抗体阴性重症肌无力的短程血浆置换疗法初探

血浆置换(plasma exchange,PE)在重症肌无力(MG)上的疗效已有报道,但缺乏明确一致的置换方案。我们对12例MG患者进行了37人次的短程PE,各例均在10d内行3～4次置换术,术前和术后第7天按Mantegazza肌力评分表进行临床疗效评定,结果除1例外,均获得肯定疗效,仅1人次发生较严重的副反应。4例抗体阴性病人置换后均获显著疗效,提示抗体阴性MG血浆中存在某些未知的致病因子。短程PE可供选择作为MG危象的治疗方案。     

APPRAISAL OF LONG-TERM LEVODOPA TREATMENT OF PARKINSONISM WITH SPECIAL REFERENCE TO THERAPY LIMITING FACTORS

The efficacy of levodopa in long-term treatment has still not been sufficiently demonstrated. In this study 126 parkinsonians have been treated for a minimum of 12 and a maximum of 36 months. The patients were evaluated clinically at regular intervals according to a protocol. The maximal therapeutic effect was achieved after 6 months of treatment. The patients with a slight to moderate degree of disease showed the best response to treatment. 13.6 per cent of the patients continued to improve after 1 year of treatment, and all these patients had a short history of the disease. Patients treated with thalamotomy prior to levodopa treatment showed a less favourable late prognosis. Based on information from the patients' relatives satisfactory treatment was achieved in ? of the patients. 10 patients reported subjective improvement although no definite therapeutic effect was observed. 92 per cent of all patients who had been treated a minimum of 12 months showed a beneficial response further on in the course of the treatment. Nausea and vomiting declined, whereas involuntary movements increased with the length of the treatment and were observed in 80 per cent of the patients at the last registration. Serious mental disturbances occurred in 26 per cent of the patients. 12 per cent of the patients developed akinesia paradoxica during the treatment. The major problem yet to be solved is the alleviation of the adverse effects of mental disturbance and hyperkinesia.     

A double-blind controlled pilot study of plasma exchange versus sham apheresis in chronic progressive multiple sclerosis

Twenty patients with chronically progressive multiple sclerosis (MS) were randomised in a double-blind controlled study to assess the efficacy of plasma exchange therapy. All patients were immunosuppressed with prednisone and azathioprine and underwent either plasma exchange or sham apheresis. The 10 patients in each group were similar in age, sex, duration of disease and degree of disability. Clinical and laboratory responses were assessed immediately following the course of exchange or sham therapy, and 3 to 6 months later, by individuals blinded to the type of therapy administered. Although modest improvement was suggested on clinical examination in 7 of 10 patients exchanged and 3 of the 10 sham treated group, this was transient and was not accompanied by any change in disability status scores. No differences in abnormal laboratory investigations were demonstrable between the two patient groups following therapy. We conclude that plasma exchange therapy using this protocol is unlikely to be of clinical benefit as an adjunct in the management of chronically progressive M.S.     

Heat-shock protein-70 genes and response to antidepressants in major depression

In the search of predictors of antidepressant efficacy, much interest has recently focused on pro-inflammatory proteins, as they were found to be elevated during major depressives states and decreased by antidepressant drugs. In the present paper we investigated the role of the genes coding for heat-shock-70 family proteins, recently hypothesized to be activated by antidepressants and thus mediate the reduction of pro-inflammatory cytosines. One hundred and forty two hospitalised patients, affected by major depression and treated with antidepressants drugs for a major depressive episode were evaluated for depressive severity at the baseline and at the discharge and genotyped for five SNPs within the genes HSPA1L, HSPA1A and HSPA1B. Markers were not individually associated with symptom severity after treatment. Instead, we found a three markers haplotype, including SNPs within HSPA1L and HSPA1A, associated with a poorer response to antidepressant treatment (p=0.005). Single markers as well as haplotypes were not associated with other clinical features. In conclusion, genetic variants within the genes coding for HSP-70 family proteins may affect the action of antidepressants and thus their therapeutic efficacy.     

