Abstract We analysed the parkin gene in a large consecutive series (146) of unrelated early onset Parkinson's disease (onset ⩽40 years of age) patients. Twelve cases (8.2%) had homozygous or compound ...heterozygous point mutations and/or exon rearrangements, while a single mutation was found in four subjects (2.7%). We identified eight exon rearrangements and nine point mutations, two of which were novel: c.735delT (p.C212/X224) and c.815C>G (p.C238W). Genotype–phenotype correlation revealed that parkin carriers had features similar to those of non-carrier early onset Parkinson disease patients.
Objectives—To report the long term effect of the combined treatment with high dose intravenous immunoglobulins (IVIg) and oral cyclophosphamide (CTX) in patients with multifocal motor neuropathy, and ...to determine whether the association of oral CTX in these patients may help to delay and, possibly, suspend IVIg infusions. METHODS Six patients with multifocal motor neuropathy responding to an initial course of IVIg (0.4 g/kg/day for five consecutive days) were followed up for 37 to 61 (mean 47) months. All patients were subsequently treated with periodic IVIg infusions (0.4 g/kg/day for two days at clinical worsening) and oral CTX (1-3 mg/kg/day). Improvement was assessed using the Rankin disability scale, a functional impairment scale for upper and lower limbs, and the MRC rating scale on the 20 most affected muscles. Electrophysiological and antiglycolipid antibody studies were performed before treatment, then yearly during follow up. RESULTS All patients improved during treatment and, by the end of follow up or before worsening after therapy suspension, the median Rankin (P=0.0335) and upper (P=0.0015) and lower limb (P=0.0301) impairment scores and the mean MRC (P=0.0561) score were improved. By that time the number of nerves with partial motor conduction block was reduced (P=0.0197) and antiglycolipid antibody titres had decreased in all but one patient. All patients required periodic IVIg infusions to maintain improvement but, after three to seven months of oral CTX, the interval between IVIg infusions could be progressively prolonged until, in three patients, both treatments could be stopped for up to two years before clinical worsening. The main complications, both related to oral CTX, were haemorrhagic cystitis in two patients and persistent amenorrhea in one patient. Conclusions—IVIg can induce and maintain improvement in multifocal motor neuropathy but does not eradicate the disease. Oral CTX may help to induce a sustained remission but it is not devoid of side effects and might therefore be reserved for patients with multifocal motor neuropathy who require frequent IVIg infusions to maintain improvement.
High titers of anti‐GD 1a antibodies have been found in patients with Guillain‐Barŕe syndrome or motor neuropathy. To determine the possible diagnostic relevance of these antibodies, we measured ...serum anti‐GD 1a IgG and IgM antibodies by enzyme‐linked immunosorbent assay in 195 patients with different motor syndromes and in 335 control subjects. Moderately high antibody titers (I/ 1,280‐1/5,120) were occasionally found in patients with chronic inflammatory demyelinating polyneuropathy (5%), multifocal motor neuropathy (18%), lower motor neuron disease (3.8%), or amyotrophic lateral sclerosis (1.8%) and in immunological control subjects (1.2%), while titers of 1/20,480 or higher were only found in 2 patients with Guillain‐Barri! syndrome (IgG in both) and 2 with motor neuropathy and IgMλ monoclonal gam‐mopathy improving with immunotherapy. In both motor neuropathy patients and the Guillain‐Barŕe syndrome patient who were retested during recovery, anti‐GD 1a titers decreased concomitantly with clinical improvement. High anti‐GD 1a antibody titers may be found in several motor syndromes but only markedly increased anti‐GD 1a titers are strictly associated with potentially treatable dysimmune neuropathies.
Seven consecutive patients with amyotrophic lateral sclerosis (ALS) were treated with intravenous immunoglobulins (IVIg; 0.4 g/kg per day for 5 consecutive days followed by monthly 2-day infusions at ...the same daily dosage) continued with oral cyclophosphamide (1-2 mg/kg per day), for 4-13 months (mean 8.1). Response to treatment was assessed by means of the Medical Research Council (MRC) rating scale for muscle strength on 40 muscles (10 per limb), a clinical scale for bulbar function and a modified Rankin disability scale. All patients continued to deteriorate during treatment on as regards both their MRC score and either their bulbar or Rankin score or both. The progression of the disease during treatment, expressed as the monthly variation in MRC score (mean = -2.71; SD = 1.36), was no slower than that estimated before therapy (mean = -1.81; SD = 0.93). Even if the results of this small, uncontrolled study do not permit the exclusion of an effect of IVIg on the progression of ALS, they also do not provide any evidence that this expensive form of therapy consistently slows the course of the disease.
