Reliability of clinical diagnosis of dystonia.

BACKGROUND: There is only one small single-center study on the reliability of the diagnosis of focal dystonia. The aim of this study was to assess the inter-rater reliability of dystonia diagnosis among neurologists with different professional experience. METHODS: Twenty-nine adults (18 with dystonia, 9 with other movement disorders, and 2 healthy controls) were videotaped while undergoing neurological examination and during the process of collecting information on the history of their condition. Each case was diagnosed by 35 blind raters (12 general neurologists, 21 neurology residents, and 2 experts in movement disorders) from different hospitals. Sensitivity and specificity were calculated confronting raters with the gold standard (the caring physician). Inter-rater agreement was measured by the Kappa statistic. RESULTS: Specificity and sensitivity were 95.2 and 66.7%, 76.3 and 75.2%, 84.6 and 71.6% for experts, general neurologists, and residents, respectively. Kappa values on dystonia diagnosis ranged from 0.30 to 0.46. The agreement was moderate for experts and residents (0.40-0.60) and fair for general neurologists (0.20-0.40). Kappas were the highest among experts for cranial and laryngeal dystonia (0.61-1), but not for cervical dystonia (0.37). CONCLUSIONS: The diagnosis of dystonia is difficult and only partially mirrors a physician's background.

Pilot trial of simvastatin in the treatment of sporadic inclusion-body myositis.

Sporadic inclusion-body myositis (s-IBM) is a chronic progressive inflammatory myopathy leading to severe disability. It has been suggested that statins may benefit s-IBM patients based on their pleiotropic effects on autoimmunity and possible adverse influence of increased cholesterol on muscle pathological changes. We carried out a pilot, open-label trial to evaluate safety and tolerability of oral simvastatin in s-IBM patients. Fourteen patients were treated with 40 mg of simvastatin over 12 months. Primary outcome measures included the assessment tools proposed by International Myositis Outcome Assessment Collaborative Study group and the IBM-Functional Rating Scale. As additional data, we report the results obtained from muscle MRI, biopsy and oropharyngeal scintigraphy. Ten patients completed the trial and the treatment appeared safe and well tolerated. None of the patients showed a significant clinical improvement. Outcome measures used in this study proved to be valuable tools for global assessment of s-IBM patients. At present, we cannot recommend simvastatin as a treatment for s-IBM though our data may warrant a placebo-controlled study.

Prevalence of small intestinal bacterial overgrowth in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with gastrointestinal motility abnormalities that could favor the occurrence of small intestinal bacterial overgrowth. The aim of the study was to assess the prevalence of small intestinal bacterial overgrowth in PD patients. METHODS: Consecutive PD patients were enrolled. The controls were subjects without PD. All patients and controls underwent the glucose breath test to assess small intestinal bacterial overgrowth. RESULTS: Forty-eight PD patients and 36 controls were enrolled. The prevalence of small intestinal bacterial overgrowth was significantly higher in PD patients than in controls (54.17% vs 8.33%; P < .0001; OR, 2.24; 95% CI, 3.50-48.24). Multivariate analysis showed Hoehn and Yahr stage (OR, 3.07; 95% CI, 1.14-8.27) and Unified PD Rating score (OR, 1.12; 95% CI, 1.02-1.23) were significantly associated with small intestinal bacterial overgrowth in PD patients. CONCLUSIONS: Small intestinal bacterial overgrowth is highly prevalent in PD. Gastrointestinal motility abnormalities might explain this association.

Inter-rater agreement in the assessment of response to motor and cognitive rehabilitation of children and adolescents with epilepsy.