Azathioprine as a single drug or in combination with steroids in the treatment of myasthenia gravis

Summary Azathioprine (Aza) has been used alone or in combination with steroids for two groups of myasthenic patients. Positive responses were noted in 75% of patients on Aza alone and in 70% receiving the combined regimen. The clinical course of the two groups differed in terms of respiratory crisis and need for plasma exchange. With an appropriate Aza administration schedule side-effects were not a limiting factor to its use. Aza treatment induced a reduction in anti-AchR-antibody level that was correlated with clinical improvement and greatly decreased the need for steroids.     

Clinical Effects of Allopurinol on Intractable Epilepsy

We studied the clinical efficacy of allopurinol as add-on therapy in 31 patients with intractable epilepsy. When administered for a short time, allopurinol was effective in 17 patients (55%); 8 were seizure-free, 8 had 75% decrease in seizure frequency, and 1 had greater than 50% decrease. Allopurinol was most effective in patients with localization-related epilepsy, especially in secondarily generalized tonic-clonic seizures. Allopurinol was not as effective in patients with Lennox syndrome or West syndrome, or in severe myoclonic epilepsy in infants. When allopurinol was administered greater than 1 year, its initial effectiveness continued in 8 of 14 patients who exhibited initial improvement. In 2 of the remaining 6 patients, the initial improvement disappeared during the course of treatment but control was regained by increasing the dosage of allopurinol. Mild side effects were observed in 4 patients (13%): drowsiness in 3 and abdominal pain in 1. Allopurinol may be a useful antiepileptic drug (AED), and a double-blind placebo-controlled trial should be performed.     

Extraocular light therapy in winter depression: a double-blind placebo-controlled study.

BACKGROUND: It has been hypothesized that the circadian pacemaker is phase delayed in seasonal affective disorder, (SAD) winter type, and that the phase advance resulting from morning ocular light accounts for the efficacy of light therapy. Extraocular light has been reported to produce phase-shifts of the human circadian pacemaker. This allows a double-blind, placebo-controlled study of light therapy in SAD. METHODS: Twenty-nine SAD patients participated. Clinical state was measured on days 1, 8, and 15 of the protocol. From days 4 through 8, 15 patients (4 M, 11 F) received extraocular light by fiberoptic illumination, and 14 (4 M, 10 F) placebo (no light) in the popliteal fossae, from 8 AM to 11 AM. In the evenings of days 3 and 8, the salivary dim light melatonin onset (DLMO) was assessed. Patients completed daily self-ratings on mood, alertness, and sleep. RESULTS: Both conditions showed a progressive improvement of clinical state over time. Between conditions, no significant differences were observed in clinical scores, the self-ratings on mood and alertness, and in timing of the DLMO before and directly after treatment. CONCLUSIONS: The response to extraocular light therapy in SAD patients did not exceed its placebo effect. Extraocular light did not induce a phase shift of the circadian pacemaker.     

Cyclophosphamide in chronic progressive multiple sclerosis: a comparative study

No effective treatment is presently available for progressive multiple sclerosis (MS). Cyclophosphamide (CFX), a cytotoxic immunosuppressive drug widely used in systemic dysimmune diseases, has been proposed for the treatment of multiple sclerosis with different schedules and controversial results. To evaluate the safety and clinical efficacy of CFX, we compared three different treatment schedules in patients with progressive MS: induction followed by bimonthly boosters for one year (17 patients); bimonthly boosters for one year without previous induction (15 patients); and monthly boosters for one year (21 patients). Survival analysis showed that the percentage of stable patients was significantly higher in the first and third treatment schedule groups. Myelotoxicity occurred in patients treated with induction and boosters (Group A). A high incidence of broncopneumonia was observed in patients undergoing the second treatment schedule (Group B). No major effects were observed in patients treated with monthly boosters (Group C). Response to treatment was limited to secondary progressive form. This study suggests that monthly treatment with CFX might be safely administered in progressive MS patients; its clinical efficacy must be confirmed by an appropriately designed clinical trial.     

