepted for the study. Two hundred sixty-one patients had elective surgery, and 15 patients had emergency surgery for their rectal tumors. The postoperative mortality rate was 4 percent. A radical resection (R0) was possible in 197 patients (75 percent). Anterior resection was the most common procedure (n = 87), and intersphincteric resection with coloanal anastomosis was the preferred method for low tumors (n = 65). Abdominoperineal resection was necessary in 15 cases. Thirteen patients had an immediate restoration of sphincter function by means of a dynamic graciloplasty, and 2 patients needed emergency abdominoperineal resection for bleeding. The follow-up was relatively short (median, 36.4 months) at the time of data analysis and showed a local recurrence rate of 8 percent. Although postoperative continence according to the Williams score revealed satisfactory results, subjective quality of life and the scale for specific symptoms showed a significantly worse outcome in patients with ultralow (coloanal) anastomoses compared with those with anterior resection. CONCLUSIONS: We conclude that for elective curative surgery of rectal cancer, a permanent colostomy is not necessary provided all presently available techniques of sphincter salvage and restoration are applied. However, the patient has to be informed about possible side effects associated with surgical procedures such as coloanal anastomosis or neosphincter reconstruction, to avoid severe psychological difficulties.

[Anal sphincter restoration using dynamic graciloplasty--results of 50 patients]. / Analer Schliessmuskelersatz mittels dynamischer Gracilisplastik--Ergebnisse der Anwendung an 50 Patienten.

During the period from 1992 to 1998, 50 patients underwent anal sphincter restoration by dynamic graciloplasty for primary (n = 26) or secondary (n = 6) total anorectal reconstruction (TAR) following abdominoperineal rectal resection (APR) or acquired (n = 9) or congenital (n = 9) fecal incontinence, respectively. Forty-seven patients were operated on by a single-stage procedure using a modified technique for the muscle wrap ("split sling"). Muscle fiber transformation by controlled stimulation was achieved at the beginning of the learning curve within 8 weeks and in the meantime within 4 weeks. Rectal injury (n = 10) turned out to be the most serious postoperative complication and was observed mainly in patients following TAR (n = 8). As the most prominent functional problem constipation in patients following TAR hampered the postoperative functional result; however, this was overcome by regular enemas. An improvement in the continence status was observed in 80% of the patients treated for fecal incontinence, and following APR 66% of the patients had acceptable results without a permanent colostomy.

Restoration of anal sphincter function by single-stage dynamic graciloplasty with a modified (split sling) technique.

BACKGROUND: Controlled muscle fiber conversion by electrostimulation makes transformation of fast twitching type II muscle fibers to slow twitching type I fibers possible, which gives skeletal muscles the capacity for tetanic contraction. This phenomenon has been recently applied in the so-called "dynamic graciloplasty" to restore function of an insufficient or excised anal sphincter. This paper describes our results with this method in patients with fecal incontinence or following an abdomino-perineal resection (APR) of the anorectum. METHODS: From April 1992 through April 1997, 28 patients (12 women and 16 men) were treated by dynamic graciloplasty. The median age was 53.5 years (range 16 to 79). Indications were as follows: APR + synchronous restoration of the excised sphincter by graciloplasty (n = 12); total anorectal reconstruction (TAR) following APR in the past (n = 6); Patients with acquired fecal incontinence (n = 4); and Congenital atresia (n = 6). Muscle transposition, implantation of stimulation electrodes and pulse generator were done as a single-stage procedure, the "neosphincter" was wrapped in a modified technique (split-sling technique). Muscle transformation was performed by controlled neuromuscular stimulation during 8 weeks (from 1992 to 1995) and 4 weeks (since 1996), respectively. RESULTS: No postoperative mortality (90 days) was observed in either group. In our early experience, rectal injury occurred in 4 patients as the most prominent complication. Evaluation of the functional outcome showed the best results in patients operated either for congenital of acquired incontinence who achieved a continence for solids and liquids or solids alone, respectively (1 or 2 according to Williams' score) in 90%, while patients following APR showed a satisfying outcome (continence for solids and liquids, solids alone or with occasional episodes for liquids) in only 55.5%. In patients following APR, defecation disorders turned out to be the most prominent functional problem and had to be treated by enemas. CONCLUSION: In this series, we have been able to perform dynamic graciloplasty as a one-stage procedure using a modified muscle wrap (split-sling-technique) thus reducing the time period until continence could be achieved to 7 weeks. We found the appropriate tension of the muscle wrap essential to prevent direct injury to the rectum as it was seen in our early experience. For this reason, we have introduced a modified device to perform intraoperative anal manometry and to measure pressures created by the neosphincter objectively.

The electrically stimulated (dynamic) graciloplasty for faecal incontinence--first experiences with a modified muscle sling.

Continence following the gracilis stimulated neosphincter reconstruction after total rectal excision is inferior to that obtained in the presence of an intact anal canal. We describe a modification of the alpha loop in which the tendon is brought through the belly of the gracilis muscle. The results in three patients are presented.

[Evaluation of 10 patients with stable stress angina using an ergometric test and Holter's dynamic ECG monitoring]. / Valutazione di 10 pazienti con angina stabile da sforzo mediante test ergometrico e monitoraggio con ECG dinamico secondo Holter.

10 male patients with stable angina of effort were studied via bicycle ergometer test and Holter's dynamic ECG. Effort produced asymptomatic ischaemia which were well tolerated and statistically much shorter and less intense than symptomatic attacks in the same patients. The primary qualification for admission to the survey was the presence of stable angina of effort verified by two ergometric tests revealing a stable ischaemic threshold. No predictive figure for asymptomatic ischaemic attacks was found in subjects with a latency period between the appearance of the ischaemia signal and onset of increased angor. It is therefore concluded that Holter ECG test must be added to ergometry for a correct evaluation of subjects with stable angina of effort.