INTRODUCTION: To assess inter-rater agreement among child neurologists and psychiatrists on evaluation of response to physical and cognitive rehabilitation of children and adolescents with epilepsy. MATERIALS AND METHODS: Five child neurologists/psychiatrists ("raters") were invited to draw 2-3 short case reports among those most commonly seen. 14 case histories were presented and raters used a structured questionnaire to report changes after selected rehabilitation programs. Response was coded as "Yes", "No", or "Uncertain" in different functional domains (Motor, Social, Alimentary, Communication, Personal Autonomy). Inter-rater agreement was measured using the kappa statistic. Raters where then asked to discuss any reason for disagreement. The test was repeated with different cases (16 case histories) adding a sixth rater, who had participated to the discussion. RESULTS: Even with this small number of cases, the agreement mostly ranged from poor to good in the first test (worse for Social, Personal Autonomy and Communication). Training improved agreement in almost all domains. There were no frank outliers. The agreement was lower with a specific approach (i.e. grouping "Uncertain" to "No") than with sensitive approach (i.e. grouping "Uncertain" to "Yes"). DISCUSSION: The interpretation of patients' response to physical and cognitive rehabilitation tends to vary among Italian child neurologists/psychiatrists depending on measures and training procedures. Discussion and training improves agreement, although this is only a pilot study conducted using a non standardized questionnaire.

Polymorphism of CAG motif of SK3 gene is associated with acute oxaliplatin neurotoxicity.

PURPOSE: There is no agreement on which channel is involved in oxaliplatin neurotoxicity, most investigators favouring voltage-gated sodium channels. However, the small conductance Ca(++) activated K(+) channels, encoded by the SK1-3 genes, are also involved in membrane excitability, playing a role in after-hyperpolarization at the motor nerve terminal. As the SK3 gene is characterized in Caucasians by a highly polymorphic CAG motif within the exon 1, we hypothesize that SK3 gene polymorphism may influence the development of acute nerve hyperexcitability in oxaliplatin-treated patients. METHODS: Patients eligible for an oxaliplatin-containing regimen were enrolled. Detailed neurological examination, nerve conduction studies and needle electromyography were performed before and after oxaliplatin administration. DNA was extracted by polymerase chain reaction, and each allele was isolated and sequenced. RESULTS: We evaluated 40 patients. After oxaliplatin administration, 28 patients developed symptoms of neurotoxicity, which were severe in 11. Patients were divided into three groups according to neurophysiological data: G0 (normal peripheral nerve excitability [PNE]), 16 patients; G1 (mild PNE), 15 patients; G2 (severe PNE), 9 patients. Genetic analysis showed different alleles ranging from 13 to 23 CAG repeats. Patients carrying alleles containing 13-15 CAG repeats experienced a significantly higher incidence of severe nerve hyperexcitability (chi-square 48.6; df 16; P = 0.0001). CONCLUSION: The results suggest that OXA-neurotoxicity may be related to distribution of the polymorphic CAG motif of the SK3 gene, which might modulate nerve after-hyperpolarization. The 13-14 CAG repeat allele could mark patients susceptible to acute OXA neurotoxicity.

Mixed connective tissue disease presenting as a peculiar myositis with poor muscle regeneration.

Mixed connective tissue disease (MCTD) is a rheumatological disease which has to be distinguished from other entities causing inflammatory myopathy. The usual clinical presentation of inflammatory myopathy associated with connective tissue disease is not different from isolated polymyositis or dermatomyositis, i.e., subacute onset of proximal weakness affecting both upper and lower girdle with high serum CK level. Here we report a patient with MCTD/myositis overlap syndrome displaying an uncommon clinical presentation and a distribution of muscle weakness involving facial, neck and arm muscles with sparing of lower limbs. We also describe the scarcity of muscle regeneration signs on the muscle biopsy with complete absence of alkaline phosphatase positivity in the endomysial and permysial connective tissue as a novel finding of this condition.

Cephalometric findings in facioscapulohumeral muscular dystrophy patients with obstructive sleep apneas.

