Prior poliomyelitis-IVIg treatment reduces proinflammatory cytokine production

The postpolio syndrome (PPS) is characterized by progressive disabilities decades after recovery from the acute paralytic disease. There are reports on intrathecal inflammatory reactions in PPS, including increased expression of cytokines by cerebrospinal fluid (CSF) mononuclear cells (CSF-MC). This is potentially of relevance for the clinical condition. We here explored if cytokine expression in the CSF of PPS patients could be modulated by high-dose intravenous immunoglobulins (IvIg). The expression of TNF-alpha, IFN-gamma, IL-10 and IL-4 mRNAs was measured by real-time RT-PCR in CSF and peripheral blood mononuclear cells (PBMC) of 16 PPS patients before, and 6-8 weeks after IvIg treatment, and in 26 patients with noninflammatory other neurological diseases (OND). TNF-alpha, IFN-gamma and IL-10 CSF mRNA levels were elevated in samples from untreated persons with PPS compared to OND. Upon IvIg treatment, IFN-gamma and TNF-alpha mRNA levels were dramatically reduced, while IL-10 remained unchanged. Placebo-controlled studies are now warranted to evaluate if IvIg treatment also has any effects on the clinical manifestations of PPS.     

A multicenter, randomized, double-blinded trial of pyridostigmine in postpolio syndrome.

BACKGROUND: Postpoliomyelitis syndrome (PPS) is likely due to degeneration and dysfunction of terminal axons of enlarged postpolio motor units. Age-related decline in growth hormone and insulin-like growth factor (IGF-I) may be a contributing factor. Neuromuscular junction abnormalities and decreased IGF-I levels may respond to the anticholinesterase pyridostigmine, with consequent improvement in strength, fatigue, and quality of life. OBJECTIVES: To determine the effect of pyridostigmine in PPS on health-related quality of life, isometric muscle strength, fatigue, and serum IGF-I levels; and to assess the safety of pyridostigmine in PPS. METHODS: The study was a multicenter, randomized, double-blinded, placebo-controlled trial of a 6-month course of pyridostigmine 60 mg three times per day in 126 PPS patients. The primary data analysis compared mean changes of outcomes between treatment and control groups at 6 months using an intention to treat approach. Secondary analyses included a comparison of outcomes at 6 and 10 weeks, and in compliant patients. RESULTS: The study showed no significant differences in pyridostigmine and placebo-treated patients with regard to changes in quality of life, isometric strength, fatigue, and IGF-I serum levels at 6 months in the primary analysis and in compliant patients. There were no differences in outcomes at 6 and 10 weeks between groups. However, very weak muscles (1 to 25% predicted normal at baseline) were somewhat stronger (p = 0.10, 95% CI of difference -9.5 to 73.3%), and in compliant patients IGF-I was somewhat increased (p = 0.15, 95% CI of difference -6.4 to 44.8 ng/mL) at 6 months with the medication. Pyridostigmine was generally well tolerated. CONCLUSIONS: This study showed no significant differences between pyridostigmine and placebo-treated PPS patients on measures of quality of life, isometric strength, fatigue, and serum IGF-I.     

Elevated serum inflammatory markers in post-poliomyelitis syndrome

OBJECTIVES: To determine (i) whether serum inflammatory markers TNFalpha, IL-1beta. IL-6, and leptin are increased in post-poliomyelitis syndrome (PPS) compared to healthy controls; and (ii) whether an association exists between elevated inflammatory markers and clinical parameters in PPS. The cause of PPS is unknown, but abnormal inflammatory responses have been implicated in several small studies. METHODS: Serum inflammatory markers were measured (by Luminex) in 51 PPS patients and 26 normal controls. Clinical parameters assessed included disease duration, muscle strength (Medical Research Council sumscore), fatigue (Fatigue Severity Scale and Multidimensional Fatigue Inventory), and pain (visual analog scale scores). RESULTS: In PPS, TNFalpha levels, as well as IL-6 and leptin were significantly increased compared to controls (Wilcoxon rank-sum test, p=0.03 for TNFalpha, p=0.03 for IL-6, p=0.01 for leptin). The elevated TNFalpha levels in PPS were associated with increased pain due to illness (Spearman correlation coefficient r=0.36, 95% C.I. 0.09 to 0.57) and specifically, with muscle pain (r=0.38, 95% C.I. 0.11 to 0.59). There were no correlations between inflammatory markers in PPS and joint pain, muscle strength, fatigue, or disease duration. CONCLUSIONS: Serum TNFalpha, IL-6 and leptin levels are abnormally increased in PPS patients. Elevated TNFalpha levels appear to be specifically associated with increased muscle pain.     

