The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: a randomized, double-blind, crossover study. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group. Treatment of multifocal motor neuropathy with high dose intravenous immunoglobulins: a double blind, placebo controlled study. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: a double blind, placebo controlled study. Multifocal motor neuropathy improved by IVIg: randomized, double-blind, placebo-controlled study. Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double-blind, placebo-controlled study. Double-blind, placebo-controlled study of vigabatrin (gamma-vinyl GABA) in drug-resistant epilepsy. A randomised clinical trial comparing interferon-alpha and intravenous immunoglobulin in polyneuropathy associated with monoclonal IgM. The IgM-associated Polyneuropathy Study Group. Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy.
We report a double-blind, placebo-controlled crossover study of lamotrigine (LTG) as add-on treatment in therapy-resistant, generalized epilepsy in children and adolescents (n = 30).
                Twenty patients had Lennox-Gastaut syndrome. Each patient acted as his or her own control. LTG and placebo were randomly added to existing antiepileptic medication (AEDs). The LTG dosage was individualized in an open phase preceding the placebo/treatment phase. Patients who responded to LTG in the open phase went on to the double-blind phase. "Responders " were defined as patients with a >50% seizure reduction or less severe seizures or both, or improved behavior or improved motor skills or both. "Nonresponders" were defined as children who showed no positive effects of LTG with plasma levels of < or = 10 microg/ml or children who had adverse events during the open phase.
                There was a clear statistically significant reduction of seizure frequency in LTG compared with placebo treatment. None of the children studied showed abnormal biochemical or hematologic findings, or changes in plasma levels of concomitantly administered AEDs.
                LTG is a well-tolerated and effective treatment in children with intractable generalized epilepsies, including those with Lennox-Gastaut syndrome. The study design allowed a double-blind placebo-controlled assessment of LTG although the participating children used 19 different AED combinations at entry. Multiple sclerosis is an autoimmune disorder characterised by the repeated occurrence of demyelinating lesions within the central nervous system. Uncontrolled studies and experimental evidence suggest beneficial effects of repeated administration of intravenous immunoglobulin (IVIg) by immunomodulating mechanisms and induction or remyelination. We aimed to investigate the efficacy of IVIg in a randomised double-blind multicentre study.
                Patients with relapsing-remitting multiple sclerosis were randomly assigned a monthly dose of IVIg (0.15-0.2 g/kg bodyweight) or placebo. Duration of treatment was 2 years. The primary outcome measures were the effect of treatment on clinical disability-measured by the absolute change in Kurtzke's expanded disability status scale (EDSS) score- and the proportion of patients with improved, stable, or worse clinical disability (> or = 1.0 grade on EDSS score).
                Of the 243 patients screened, 150 met our eligibility criteria and were randomly assigned to IVIg or placebo. Before the start of treatment two patients in the placebo group dropped out, so there were 75 patients in the IVIg group and 73 in the placebo group. Intention-to-treat analysis showed that IVIg treatment had a beneficial effect on the course of clinical disability. The EDSS score decreased in the IVIg-treated patients and increased in the placebo group (-0.23 [95% CI -0.43 to -0.03] vs 0.12 [-0.13 to 0.37], p = 0.008). In the IVIg group, the numbers of patients with improved, stable, or worse clinical disability were 23 (31%), 40 (53%), and 12 (16%) compared with ten (14%), 46 (63%), and 17 (23%) in the placebo group. Side-effects were reported in three (4%) IVIg-treated patients and in four (5%) placebo-group patients, but were not directly linked to study medication.
                Monthly IVIg is an effective and well-tolerated treatment for patients with relapsing-remitting multiple sclerosis. The effect of high dose intravenous immunoglobulin (IVIg) treatment was studied in six patients with multifocal motor neuropathy (MMN). All patients responded to treatment (0.4 g/kg for five consecutive days) in an open trial. The effect of IVIg treatment was confirmed for each patient in a single patient, double blind, placebo controlled trial. Four patients received two IVIg treatments and two placebo treatments, and two patients received one IVIg and one placebo treatment in a randomised order. Five out of six patients responded to IVIg but not to placebo. One patient responded to IVIg in the same manner as to placebo treatment. Thus IVIg treatment can lead to improvement of muscle strength in patients with MMN. Patients with a clinical diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) were randomised in a double-blind, placebo-controlled multicentre trial to investigate whether high-dose intravenous immunoglobulin treatment (IVIg) for 5 consecutive days has a beneficial effect. Fifteen patients were randomised to IVIg and 13 to placebo. In the IVIg treatment group 4 patients improved and 3 patients in the placebo group. The degree of improvement of the patients in the IVIg treatment group was no different from the patients in the placebo group. Electrophysiological studies did not show significant differences between the groups. Since a previously performed cross-over trial showed that a selected group of CIDP patients responded better to IVIg than to placebo, it is concluded that we need better criteria to select CIDP patients for treatment with IVIg. To determine the effect of IV immunoglobulin (IVIg) on neurologic function and electrophysiologic studies in multifocal motor neuropathy with conduction block (MMN).