Monoclonal antibodies in inflammatory disease of the muscle and peripheral nervous system

Introduction

A significant group of neuromuscular diseases are of autoimmune origin, but the classic immunomodulatory drugs are not often effective. For this reason, there is a need to find new more effective treatments that will lead to better control of these conditions, particularly those that are usually more resistant. In the last few years, the use of monoclonal antibodies against specific antigens of lymphocyte populations or against pro-inflammatory molecules has seen a great expansion, and has been demonstrated to be a useful alternative in autoimmune diseases.An intensive search was made in Medline using the Keywords neuromuscular, myopathy, neuropathy, myasthenia, Lambert-Eaton, monoclonal antibody, rituximab, alemtuzumab, and anti-TNF-α.

Development

Clinical trials performed to evaluate the efficacy of monoclonal antibodies in neuromuscular disease are very limited and of reduced size. Thus, the experience in this field is basically limited to anecdotal cases or short series of patients on open-label treatment. The published data are encouraging, with favourable responses having been observed in patients resistant to classic treatments and in diseases that do not normally respond to the usual immunosuppressant drugs. On the other hand, it has been observed that anti-TNF-α antibodies may trigger the appearance of autoimmune neuromuscular diseases.

Conclusions

Monoclonal antibodies could be an effective alternative treatment in autoimmune neuromuscular diseases, but the favourable responses observed need to be confirmed by means of controlled clinical trials with a sufficient number of patients.     

Topiramate in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center

For the treatment of patients with chronic refractory epilepsies, information about the long-term efficacy and safety profile of any new antiepileptic drug is crucial. Topiramate has been proven to be effective in patients with refractory chronic partial epilepsies in short-term controlled clinical trials, but the long-term retention, long-term efficacy, and long-term side-effect profile have not been sufficiently investigated. We analyzed all patients who had been treated with topiramate in the Epilepsy Centre Kempenhaeghe from the introduction of the drug in the spring of 1993 up to a final assessment point in mid-2002. In total, 470 patients were identified. The data show that the clinical dose achieved was about 200mg/day, reached after approximately 6 months of treatment. Further dose escalation in the survivors was slow, with a mean dose of about 300 mg/day after 24 months of treatment. Mean titration dose is 25mg/week, but titration strategy is mostly individual and responds to patient complaints. With respect to seizure frequency, 10-15% of the patients were seizure-free at the 6-month evaluation; 4 patients achieved a 2-year remission. Retention rate was 53% after 1 year, 45% after 2 years, 38% after 3 years, and 30% after 4 years. At 4 years, almost 70% of the patients had discontinued topiramate. The main reason was adverse events, which accounted for about 65% of the discontinuations. Behavioral side effects were dominant, with mental slowing (27.6%), dysphasia (16.0%), and mood problems (agitation: 11.9%) being the most frequently reported side effects. In about 10% of the patients side effects led to discontinuation despite the obvious favorable effects on seizure frequency. Comparisons between the patients who discontinued topiramate treatment and those who continued topiramate showed that discontinuation was associated with comedication (vigabatrin and lamotrigine). Our conclusion is that TPM is associated with a high incidence of side effects in clinical practice, affecting long-term retention. Meaningful prognostic factors that may help us in clinical decision making, i.e., to prevent the side effects or to help us identify those at risk, have not been found.     

阿米三嗪-萝巴新对缺血性卒中恢复期患者的疗效

目的　评估阿米三嗪 萝巴新对缺血性卒中后功能恢复的疗效。方法　采用多中心、随机、双盲、安慰剂对照研究。缺血性卒中后 1个月患者 ,随机服用阿米三嗪 萝巴新或安慰剂每日 2片 ,共服 3个月。每个月随诊 1次 ,以巴氏指数 (BI) ,神经功能缺损量表 (NFDS)和长谷川痴呆量表(HDS)作为疗效评估指标。结果　 74例最终完成了 3个月随访 ,其中药物组 38例 ,安慰剂组 36例。巴氏指数在治疗后 1、2、3个月药物组均优于安慰剂组 (P <0 0 5 ) ;神经功能缺损量表分在治疗第 1个月药物组 (6 7± 4 7)优于安慰剂组 (9 6± 6 8,P =0 0 34<0 0 5 ) ,第 2、3个月两组无显著性差异 ;长谷川痴呆量表分在治疗 1、2、3个月均无显著性差异。阿米三嗪 萝巴新的不良反应发生率为 7 9% ,安慰剂组为 2 7% ,主要表现为头晕、失眠 ,并不影响患者继续治疗。结论　阿米三嗪 萝巴新在一定程度上加快缺血性卒中后患者神经功能恢复 ,不良反应少     