脊髓灰质炎后综合征临床及电生理研究

目的研究脊髓灰质炎后综合征的临床表现和电生理特点,探讨其诊断、鉴别诊断及诊疗方法。方法回顾性分析10例脊髓灰质炎后综合征患者的临床资料。结果 10例患者受累肢体肌力均有减弱,5例伴易疲劳,3例伴寒冷不耐受,5例伴肢体疼痛。典型电生理表现为运动单位电位时限增宽、波幅增高、募集相减少;运动及感觉神经传导均正常。结论脊髓灰质炎后综合征最常见表现为无力、慢性疲劳、疼痛,诊断主要依赖于病史、临床表现、电生理等相结合的综合分析,治疗主要为康复及药物治疗,早期干预可改善患者生活质量。     

Intravenous immunoglobulin for post-polio syndrome: a randomised controlled trial

BACKGROUND: Survivors of poliomyelitis often develop increased or new symptoms decades after the acute infection, known as post-polio syndrome. Production of proinflammatory cytokines within the CNS indicates an underlying inflammatory process, accessible for immunomodulatory treatment. We did a multicentre, randomised, double-blind, placebo-controlled study of intravenous immunoglobulin in post-polio syndrome. METHODS: 142 patients at four university clinics were randomly assigned infusion of either 90 g in total of intravenous immunoglobulin (n=73) or placebo (n=69) during 3 consecutive days, repeated after 3 months. Seven patients were withdrawn from the study. Thus, 135 patients were assessed per protocol. Primary endpoints were muscle strength in a selected study muscle and quality of life as measured with the SF-36 questionnaire (SF-36 PCS). Secondary endpoints were 6-minute walk test (6MWT), timed up and go (TUG), muscle strength in muscles not chosen as the study muscle, physical activity scale of the elderly (PASE), visual analogue scale (VAS) for pain, multidimensional fatigue inventory (MFI-20), balance, and sleep quality. Outcome tests were done immediately before the first infusion and 3 months after the second infusion. This study is registered with , number NCT00160082. FINDINGS: Compared with baseline, median muscle strength differed by 8.3% between patients receiving intravenous immunoglobulin and placebo, in favour of the treatment group (p=0.029). SF-36 PCS did not differ significantly between the groups after treatment (p=0.321). Differences in the subscale vitality score (p=0.042) and PASE (p=0.018) favoured the active treatment group. MFI-20, TUG, muscle strength in the muscles not chosen as the study muscle, 6MWT, balance, and sleep quality did not differ between groups. For the whole study population there was no significant change in pain, as determined by VAS. Nevertheless, patients who reported pain at the study start improved in the intervention group but not in the placebo group (p=0.037). Intravenous immunoglobulin was well tolerated. INTERPRETATION: Intravenous immunoglobulin could be a supportive treatment option for subgroups of patients with post-polio syndrome. Further studies on responding subgroups, long-term effects, and dosing schedules are needed.     

EFNS guideline on diagnosis and management of post-polio syndrome. Report of an EFNS task force

Post-polio syndrome (PPS) is characterized by new or increased muscular weakness, atrophy, muscle pain and fatigue several years after acute polio. The aim of the article is to prepare diagnostic criteria for PPS, and to evaluate the existing evidence for therapeutic interventions. The Medline, EMBASE and ISI databases were searched. Consensus in the group was reached after discussion by e-mail. We recommend Halstead's definition of PPS from 1991 as diagnostic criteria. Supervised, aerobic muscular training, both isokinetic and isometric, is a safe and effective way to prevent further decline for patients with moderate weakness (Level B). Muscular training can also improve muscular fatigue, muscle weakness and pain. Training in a warm climate and non-swimming water exercises are particularly useful (Level B). Respiratory muscle training can improve pulmonary function. Recognition of respiratory impairment and early introduction of non-invasive ventilatory aids prevent or delay further respiratory decline and the need for invasive respiratory aid (Level C). Group training, regular follow-up and patient education are useful for the patients' mental status and well-being. Weight loss, adjustment and introduction of properly fitted assistive devices should be considered (good practice points). A small number of controlled studies of potential-specific treatments for PPS have been completed, but no definitive therapeutic effect has been reported for the agents evaluated (pyridostigmine, corticosteroids, amantadine). Future randomized trials should particularly address the treatment of pain, which is commonly reported by PPS patients. There is also a need for studies evaluating the long-term effects of muscular training.     