                MMN is characterized by progressive, asymmetric, lower motor neuron weakness and is probably immune-mediated. IVIg treatment has been shown to have beneficial effects in several open-label studies and in one small controlled trial. However, larger randomized controlled studies are lacking.
                The authors recruited 16 patients with MMN. All subjects were given each of two treatments (IVIg [0.4 g/kg/d for 5 consecutive days] or placebo [dextrose or saline]) that were assigned according to a randomized, crossover design under double-blind conditions. Patients were evaluated before and about 28 days after trial treatment for subjective functional improvement, neurologic disability score, grip strength, distal and proximal compound muscle action potential amplitude, and conduction block.
                Subjective functional improvement with IVIg treatment was rated as dramatic or very good in nine patients, moderate in one, mild in one, and absent in five patients. This improvement was absent after placebo. The neurologic disability score improved by 6.7+/-3.3 points with IVIg treatment, whereas it decreased by 2.1+/-3.0 with placebo (p = 0.038). Grip strength on the weaker side was increased by 6.4+/-1.9 kg with IVIg treatment; it decreased by 1.0+/-0.8 kg with placebo (p = 0.0021). Conduction block worsened by 12.98+/-6.52 % with placebo, but improved by 12.68+/-5.62 % with IVIg treatment (p = 0.037). Conduction block was reversed in five patients with IVIg but not placebo.
                IVIg improved conduction block as well as subjective and objective clinical measures of function in patients with MMN. We conducted a double-blind, placebo-controlled, study of 19 patients fulfilling eligibility criteria for multifocal motor neuropathy with persistent conduction block. They were enrolled and divided into two groups: those who had never been treated previously with intravenous immunoglobulins (IVIg) (Group 1: 10 patients) and those who presented recurrent symptoms after previously successful treatment with IVIg (Group 2: nine patients). They were randomized prospectively to receive either IVIg or placebo at a dose of 500 mg/kg/day for 5 consecutive days, once a month for 3 months. At month 4, patients found to be responders remained on the same treatment for the 3 following months, while non-responders were switched to the alternative study drug for the 3 following months. Clinical assessment was conducted with the MRC score in 28 muscles and a self-evaluation scale (five daily motor activities scored from 0 to 5). In Group 1, nine patients completed the study, of whom initially four received IVIg and five placebo; four patients responded to IVIg (two at months 4 and 7, and a further two at month 7 after switching treatment at month 4), two patients responded to placebo at months 4 and 7, and three patients did not respond to either treatment. In Group 2, nine patients completed the study. Five patients first received IVIg and all responded at months 4 and 7. Four patients first received placebo and none responded at month 4; all were then switched to IVIg and three responded at month 7. When the 18 patients were considered together, seven out of the nine patients who received IVIg first were responders at month 4, compared with two of the nine patients who received placebo first, a difference that was statistically significant (P = 0.03). On the other hand, there was no significant difference in MRC score but a significant difference in the self-evaluation score, at month 4, between IVIg patients and placebo patients. Electrophysiological studies did not show significant differences at month 4 in motor parameters between IVIg patients and placebo patients. IgM anti-GM1 titres did not change significantly in patients treated with IVIg compared with those who received placebo, between baseline, month 4 and month 7. However, of five patients who had significantly high anti-GM1 titres (>3200) at baseline, four responded to IVIg. This trial confirms that IVIg is a promising therapeutic option for multifocal motor neuropathy. Vigabatrin (GVG) (3 g/day) and placebo were compared as an add-on to standard therapy in therapy-resistant epileptic patients using a double-blind crossover design with randomized treatment allocation. Twenty-three patients entered the trial, with four dropping out due to either increased seizure frequency following the cross-over from GVG to placebo (n = 1), intolerance to GVG therapy (n = 2), or poor seizure record (n = 1). Of the 19 patients who completed