Agitation observed during treatment with newer hypnotic drugs

Side effects involving agitation, e.g., sleepwalking, anger, and panic, were observed in 10 insomniac patients treated with temazepam or triazolam but not other benzodiazepines. Each patient described these side effects as uncharacteristic. Milder agitation was observed in 2 cases. In 4 cases, these effects were doubted by the prescribing physician. This type of side effect has been only slowly recognized for other benzodiazepines and has not been much reported for these newer agents. Agitation observed during treatment with these agents may be related to their short elimination half-lives.     

Effect of flumazenil on the electroencephalogram of patients with portosystemic encephalopathy. Results of a double blind,randomised, placebo-controlled multicentre trial

The efficacy of the benzodiazepine antagonist flumazenil has been assessed clinically in a double blind, randomised, placebo-controlled multicentre study in patients with grade I–III portosystemic encephalopathy. In an ancillary study reported here the effect of flumazenil on the electroencephalogram (EEG) was analysed in 32 patients who had EEG grading according to protocol. Following the baseline observation period, patients were randomised to receive (at 1 min interval) 3 sequential bolus injections of flumazenil (0.4, 0.8 and 1 mg) or placebo followed by infusions of flumazenil (1 mg/h) or placebo for 3 h. Patients were monitored for 5 h after infusion. A positive response was defined as 1 point improvement in EEG grade. After independent analysis of the EEG gradings 5 out of 17 (29%) flumazenil treated patients showed an improvement in EEG grading (3 after bolus, 2 during follow-up) compared to 2 out of 15 (13%) placebo treated patients (1 afterbolus, 1 during follow-up) (95% confidence interval of difference: −12% to +50%). Of the 5 EEG responders after flumazenil, 3 also had an improvement in clinical PSE grading (none after bolus, 2 during infusion, 1 during follow-up), compared to neither of the 2 EEG responders after placebo. EEG responders did not differ from non-responders with respect to Child-Pugh score, basal EEG, PSE grade and positivity for benzodiazepines. In conclusion, treatment perspectives for flumazenil in portosystemic encephalopathy appear to be present for only a minority of patients; however, this study yields no support for a major role of benzodiazepine antagonists in the treatment of hepatic encephalopathy.     

Deep brain stimulation of the subthalamic nucleus: selection of patients and clinical results

Deep brain stimulation of the subthalamic nucleus has been proved to be an effective treatment for advanced Parkinson's disease when therapeutical strategies have failed. A correct selection of candidates for surgery is fundamental to obtain a good clinical effect. In this study we present our protocol of patient selection. In addition we report the data relative to the different causes of exclusion and the clinical efficacy of the electrical stimulation of the subthalamic nucleus at 3 months and 1 year follow-up.     

9-OH risperidone response in risperidone poor responders: An open study of drug response concordance

A major topic about the pharmacotherapy of schizophrenia is the wide variability of antipsychotic effects among patients when treated with each drug, leading to the clinical judgement of a limited ‘class effect’, also for similar molecules. Paliperidone is the major metabolite of risperidone and pharmacodynamic activities are highly comparable, even though some differences have been reported. Paliperidone showed to be effective in the treatment of schizophrenia in a number of short and long term studies, however only two short term studies evaluated the differences in clinical response among patients switched from risperidone to paliperidone. The aim of this study is to evaluate, by means of a naturalistic observational follow-up, the possible concordance of clinical response to risperidone and paliperidone. Thirty-one patients affected by schizophrenia treated with risperidone and showing poor clinical response were enrolled in the study. Patients were switched to paliperidone and assessed for psychopathology, cognition, general functioning, extrapyramidal tolerability and attitude towards treatment at baseline and after 2, 6 and 12 weeks of treatment. The repeated measures analysis showed an overall significant improvement on several domains after 12 weeks of treatment (Table 1). Remarkably over 40% of patients showed a non-concordant clinical response to paliperidone and risperidone. In conclusion, this naturalistic observation suggests that paliperidone and his mother drug, risperidone may show significant differences both in efficacy and tolerability at individual level. Reasons for this should be looked for at biological levels not necessarily involving the receptor affinity and pharmacological activity profile.     