PURPOSES: The purposes of the study are: (1) to establish if cephalometry and upper airway examination may provide tools for detecting facioscapulohumeral (FSHD) patients at risk for obstructive sleep apnea syndrome (OSAS); and (2) to correlate cephalometry and otorhinolaryngologic evaluation with clinical and polysomnographic features of FHSD patients with OSAS. METHODS: Patients were 13 adults affected by genetically confirmed FSHD and OSAS, 11 men, with mean age 47.1 ± 12.8 years (range, 33-72 years). All underwent clinical evaluation, Manual Muscle Test, Clinical Severity Scale for FSHD, Epworth Sleepiness Scale, polysomnography, otorhinolaryngologic evaluation, and cephalometry. RESULTS: Cephalometric evidence of pharyngeal narrowing [posterior airways space (PAS) < 10 mm] was present in only one patient. The mandibular planus and hyoid (MP-H) distance ranged from 6.5 to 33.1 mm (mean, 17.5 ± 7.8 mm). The mean length of soft palate (PNS-P) was 31.9 ± 4.8 mm (range, 22.2 to 39.7 mm). No patient presented an ANB angle > 7°. There was no significant correlation between cephalometric measures, clinical scores, and PSG indexes. PAS and MP-H were not related to the severity of the disease. CONCLUSIONS: Upper airway morphological evaluation is of poor utility in the clinical assessment of FSHD patients and do not allow to predict the occurrence of sleep-related upper airway obstruction. This suggests that the pathogenesis of OSAS in FSHD is dependent on the muscular impairment, rather than to the anatomy of upper airways.

Response to rehabilitation of children and adolescents with epilepsy.

One hundred fifty-six children and adolescents with epilepsy from six Italian rehabilitation units were retrospectively enrolled to define the proportion of patients with epileptogenic developmental disorders who benefit from comprehensive rehabilitation programs and to identify factors predicting treatment response. The rehabilitation programs were classified as neuromotor, psychomotor, and speech and language. For each program, the response was coded as present or absent according to the caring physician's judgment. Selected demographic and clinical variables were correlated to treatment response. Neuromotor rehabilitation was performed in 86 cases (55%), psychomotor rehabilitation in 54 cases (34%), and speech and language rehabilitation in 40 cases (26%). Response rates were 58, 74, and 90%, respectively. Independent negative predictors of treatment response included severity of functional impairment (odds ratio=0.02, 95% confidence interval=0.01-0.14) and daily seizures (odds ratio=0.22, 95% confidence interval=0.08-0.58).

Mesoangioblasts from facioscapulohumeral muscular dystrophy display in vivo a variable myogenic ability predictable by their in vitro behavior.

Facioscapulohumeral muscular dystrophy (FSHD) is the third most frequent inherited myopathy. We previously demonstrated that mesoangioblasts can be efficiently isolated from FSHD muscles, although their differentiation ability into skeletal muscle was variably impaired. This correlates with overall disease severity and degree of histopathologic abnormalities, since mesoangioblasts from morphologically normal muscles did not show any myogenic differentiation block. The aim of our present study was to verify whether mesoangioblasts from differentially affected FSHD muscles reproduce in vivo the same differentiation ability shown in vitro by studying their capability to form new muscle fibers during muscle regeneration of experimentally damaged muscles. We show that a diverse ability of FSHD mesoangioblasts to engraft and differentiate into skeletal muscle of SCID mice is strictly related to the characteristics of the muscle of origin, closely replicating in vivo what was previously observed in vitro. Moreover, we demonstrate that mesoangioblasts obtained from severely affected muscles scarcely integrate into muscle fibers, remaining mainly localized in the connective tissue. This suggests a defective migration in response to chemoattractants released by damaged fibers, as indicated by cell migration assays in response to HMGB1 and very low levels of RAGE expression, along with a decreased ability to fuse or to appropriately trigger the myogenic program. Our study indicates that FSHD mesoangioblasts from unaffected muscles can be used as selective treatment to halt muscle degeneration in severely affected muscles, and suggests that pharmacological and molecular interventions aimed to ameliorate homing and engraftment of transplanted autologous mesoangioblasts may open the way to cell therapy for FSHD patients, without requiring immunosuppression or genetic correction in vitro.

CD8(+) T cells in facioscapulohumeral muscular dystrophy patients with inflammatory features at muscle MRI.