Motor conduction block (MCB) has been used as the main diagnostic criterion in multifocal motor neuropathy (MMN). Nonetheless, no agreed definition of block currently exists; the proposed required ...percent decrement of proximal compound muscle action potential (CMAP) amplitude varies from > 20% to > 50%. The aim of this work was to evaluate, through a follow-up study of patients with MMN, the behaviour of MCB over time. The percent decrement and temporal dispersion of proximal CMAP have also been calculated in normal controls and in patients affected by amyotrophic lateral sclerosis (ALS). The results show that MCB in patients with MMN is a dynamic entity which greatly varies over time and that a > 50% CMAP amplitued reduction may well be preceded by a smaller decrement that is nonetheless indicative of focal myelin damage in the appropriate clinical context. This datum and the results obtained in the control group and in patients with ALS suggest that a reappraisal of the diagnostic criteria for MCB, in cases with clinical and electrophysiological data strongly indicative of MMN, should be considered. Since MMN is a treatable disorder, the use of the proposed less restrictive criteria for the identification of MCB could allow for a promp and more effective treatment.
We found high titers of anti-GM1 antibodies (1/1280 or more) in 3 of 14 consecutive patients (21%) with Guillain-Barré syndrome (GBS) and in 2 additional patients who developed GBS, 10-11 days after ...starting parenteral treatment with gangliosides. Antibodies were IgG in 4 patients and IgM in one, and they all bound to asialo-GM1, and, in 3, to GD1b as well. Although the clinical features in all the patients with high anti-GM1 titers fulfilled the criteria for the diagnosis of GBS and in 4 of them, proteins but not cells were elevated in cerebrospinal fluid, electrodiagnostic studies in 3 patients showed prominent signs of axonal degeneration, that in one case were confirmed by morphological studies on sural nerve biopsy. No recent antecedent infection was reported by these patients, but in 3, including patients treated with gangliosides, anti-Campylobacter jejuni antibodies were elevated. In 3 patients a consistent decrease in anti-GM1 levels was observed after the acute phase of the disease suggesting that the frequent occurrence of these antibodies in patients with GBS and their frequent association with a prominent axonal impairment may have pathogenetic relevance.
Abstract
High titers of anti‐GD 1a antibodies have been found in patients with Guillain‐Barŕe syndrome or motor neuropathy. To determine the possible diagnostic relevance of these antibodies, we ...measured serum anti‐GD 1a IgG and IgM antibodies by enzyme‐linked immunosorbent assay in 195 patients with different motor syndromes and in 335 control subjects. Moderately high antibody titers (I/ 1,280‐1/5,120) were occasionally found in patients with chronic inflammatory demyelinating polyneuropathy (5%), multifocal motor neuropathy (18%), lower motor neuron disease (3.8%), or amyotrophic lateral sclerosis (1.8%) and in immunological control subjects (1.2%), while titers of 1/20,480 or higher were only found in 2 patients with Guillain‐Barri! syndrome (IgG in both) and 2 with motor neuropathy and IgMλ monoclonal gam‐mopathy improving with immunotherapy. In both motor neuropathy patients and the Guillain‐Barŕe syndrome patient who were retested during recovery, anti‐GD 1a titers decreased concomitantly with clinical improvement. High anti‐GD 1a antibody titers may be found in several motor syndromes but only markedly increased anti‐GD 1a titers are strictly associated with potentially treatable dysimmune neuropathies.
Several studies have addressed the issue of a possible immunological involvement in the pathogenesis of amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), particularly when the ...disease was associated with cancer, lymphoma or other monoclonal gammopathies or with the presence of serum antibodies to neural antigens. The hypothesis of the existence of immunologically treatable MND was reinforced by the occasional report of MND patients responding to immune or cytostatic therapies and by the identification among those with a purely lower motor neuron syndrome (LMNS) of a motor neuropathy, presently known as multifocal motor neuropathy (MMN), which almost invariably responded to immune therapies. These observations have led to several attempts to treat patients with MND or LMNS, either idiopathic or associated with the above mentioned conditions, with a number of immune or cytostatic therapies. The aim of this review is to verify whether the available data provide enough evidence to support the concept of dysimmune MND and to justify the use in these patients of potentially harmful immune cytostatic therapies. (ALS 2001; 2 (suppl 1): S23AS30)
Several studies have addressed the issue of a possible immunological involvement in the pathogenesis of amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), particularly when the ...disease was associated with cancer, lymphoma or other monoclonal gammopathies or with the presence of serum antibodies to neural antigens. The hypothesis of the existence of immunologically treatable MND was reinforced by the occasional report of MND patients responding to immune or cytostatic therapies and by the identification among those with a purely lower motor neuron syndrome (LMNS) of a motor neuropathy, presently known as multifocal motor neuropathy (MMN), which almost invariably responded to immune therapies. These observations have led to several attempts to treat patients with MND or LMNS, either idiopathic or associated with the above mentioned conditions, with a number of immune or cytostatic therapies. The aim of this review is to verify whether the available data provide enough evidence to support the concept of dysimmune MND and to justify the use in these patients of potentially harmful immune cytostatic therapies.
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