Filling the evidence gap: how can we improve the outcome of neonatal encephalopathy in the next 10 years?

Neonatal encephalopathy associated with perinatal hypoxia-ischaemia is one of the most common causes of death and permanent disability worldwide. However, of a wide range of “experimentally neuroprotective treatments” invented so far, only therapeutic hypothermia has been promoted into a standard clinical practice. Such a wide gap in the efficacy of neuroprotective treatments between the experimental setting and clinical practice may be attributed to the strategic flaw in translating basic knowledge into clinical care. When previous clinical studies are carefully reviewed, one may notice that few therapeutic options were chosen based on their track records in experimental studies; protective effects of some drugs had been assumed only based on their pharmacokinetics in adult species; several therapies were chosen merely because clinicians were familiar to these treatments for other purpose; some other therapies were imported too preliminarily from laboratory to clinical practice, potentially ignoring the difference in physiological and pathological backgrounds between rodent models and human patients. When further clinical trials are planned, it is important to ask whether (i) the treatment is supported by pharmacokinetics specific to immature brain, and (ii) the neuroprotective effect of the treatment has consistently been demonstrated using clinically relevant models and study designs. The use of translational large animal models allows the practical simulation and fine-tuning of clinical protocols, which may further assist successful translation of basic knowledge. In addition to the effort to develop alternative therapeutic options, it is important to maximise the effect of the current only neuroprotective option, or therapeutic hypothermia. Independent variables which influence the efficacy of hypothermia have to be elucidated to improve its therapeutic protocol, and to increase the number of patients who will benefit from this treatment.     

Duloxetine in the treatment of generalized anxiety disorder

Duloxetine, a medication with effects on both serotonin and noradrenaline transporter molecules, has recently been approved for the treatment of generalized anxiety disorder. The evidence for its efficacy lies in a limited number of double blind, placebo controlled comparisons. Statistically significant improvements in the Hamilton Anxiety Rating Scale from baseline were demonstrated in all studies at doses of 60 to 120 mg per day. The significance of such changes in terms of clinical improvements compared to placebo is less certain, particularly when the effect size of the change is calculated. In comparative trials with venlafaxine, duloxetine was as effective in providing relief of anxiety symptoms. In addition to improvements in clinical symptoms duloxetine has also been associated with restitution of role function as measured by disability scales. Duloxetine use is associated with nausea, dizziness, dry mouth, constipation, insomnia, somnolence, hyperhidrosis, decreased libido and vomiting. These treatment emergent side effects were generally of mild to moderate severity and were tolerated over time. Using a tapered withdrawal schedule over two weeks in the clinical trials, duloxetine was associated with only a mild withdrawal syndrome in up to about 30% of patients compared to about 17% in placebo treated patients. Duloxetine in doses of up to 200 mg twice daily did not prolong the QTc interval in healthy volunteers. Like other agents with dual neurotransmitter actions duloxetine reduces the symptoms of generalized anxiety disorder in short term treatments. Further evidence for its efficacy and safety in long term treatment is required.     

Efficacy of Clobazam as Add-On Therapy in Patients with Refractory Partial Epilepsy

PURPOSE: Clobazam (CLB) has an important antiepileptic effect and is less expensive than the new antiepileptic drugs (AEDs), but still has not been considered as first-line drug in the treatment of epilepsy. We evaluated the efficacy of CLB as add-on therapy in patients with refractory partial epilepsy. METHODS: This was an open, retrospective study, conducted at the epilepsy clinic of our university hospital. All patients had chronic epilepsy and were being evaluated for epilepsy surgery. CLB was introduced as add-on therapy (starting with 10 mg/ day) in patients with previous failure of at least two AEDs. Information was obtained from clinical notes and follow-up visits. RESULTS: We evaluated 97 patients, 37 men and 60 women. Ages ranged from 15 to 70 years (mean, 35.8 years). Etiology of epilepsy was hippocampal atrophy in 67 (69%), cortical dysgenesis in nine (9.3%), and other etiologies in nine (9.3%). In 12 (12.3%) patients, the etiology of epilepsy was not identified despite clinical and neurologic investigation. Patients used CLB for a period ranging from 1 month to 7 years and 9 months (mean, 16.7 months) with doses ranging from 10 to 60 mg/day (mean, 29.7 mg/day). Seven (7.2%) patients were seizure free, 48 (49.4%) had > or =50% of improvement in seizure control, 39 (40.2%) had <50% of improvement in seizure control, and in three (3.1%), no data were available. CONCLUSIONS: We conclude that CLB may have efficacy equivalent to that of the new AEDs when used as add-on therapy in patients with refractory epilepsy. CLB should be considered an economic alternative in the treatment of patients with refractory epilepsy.     

Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. The Canadian Vigabatrin Study Group.

Vigabatrin (VGB) is a novel antiepileptic drug effective as adjunctive therapy in patients with partial seizures. In this study, the efficacy and tolerability of VGB as adjunctive therapy were evaluated in patients with refractory epilepsy. Adult patients with a definite diagnosis of complex partial seizures and/or partial seizures secondarily generalized were recruited from 10 Canadian centres. Patients were randomized to receive either active medication or placebo in a double- blind fashion and entered a 36-week titration and maintenance phase with regularly scheduled visits. Both efficacy parameters and safety assessments were monitored. Clinical laboratory, evoked potential studies, MRI, and neuropsychological tests were also performed. Forty-eight percent of VGB-treated patients vs. 26 percent of placebo-treated patients had a 50 percent or greater reduction in the frequency of complex partial seizures and partial seizures secondarily generalized. Vigabatrin was well tolerated by the majority of patients. Minor neurological side effects were observed in a number of patients in both treatment groups. No serious systemic toxicity was observed. No changes in evoked potential studies or MRI findings were noted. Vigabatrin was found to be an effective and well-tolerated antiepileptic drug when used as adjunctive therapy in patients with difficult to control complex partial seizures and for partial seizures secondarily generalized. Vigabatrin is a selective irreversible inhibitor of the GABA- degradating enzyme GABA transaminase and has shown efficacy in a number of clinical trials in patients with difficult to control partial seizures. Vigabatrin has been found most effective against complex partial and secondarily generalized tonic-clonic seizures in both adults and children. Vigabatrin has also been shown to reduce infantile spasms secondary to various aetiologies and is most effective in spasms associated with tuberous sclerosis. The aim of this study was to further extend the clinical experience with VGB as adjunctive therapy in the treatment of adult patients with difficult to control complex partial seizures and/or partial seizures secondarily generalized. In addition to the assessments of efficacy and tolerability to VGB, neuropsychological evaluations were also carried out.     

Ultrasound-Guided Botulinum Toxin Type A Salivary Gland Injection in Children for Refractory Sialorrhea: 10-Year Experience at a Large Tertiary Children's Hospital

BackgroundSialorrhea is problematic for neurologically impaired children, and botulinum toxin A salivary gland injection has been reported as effective in reducing sialorrhea. This article assesses the success and safety of ultrasound-guided weight-based botulinum toxin A injection for the management of sialorrhea in children.MethodsA total of 111 patients (63 males; 48 females; average age 7 years) with refractory sialorrhea were treated with ultrasound-guided botulinum toxin type A salivary gland injections (144 procedures) from July 1, 2004, to July 1, 2014, using a single weight-based protocol. Patient history, procedural records, and clinical follow-up documents were retrospectively reviewed. Clinical data were compared with reported effectiveness and complications using odds ratios.ResultsA total of 144 procedures were performed in 111 patients with refractory sialorrhea. Cerebral palsy was the most common underlying etiology for sialorrhea (29%), whereas others included encephalopathy (5%), anoxic brain injury (4%), and a variety of chromosomal anomalies (5%). There was a 100% technical success rate. Overall treatment effectiveness was 68%. Repeat injections were not associated with increased clinical success. No procedure-related deaths or major complications were identified; the minor complication rate was less than 2%.ConclusionsThe protocol used for ultrasound-guided injection of botulinum toxin A proved to be safe and effective in children suffering from sialorrhea. Image guidance technique may lead to a reduction in rates of adverse events reported in other series. Subsequent procedures do not improve upon initial efficacy.