Induction of systemic TNFα in Natalizumab-treated multiple sclerosis

The mRNA expression of eight different cytokines in peripheral blood mononuclear cells in 19 individuals with multiple sclerosis was determined at baseline and after 6 months of open-label treatment with natalizumab. Cellular expression of tumor necrosis factor α (TNFα) mRNA and number of cells secreting TNFα and interferon γ protein significantly increased over the 6 months. Kurtzke EDSS scores improved because of the resolution of relapses, but not fatigue severity scores. The observed increases in systemic proinflammatory cytokines by natalizumab treatment are discussed in relation to fatigue and systemic immunity.     

Treatment with L‐Citrulline in patients with post‐polio syndrome: A single center,randomized, double blind,placebo‐controlled trial

This single-centered, randomized, double-blind, placebo-controlled study reports the results of L-Citrulline treatment for 24 weeks in patients with post-polio syndrome (PPS). Twenty-nine patients were randomized and assigned into receiving a treatment of 15 g L-Citrulline or placebo. The primary endpoint was the change of the 6 min walking distance test. Secondary endpoints included motor function measure, quantitative muscle strength, quantitative MRI and self-reported impairment questionnaires. Patients receiving L-Citrulline walked 17.5 longer in the 6 min walking distance test when compared to placebo group, however not statistically significant (95% CI = -14.69; 49.68, p = 0.298). None of the secondary endpoints showed a statistically significant change in the L-Citrulline group when compared to placebo group. The motor function measure showed a change of -0.78 (95% CI= [-3.39; 1.83] p = 0.563). Muscle degeneration of leg muscles assessed with quantitative MRI indicated no significant change (estimate= -0.01, 95% CI =-0.13; 0.11, p = 0.869). L-Citrulline was safe and well tolerated. In conclusion, administration of 15 g L-Citrulline daily for 24 weeks to patients with PPS showed no beneficial treatment effect in timed muscle function.     

Isoelectric focusing studies of serum and cerebrospinal fluid in patients with antecedent poliomyelitis

The post-poliomyelitis syndrome (PPS) refers to symptoms of new weakness, fatigue, and pain years after recovery from acute poliomyelitis. Oligoclonal IgG bands have been reported in the cerebrospinal fluid (CSF) from PPS patients, suggesting that the syndrome is immune mediated or caused by persistent viral infection. We studied 15 paired serum and CSF samples and 6 unpaired CSF samples from a total of 21 patients with a prior history of poliomyelitis. Quantitative immune studies failed to show evidence for increased intrathecal IgG production relative to patients with noninflammatory central nervous system (CNS) disease. We found definite oligoclonal IgG bands in the CSF from only 1 patient, who also carried a diagnosis of multiple sclerosis. An isoelectric focusing poliovirus antigen overlay study showed evidence that suggested a CNS-specific antipoliovirus immune response in only 1 patient. Our results fail to support a dysimmune or persistent viral cause for post-poliomyelitis progressive muscular atrophy or PPS.     

