Nicoletta Meucci

High‐dose intravenous immunoglobulin therapy in multifocal motor neuropathy

We treated five consecutive patients with multifocal motor neuropathy (MMN) with high-dose intravenous immunoglobulin (IVIg). Four patients had increased levels of anti-asialo-GM1 IgM and two of anti-GM1 IgM as well; one patient had no reactivity. We treated them twice with 0.4 g/kg IVIg for 5 consecutive days at a 2-month interval, followed by maintenance infusions up to 6 to 12 months. All patients with high anti-asialo-GM1 had a consistent clinical improvement starting 3 to 10 days after the first IVIg course; in one patient, recovery was complete and persistent for 12 months without additional treatment, while in three patients, improvement only lasted 20 to 30 days. There was a similar improvement in these patients after the second course of IVIg which was maintained by periodic 2-day IVIg infusions. Clinical improvement in these patients was associated with a reduction of conduction block in most, but not all, motor nerves, while antibody titers were not consistently modified by treatment. There was no clinical or electrophysiologic improvement in the patient without antiglycolipid activity after 6 months of IVIg. IVIg may be a safe and effective therapy for MMN.

The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor

Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson’s disease. Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson’s disease. Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson’s disease phenotype and a broad range of onset age (34 to 73 years). Conclusions: G2019S is the most common genetic determinant of Parkinson’s disease identified so far. It is especially frequent among cases with familial Parkinson’s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson’s disease.

123I-Ioflupane/SPECT binding to striatal dopamine transporter (DAT) uptake in patients with Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy.

Abstract.We used SPECT and the tracer 123I-Ioflupane to measure dopamine transporter (DAT) binding in the caudate nucleus and the putamen of 70 patients with Parkinson’s disease (PD), 10 with multiple system atrophy (MSA-P type), and 10 with progressive supranuclear palsy (PSP). Data were compared with 12 age-matched control subjects. We found significant reductions in mean striatal values in all three forms of parkinsonism. However, decrements were significantly greater in PSP (0.51±0.39, p<0.01) compared with MSA-P (0.70±0.33) and PD (0.95±0.38). No differences were found between MSA and PD. Putamen/caudate ratios were greater in PSP (0.83±0.12, p<0.01) than in PD (0.51±0.11), suggesting a more-uniform involvement of dopamine nerve terminals in both caudate nucleus and putamen. Our results confirm that DAT binding can provide an accurate and highly sensitive measure of dopamine degeneration. PSP patients may show a different pattern of neuronal loss compared with MSA and PD.

Guillain-Barré syndrome associated with high titers of anti-GM1 antibodies

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.

Anti-GM1, IgM antibodies in motor neuron disease and neuropathy

We found anti-GM1 IgM antibodies in 23% of 56 patients with motor neuron disease (MND), in 19% of 69 patients with neuropathy, and in 7% of 107 controls with other neurologic and nonneurologic diseases. Most of these patients had anti-GM1 IgM antibody titers of 1:80 or less; slightly higher antibody titers (up to 1:640) were found in 3 patients, 1 with MND and 2 with neuropathy, and very high titers (1:20,480) in a patient with MND and an IgMμ: M protein that reacted with GM1, GD1b, and asialo GM1 Six other patients with anti-GM1 IgM had serum IgM that also bound to GD1b. Reactivity with GD1b did not correlate with anti-GM1 titers but was only present in patients with MND or neuropathy. Anti-GM1 IgM antibodies may be a normal constituent of the human antibody repertoire but their frequency and, in some cases, their levels are higher in patients with MND and neuropathy. The origin and the pathogenetic role of these antibodies in neural impairment remain to be established.

Long term effect of intravenous immunoglobulins and oral cyclophosphamide in multifocal motor neuropathy

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.