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited disease, and although strongly suggested, a contribution of inflammation to its pathogenesis has never been demonstrated. In FSHD patients, we found by immunohistochemistry inflammatory infiltrates mainly composed by CD8(+) T cells in muscles showing hyperintensity features on T2-weighted short tau inversion recovery magnetic resonance imaging (T2-STIR-MRI) sequences. Therefore, we evaluated the presence of circulating activated immune cells and the production of cytokines in patients with or without muscles showing hyperintensity features on T2-STIR-MRI sequences and from controls. FSHD patients displaying hyperintensity features in one or more muscles showed higher CD8(+)pSTAT1(+), CD8(+)T-bet(+) T cells and CD14(+)pSTAT1(+), CD14(+)T-bet(+) cells percentages and IL12p40, IFNγ and TNFα levels than patients without muscles displaying hyperintense features and controls. Moreover, the percentages of CD8(+)pSTAT1(+), CD8(+)T-bet(+) and CD14(+)pSTAT1(+) cells correlated with the proportion of muscles displaying hyperintensity features at T2-STIR sequences. These data indicate that circulating activated immune cells, mainly CD8(+) T cells, may favour FSHD progression by promoting active phases of muscle inflammation.

Neuropathy with predominant small fiber involvement associated with abnormal anti-MAG titer.

We describe a patient with painful neuropathy associated with an abnormal anti-MAG titer in which predominant involvement of intra-epidermal nerve fiber was documented. Electrophysiological studies revealed low-borderline amplitude of sensory and compound motor action potentials registering from lower limbs and normal conduction velocity. Sural nerve biopsy disclosed only a slight loss of myelinated fiber. Skin biopsy performed at the proximal thigh and at the distal leg was consistent with a non-length-dependent small fiber neuropathy. It is likely that in this case anti-MAG antibodies played a role in the pathogenesis of small fiber neuropathy.

Substrate reduction therapy with miglustat in chronic GM2 gangliosidosis type Sandhoff: results of a 3-year follow-up.

GM2 gangliosidosis type Sandhoff is caused by a defect of beta-hexosaminidase, an enzyme involved in the catabolism of gangliosides. It has been proposed that substrate reduction therapy using N-butyl-deoxynojirimycin (miglustat) may delay neurological progression, at least in late-onset forms of GM2 gangliosidosis. We report the results of a 3-year treatment with miglustat (100 mg t.i.d) in a patient with chronic Sandhoff disease manifesting with an atypical, spinal muscular atrophy phenotype. The follow-up included serial neurological examinations, blood tests, abdominal ultrasound, and neurophysiologic, cognitive, brain, and muscle MRI studies. We document some minor effects on neurological progression in chronic Sandhoff disease by miglustat treatment, confirming the necessity of phase II therapeutic trials including early-stage patients in order to assess its putative efficacy in chronic Sandhoff disease.

Analysis of MTMR1 expression and correlation with muscle pathological features in juvenile/adult onset myotonic dystrophy type 1 (DM1) and in myotonic dystrophy type 2 (DM2).

Among genes abnormally expressed in myotonic dystrophy type1 (DM1), the myotubularin-related 1 gene (MTMR1) was related to impaired muscle differentiation. Therefore, we analyzed MTMR1 expression in correlation with CUG-binding protein1 (CUG-BP1) and muscleblind-like1 protein (MBNL1) steady-state levels and with morphological features in muscle tissues from DM1 and myotonic dystrophy type 2 (DM2) patients. Semi-quantitative RT-PCR for MTMR1 was done on muscle biopsies and primary muscle cultures. The presence of impaired muscle fiber maturation was evaluated using immunochemistry for neural cell adhesion molecule (NCAM), Vimentin and neonatal myosin heavy chain. CUG-BP1 and MBNL1 steady-state levels were estimated by Western blot. RNA-fluorescence in situ hybridization combined with immunochemistry for CUG-BP1, MBNL1 and NCAM were performed on serial muscle sections. An aberrant splicing of MTMR1 and a significant amount of NCAM-positive myofibers were detected in DM1 and DM2 muscle biopsies; these alterations correlated with DNA repeat expansion size only in DM1. CUG-BP1 levels were increased only in DM1 muscles, while MBNL1 levels were similar among DM1, DM2 and controls. Normal and NCAM-positive myofibers displayed no differences either in the amount of ribonuclear foci and the intracellular distribution of MBNL1 and CUG-BP1. In conclusion, an aberrant MTMR1 expression and signs of altered myofiber maturation were documented in both DM1 and in DM2 muscle tissues. The more severe dysregulation of MTMR1 expression in DM1 versus DM2, along with increased CUG-BP1 levels only in DM1 tissues, suggests that the mutual antagonism between MBNL1 and CUG-BP1 on alternative splicing is more unbalanced in DM1.