Risk factors for post-polio syndrome among an Italian population: a case–control study

Post-polio syndrome (PPS) is a clinical syndrome of new weakness, fatigue and musculoskeletal pain occurring in a variable proportion of polio survivors decades after acute disease. To date, several risk factors for PPS development have been reported, although the etiology of this disorder remains elusive. Using a case–control design, we aimed to assess risk indicators for PPS in a group of Italian polio survivors. Subjects with prior poliomyelitis attending the rehabilitation hospital of Malcesine, Italy, were the target population. Patients with PPS, diagnosed according to the European Federation of Neurological Societies criteria, served as cases, while patients not meeting diagnostic criteria for PPS were used as controls. All subjects were assessed through a structured questionnaire made of 82 questions and neurological examination. The association with investigated risk factors (sex, age at polio onset, age at onset of symptoms, extension and severity of polio, employment) was analyzed by the calculation of the odds ratio. A total of 161 out of 391 eligible patients met the adopted diagnostic criteria for PPS, giving a frequency of 41.2%. Symptoms most frequently complained by PPS patients were loss of muscle strength, loss of resistance, loss of muscle volume and generalized fatigue. Female gender, the presence of respiratory disturbance during the acute phase of polio and the use of orthoses and aids during the recovery and stabilization represented independent risk factors for PPS in the studied population.     

Neuroactive steroids and fatigue severity in patients with primary biliary cirrhosis and hepatitis C

Abstract  Fatigue is one of the most common non-specific symptoms associated with several disease states including liver diseases. Recently, it was reported that levels of progesterone metabolites such as allopregnanolone (3α,5α-tetrahydroprogesterone; 3α,5α-THP) and isopregnanolone (3β,5α-THP) were increased in plasma of patients with chronic fatigue syndrome. We hypothesize that THP metabolites might be associated with fatigue commonly observed in chronic liver diseases. We evaluated fatigue scores and plasma levels of five progesterone metabolites in 16 patients with primary biliary cirrhosis (PBC), 12 patients with chronic hepatitis C (CHC) and 11 age-matched controls. The fatigue impact scale (FIS) ratio was significantly increased ( P  < 0.01) in patients with PBC and CHC compared to controls. Plasma levels of 3α,5α-THP and pregnanolone (3α,5β-THP) were significantly increased in PBC and CHC patients. The other progesterone metabolites, i.e. 3β,5α-THP, 3β,5β-THP and 3α,5α-tetrahydrodeoxycorticosterone were either undetectable or detected only in some patients. Plasma levels of 3α,5α-THP and 3α,5β-THP were found to be significantly higher in patients with fatigue ( P  < 0.05), while those of patients without fatigue were not significantly different from controls. Both 3α,5α-THP and 3α,5β-THP are positive allosteric modulators of the gamma-aminobutyric acid type A (GABA-A) receptor and readily cross the blood–brain barrier. The present preliminary findings suggest that increased inhibition through GABA-A receptors due to the accumulation of neuroinhibitory steroids may represent an important pathophysiological mechanism of fatigue in chronic liver diseases.     

Efficacy of Silver Nanoparticles-Impregnated External Ventricular Drain Catheters in Patients with Acute Occlusive Hydrocephalus

Introduction  Catheter-associated infection of cerebrospinal fluid (CSF) is a potentially life-threatening complication of external ventricular drainage (EVD). The purpose of this pilot study was to address the efficacy of silver-impregnated EVD catheters in neurological and neurosurgical patients requiring external CSF drainage due to acute occlusive hydrocephalus. Methods  Nineteen consecutive patients were enrolled in the treatment arm of the study and data were prospectively recorded for these patients. The control group consisted of 20 patients for whom data were retrospectively assessed. CSF samples were drawn at least three times a week and routine bacterial cultures and CSF analyses were done according to standard protocols. The primary endpoint of the study was the occurrence of catheter-associated ventriculitis (CAV) proven by positive CSF culture. Secondary endpoints were bacterial colonization of the catheter tip and CSF pleocytosis. Results  In 20 control patients, 5 CAVs were microbiologically diagnosed. In contrast, no positive CSF cultures were found in the treatment group. This difference was statistically significant (P < 0.05). All CAVs occurred later than day 10 after catheter placement. Colonization of the catheter tip was found in 6 patients in the control group and in 5 patients in the treatment group (not significant). Conclusions  This pilot study indicates that EVD catheters impregnated with silver nanoparticles might be a new option for preventing CAV in neurocritical care patients, and therefore evaluation in a large prospective randomized study is warranted.     