Multifocal motor neuropathy: clinical and immunological features and response to IVIg in relation to the presence and degree of motor conduction block

Objective: To determine whether patients with clinically typical multifocal motor neuropathy (MMN) with or without definite or probable conduction block (CB) differ in terms of clinical presentation, immunological findings, or response to treatment with intravenous immunoglobulin (IVIg). Methods: 23 consecutive patients were studied with the typical clinical features of MMN, consisting of a progressive multineuropathic motor impairment with minimal or no sensory loss. In 14 patients, electrophysiological studies disclosed the presence of a definite or probable CB according to the criteria proposed by the American Association of Electrodiagnostic Medicine (AAEM) in at least one motor nerve. Six patients had possible CB, defined as a degree of CB 10% less than that required by the AAEM for probable CB, while no CB was detected in three patients. Results: Patients with possible CB did not differ from those with a definite or probable CB in terms of age at disease onset (mean 38.8 v 38.2 years, respectively), distribution and severity of limb weakness, clinical impairment (mean Rankin score 2.2 in both), and frequency of antiganglioside antibodies (33% v 29%). Patients with possible CB had a longer mean disease duration (9 v 5.9 years, p < 0.05) and a less frequent consistent response to IVIg (67% v 86%) than those with a definite or probable CB. Patients without a detectable CB had a similar frequency of antiganglioside antibodies (33%) but had a longer disease duration (20.3 years), greater impairment (Rankin score 2.7), and more frequent signs of axonal degeneration (41% of examined motor nerves) than patients with CB (13–15%, p < 0.005). Only one patient without detectable CB (33%) consistently improved with IVIg. Conclusions: Patients with possible CB were clinically and immunologically indistinguishable from those with definite or probable CB, albeit with a slightly less frequent response to IVIg. This finding suggests that failure to fulfil AAEM criteria for CB in patients with otherwise clinically typical MMN should not preclude this diagnosis and consequently a treatment trial with IVIg. Whether the longer duration and greater severity of the disease and more frequent axonal impairment in patients without detectable CB than in those with CB explain their lower response to IVIg remains to be established.

Randomized study of sertraline and low‐dose amitriptyline in patients with Parkinson's disease and depression: Effect on quality of life

We assessed the effect of 3‐month treatment of sertraline (50 mg) or low‐dose amitriptyline (25 mg) on depression and quality of life in 31 patients with Parkinsons disease in a prospective single‐blind randomized study. Both drugs significantly reduced the Hamilton Depression Rating Scale (HDRS‐17) score. Completion rate was 75% for sertraline (12 of 16) and 73% for amitriptyline (11 of 15). Responder rate (HDRS‐17 score reduction ≥ 50%) was 83.3% for sertraline and 72.7% for amitriptyline. Sertraline but not amitriptyline treatment determined a significant benefit on quality of life (PDQ‐39 scale). We found no change in Unified Parkinsons Disease Rating Scale scores. However, the improvement in specific PDQ‐39 subscores (mobility, activities of daily living, and stigma) suggests that depression affects patient self‐perception of motor function and further emphasizes the need for its treatment.

Survival and dementia in GBA-associated Parkinson's disease: The mutation matters.

The objective of this work was to investigate survival, dementia, and genotype‐phenotype correlations in patients with Parkinsons disease (PD) with and without mutations on the glucocerebrosidase gene (GBA).

Clinical features and anti-neural reactivity in neuropathy associated with IgG monoclonal gammopathy of undetermined significance.

Neuropathy has been frequently reported in patients with IgG monoclonal gammopathy of undetermined significance (MGUS) but it is still unclear whether this association has clinical or pathogenetic relevance. In order to clarify the possible role of IgG MGUS in the neuropathy we correlated the clinical and electrophysiological features of the neuropathy with the duration and anti-neural activity of the M-protein in 17 patients with neuropathy and IgG MGUS. Ten patients (59%) had a chronic demyelinating neuropathy clinically indistinguishable from chronic inflammatory demyelinating polyneuropathy (CIDP) while 7 (41%) had a predominantly sensory axonal or mixed neuropathy. In 80% of patients in the CIDP-like and 28% in the sensory group the IgG M-protein became manifest several months to years after onset of the neuropathy. Antibodies to one or more neural antigens (including tubulin, a 35KD P0-like nerve myelin glycoprotein, GD1a, GM1 and chondrotin sulfate C) were found in 40% of patients with CIDP-like and 43% with sensory neuropathy but also in 37% patients with IgG MGUS without neuropathy. Neuropathy associated with IgG MGUS is probably less heterogeneous than previously considered suggesting that this association may not be merely casual. The evidence for primary pathogenetic role of IgG M-proteins in the neuropathy remains however elusive.