An Italian case of hereditary myopathy with early respiratory failure (HMERF) not associated with the titin kinase domain R279W mutation.

Hereditary myopathy with early respiratory failure (HMERF) is a rare disorder characterized by severe respiratory involvement at onset, muscle weakness starting in the early adulthood, and cytoplasmic bodies with peculiar immunohistochemical reactivity on muscle biopsy. Here we describe a patient who presented with hypercapnic coma at age 32. A detailed light and electron microscopy analysis on muscle biopsy was performed and, together with clinical data, led to the diagnosis. The R279W mutation in the TTN gene was excluded. This report expands the geographical region of incidence and encourages additional studies to clarify the genetic heterogeneity of the condition.

Long-term motor cortex stimulation for amyotrophic lateral sclerosis.

BACKGROUND: Motor cortex stimulation has been proposed for treatment of amyotrophic lateral sclerosis (ALS) and preliminary studies have reported a slight reduction of disease progression using both invasive and noninvasive repetitive stimulation of the motor cortex. OBJECTIVE: The aim of this proof of principle study was to investigate the effects of motor cortex stimulation performed for a prolonged period (about 2 years) on ALS progression. METHODS: Two patients were included in the study; the first patient was treated with monthly cycles of repetitive transcranial magnetic stimulation (rTMS) and the second one was treated with chronic epidural motor cortex stimulation. The rate of progression of the disease before and during treatment was compared. RESULTS: The treatments were well tolerated by the patients. Both patients deteriorated during treatment; however, the patient treated with rTMS showed a slight reduction in deterioration rate. CONCLUSIONS: Although we cannot be sure whether the effects observed in the patient treated with rTMS can be attributed to this form of stimulation, our study set the groundwork for possible future studies investigating the effects of rTMS, for a prolonged period, on a larger group of ALS patients.

Decreased nocturnal movements in patients with facioscapulohumeral muscular dystrophy.

STUDY OBJECTIVES: Reduced mobility during sleep characterizes a variety of movement disorders and neuromuscular diseases. Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of muscular dystrophy in the general population, and people with FSHD have poor sleep quality. The aims of the present study were to evaluate nocturnal motor activity in patients with FSHD by means of videopolysomnography and to verify whether activity was associated with modifications in sleep structure. METHODS: We enrolled 32 adult patients affected by genetically confirmed FSHD (18 women and 14 men, mean age 45.1 +/- 13.4 years) and 32 matched control subjects, (18 women and 14 men, mean age 45.5 +/- 11.4 years). Major body movements (MBM) were scored in videopolygraphic recordings in accordance with established criteria. An MBM index was calculated (number of MBM per hour of sleep). RESULTS: The FSHD group showed a decrease in the MBM index (FSHD: 1.2 +/- 1.1; control subjects: 2.3 +/- 1.2, analysis of variance F = 13.672; p = 0.008). The sleep pattern of patients with FSHD, as compared with that of controls, was characterized by longer sleep latencies, shorter sleep durations, an increased percentage of wake during sleep, and a decreased percentage of rapid eye movement sleep. In the patient group, the MBM index was inversely correlated with severity of disease (Spearman test: r30 = -0.387; p < 0.05). CONCLUSIONS: The present findings suggest that patients with FSHD have a reduced number of nocturnal movements, which is related to disease severity. Reduced movement in bed may contribute to the sleep modifications observed in these patients.