Effect of levetiracetam on the postmastectomy pain syndrome

Background and purpose:  The aim of this randomized, double-blind, placebo-controlled, cross-over study was to test whether levetiracetam relieves the postmastectomy pain syndrome (PMPS).
Methods:  Postmastectomy pain syndrome was defined as pain of neuropathic character located in the area of the surgery and/or the ipsilateral arm. The inclusion criteria were: age more than 18 years, characteristic symptoms corresponding to PMPS more than 6 months after surgery for breast cancer, pain duration more than 3 months, peripheral nerve lesions confirmed by abnormal neurological and quantitative sensory tests, intensity of pain more than 4 on a numeric rating scale from 0 to 10 and pain present at least 4 days a week.
Results:  Forty-nine patients were screened for participation and 27 patients were included in the study. Twenty-five patients completed two treatment phases of 4 weeks duration with levetiracetam (3000 mg/day) and placebo. There was no difference in the rating of pain relief between treatment with levetiracetam ( P  = 0.83) and placebo nor when adjusted for possible period effect ( P  = 0.60). Analysis defining response as pain relief more than 4 on an eleven-point numeric rating scale showed no significant difference between treatment with levetiracetam and placebo ( P  = 1.00).
Conclusions:  Levetiracetam apparently does not relieve peripheral neuropathic pain in PMPS.     

A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM

OBJECTIVE: To investigate whether the combination of intravenous immunoglobulin (IVIg) with prednisone improves muscle strength and alters endomysial inflammation in patients with sporadic inclusion body myositis (s-IBM). BACKGROUND: In a previous controlled trial in s-IBM, IVIg did not significantly improve strength in spite of modest benefits in some muscle groups. The possibility that prednisone may have a synergistic effect with IVIg prompted another controlled trial. METHODS: Thirty-six patients with biopsy-proven IBM were randomized to receive IVIg or placebo monthly for 3 months. Before infusions, all patients were started on high-dose prednisone for 3 months. Primary outcome measures were differences in the 1) Quantitative Muscle Strength (QMT) testing; and 2) modified Medical Research Council (MRC) scores, between the patients randomized to IVIg + prednisone compared with those randomized to placebo + prednisone. Repeated open muscle biopsies were performed at random in 24 patients to determine changes in the number of autoinvasive T cells and necrotic muscle fibers. RESULTS: Nineteen patients were randomized to IVIg + prednisone and 17 to placebo + prednisone. No significant change was noted in muscle strength, assessed by QMT and MRC, from baseline to the 2nd, 3rd, or 4th month after treatment between the two groups. The number of necrotic fibers was reduced in the IVIg randomized group (p < 0.01), and the mean number of CD2+ cells was significantly decreased in both groups (p < 0.0001), denoting a steroid effect. CONCLUSION: IVIg combined with prednisone for a 3-month period was not effective in IBM. Endomysial inflammation was significantly reduced after treatment, but the reduction was not of clinical significance.     

脊髓灰质炎后综合征的临床表现（附3例报道）

目的:研究脊髓灰质炎后综合征(PPS)的临床表现。方法:评价3例PPS患者的临床表现。结果:PPS的主要表现是新出现的肌无力、疲劳、疼痛和肢体及躯干缓慢进展的运动神经损害。PPS患者既往有脊髓灰质炎的病史,有部分或完全的神经功能恢复,有长达数十年的神经功能稳定期并除外其他疾病。结论:PPS是一种感染脊髓灰质炎后出现的缓慢进展性的运动神经元综合征。     

A substantial number of Rasmussen syndrome patients have increased IgG, CD4+ T cells, TNFα, and Granzyme B in CSF