the study, 17 had partial seizures, eight of whom had secondary generalization and two who had primary generalized seizures. Compared with placebo, GVG was associated with a significant reduction in seizure frequency (p less than 0.01), with 11 of 19 patients experiencing greater than 50% reduction in weekly seizure occurrence, two showing a 25-50% reduction, four unchanged, and two showing an increase in seizures. Global efficacy ratings were greater in the GVG period for 15 patients (p less than 0.05) compared with one in whom there was no period difference and two in whom ratings were higher in the placebo period. Fourteen of the 19 patients indicated a preference for the GVG period. Adverse effects observed during GVG treatment were generally mild and consisted of drowsiness, confusion, nausea, irritability, and constipation. No clinically significant alterations in laboratory test results were observed. No treatment-related changes in plasma concentrations of concomitant antiepileptic drugs were noted. These results confirm the antiepileptic efficacy of oral GVG in refractory epileptics. The polyneuropathy associated with a monoclonal IgM directed to the myelin associated glycoprotein (MAG) is a specific entity with a putative causal link between the IgM and the neuropathy. The small benefit offered by alkylating agents or plasma exchanges in these patients justifies the search for alternative treatments.
                A 12 month multicentre, prospective, randomised, open clinical trial was carried out comparing intravenous immunoglobulin (IVIg; 2g/kg and then 1 g/kg every three weeks) and recombinant interferon-alpha (IFN-alpha; 3 MU/m2 subcutaneously three times weekly). The main end point was a clinical neuropathy disability score (CNDS) after six months of treatment. Twenty patients were enrolled; 10 were assigned to IVIg and 10 to IFN-alpha.
                At six months, one out of 10 patients treated with IVIg had a CNDS improvement of more than 20% whereas eight out of 10 patients treated with IFN-alpha had such an improvement (P=0.005). The mean CNDS worsened by 2.3 (SD 7.6) (8%) in the IVIg group whereas it improved by 7.5 (SD 11.1) (31%) in the IFN-alpha group (P=0.02). This improvement persisted after 12 months and was mainly related to an improvement of the sensory component (P=0.02) whereas the motor component was unchanged (P=0.39). Electrophysiological data did not show improvement of motor nerve conduction velocities whereas sensory nerve conduction velocities improved in the upper limbs. A decrease in the level of the monoclonal IgM was seen in two patients treated with IFN-alpha. At the end of the treatment, antibody activity to MAG was still detected in the serum of all patients.
                IVIg, as used in this study, did not improve patients with polyneuropathy and monoclonal IgM. By contrast, although its mechanism of action remains to be fully elucidated, IFN-alpha was effective in eight out of 10 patients at six months. Lamotrigine (LTG) is recognised as effective add-on therapy for focal epilepsies, but this is the first double-blind, placebo-controlled, crossover study in treatment-resistant generalised epilepsy.
                The study consisted of 2 x 8-week treatment periods followed by a 4-week washout period. Patients received doses of either 75 or 150 mg daily, depending on their concomitant antiepileptic drugs (AEDs). Long-term continuation was offered at the end of the study with open-label LTG.
                Five centres in Australia recruited 26 patients who were having absence, myoclonic, or generalized tonic-clonic seizures or a combination of these. Twenty-two patients completed the study. There was a significant reduction in frequency of both tonic-clonic and absence seizure types with LTG. A 350% decrease in seizures was observed for tonic-clonic seizures in 50% of cases and for absence seizures in 33% of evaluable cases. Rash was the only adverse effect causing discontinuation. Twenty-three of 26 opted for open-label LTG, with 20 still receiving LTG for a mean of 26 months. In these 20, 80% had > or =50% seizure reduction and five (25%) were seizure free.
                This study shows that LTG is effective add-on therapy in patients with refractory generalised epilepsies. Statistically significant reduction in seizures in both absence and tonic-clonic seizure types was seen even with low doses of LTG.
No reliable conclusions can be drawn regarding the efficacy of IVIg as a treatment for epilepsy. Further randomized controlled trials are needed.