Purpose:   We studied the immunologic molecules in cerebrospinal fluid (CSF) and discussed their evolutional changes in pediatric patients with Rasmussen syndrome (RS).
Methods:   CSF samples collected from 27 patients with RS (average onset age, 7.5 ± 5.6 years) were studied. Cell count, protein, glucose, albumin, chloride, and immunoglobulin G (IgG) levels were measured by conventional methods. Surface markers of lymphocytes in CSF were examined by a cell sorter. Granzyme B, interferon γ (IFNγ), interleukin 4 (IL-4), tumor necrosis factor α (TNFα), and IL-12 in CSF were quantitated by enzyme-linked immunosorbent assay (ELISA). Autoantibodies against GluR ε2 (NR2B) were examined by immunoblot.
Results:   The data of the first CSF examination showed that IgG levels (Mann-Whitney U test, p < 0.01), CD4⁺ T cells (p = 0.02), TNFα levels (p < 0.01), and Granzyme B levels (p < 0.01) were elevated compared with disease controls. White blood cell count, IFNγ level, IL-12 level, and Granzyme B level were elevated, especially in the early stage of disease. CD4⁺ T cells, CD8⁺ cells, CD3⁺ T cells, IgG levels, and TNFα levels were elevated at all stages of disease evolution. Protein levels and albumin levels were elevated in the progressed stage. Autoantibodies against GluR ε2 (NR2B) (IgG) were found in 50% of patients in the early stage, and the positive rate was low at the progressed stage.
Discussion:   The present findings suggest that complex pathophysiologic mechanisms involving CD4⁺ T cells and CD8⁺ T cells change evolutionally during the progression of RS. A crucial cytotoxic process occurs in the early stage, and declines in the progressed stage.     

Antibiotic-Impregnated Versus Silver-Bearing External Ventricular Drainage Catheters: Preliminary Results in a Randomized Controlled Trial

Background

Evaluation of antibiotic-impregnated (AI) and ionized silver particle coated external ventricular drainage catheters (EVD) in patients with subarachnoid (SAH) or intracranial hemorrhage (ICH).

Methods

Between February 2011 and June 2012, 40 patients with acute hydrocephalus due to SAH, ICH or intraventricular hemorrhage were enrolled in a prospective, randomized, mono-center pilot study. Primary endpoints were defined as: number of events of cerebrospinal fluid (CSF) infections. Secondary endpoints were defined as: neurosurgical complications following the placement of the EVD, number of revisions of EVD catheters, and cost effectiveness.

Results

Sixty-one EVD placements in 40 patients, 32 antibiotic-coated (Bactiseal^®), 29 silver-bearing catheters (VentriGuard^®), have been performed. Confirmed or high suspicion of CSF infections occurred in 11 out of 61 events (confirmed infection: p = 0.71, probable infection: p = 0.90). Revisions of EVD were needed in 13 cases (22 %) due to CSF infection, dysfunction, impaired healing, or malplacement (p = 0.37).

Conclusion

Regarding CSF infection rate and dysfunction, no statistical significant differences between the two EVD catheters Bactiseal^® versus VentriGuard^® were found. The silver-bearing catheter might offer a safe and cost-conscious alternative to the AI catheter.     

Zespół post-polio: Część I. „Dziedzictwo” zapomnianej choroby,wyzwanie dla lekarzy i pacjentów

The outcome of paralytic polio was believed to be a stable neurological state. Now, it is established that polio has an additional, slowly progressive phase, called post-polio syndrome (PPS) that develops 30–40 years after the acute poliomyelitis in 25–80% of paralytic and about 40% of nonparalytic polio survivors. The clinical symptoms are nonspecific and usually include muscle weakness, fatigue and muscle or joint pain. Some patients suffer from muscular atrophy, respiratory insufficiency, dysphagia, sleep disturbances or cold intolerance. The etiopathogenesis of PPS is unclear and many factors, such as dysfunction of the surviving motor units, aging, defects of neuromuscular transmission, persistence of viral infection and immunological mechanisms, are considered. This article reviews the epidemiology, pathophysiology, clinical characteristics and diagnosis of PPS patients.     

Fatigue resistance of the knee extensor muscles is not reduced in post-polio syndrome

The present study investigated whether intrinsic fatigability of the muscle fibers is reduced in patients with post-polio syndrome (PPS). This may contribute to the muscle fatigue complaints reported by patients with PPS. For this purpose, we assessed contractile properties and fatigue resistance of the knee extensor muscles using repeated isometric electrically evoked contractions in 38 patients with PPS and 19 age-matched healthy subjects. To determine whether any difference in fatigue resistance between both groups could be attributed to differences in aerobic capacity of the muscle fibers, 9 patients with PPS and 11 healthy subjects performed the same protocol under arterial occlusion. Results showed that fatigue resistance of patients with PPS was comparable to that in controls, both in the situation with intact circulation and with occluded blood flow. Together, our findings suggest that there are no differences in contractile properties and aerobic muscle capacity that may account for the increased muscle fatigue perceived in PPS.