Prospective analysis of gait characteristics in chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disorder that may lead to functional impairment, including gait abnormalities. Our aim was to analyze gait characteristics in patients with CIDP compared to healthy controls (HC). Moreover, we sought to determine changes of gait parameters after six-month follow-up period. Twenty-four patients with CIDP and 24 HCs performed basic walking task, dual-motor task, dual-mental task, and combined task using the same GAITRite system. Lower limb MRC-SS and lower limb INCAT disability score were assessed. Fourteen patients were retested after six months. Majority of gait parameters showed significant differences in all experimental conditions when compared between CIDP and HCs. The most consistent findings in CIDP were shorter stride length (SL), prolonged cycle time (CT) and double support time (DS), as well as increased variation of SL and of swing time (ST) (p < 0.05). During follow-up, INCAT improved in nine (64.3%) of 14 patients and MRC-SS improved in eight (57.1%) patients. Six-month changes of CT and its variation during combined task significantly differentiated patients with improved vs. non-improved INCAT (p < 0.05). In conclusion, patients with CIDP had slower gait with prolonged DS and with shorter SL compared to HCs. Increased variation of SL and of ST in CIDP may suggest a potential risk for instability and falls. Shorter CT duration and less CT variation during time correlated well with improvement in disability.

Prospective measurement of quality of life in myotonic dystrophy type 1.

INTRODUCTION: Generic patient reported outcome measures have had varied success in tracking QoL in myotonic dystrophy type 1 (DM1). AIM: To analyze changes of Individualized Neuromuscular Quality of Life questionnaire (INQoL) scores in clinic patients with DM1 over a 6-year period. METHOD: Patients completed the INQoL at baseline and after a 6-year period through their attendance in a neurology outpatient clinic. Severity of muscular involvement in DM1 was analyzed using the Muscular Impairment Rating Scale (MIRS). RESULTS: Ninety-nine DM1 patients completed a baseline visit. Sixty-seven of these patients were retested at an interval time. The overall INQoL score improved in our sample of patients (P<.05) as did the following subscales: myotonia (P<.05), pain (P<.05), activities (P<.01), social relationships (P<.01), and body image (P<.05). No changes were observed for the independence and emotions scales. There were no differences in mean change of INQoL scores between patients with worsened MIRS and those with no change in MIRS scale after follow-up (P>.05). CONCLUSION: Individualized Neuromuscular Quality of Life questionnaire scores improved in our cohort of DM1 patients during a 6-year period. INQoL score did not correlate with progression of muscle weakness. This must be better understood before the selection of the instrument for use in trials to measure therapeutic benefit in DM1 patients.

Extrathymic malignancies in a defined cohort of patients with myasthenia gravis.

INTRODUCTION: Myasthenia gravis (MG) may be associated with extrathymic malignancies, especially in patients with thymoma. AIM: To determine the frequency and type of extrathymic malignancies in MG patients from the Belgrade area, and to identify potential risk factors associated with tumors. PATIENTS AND METHOD: The study comprised 390 patients with MG. Different sociodemographic and clinical variables potentially associated with extrathymic neoplasms were analyzed. RESULTS: Extrathymic malignancies were present in 42 (10.8%) MG patients - 22 (52.4%) males and 20 (47.6%) females. The most frequently detected were breast (40%) and lung (40%) neoplasms. The tumors appeared with similar frequency before (45.2%) and after the onset of MG (42.9%). Significant predictors for the development of extrathymic malignancies were current age (p = 0.001) and immunoglobulin (IVIg) therapy (p = 0.021). On the other hand, current age (p=0.001), longer MG duration (p = 0.001) and generalized form of MG (p = 0.002) were significant predictors of malignancy occurring after the MG onset. CONCLUSION: Our study revealed that older MG patients, as well as those with longer duration of the disease, and those who received IVIg therapy had a higher oncogenic risk for the development of extrathymic malignancies.

Epidemiological study of adult-onset myasthenia gravis in the area of Belgrade (Serbia) in the period 1979-2008.

BACKGROUND: The aim of this study was to analyze the prevalence and incidence of adult-onset myasthenia gravis (MG) in the Belgrade population from 1979 to 2008. METHODS: Data on the number of MG patients and their basic demographic and clinical characteristics were collected from hospital records (1979-1992) and the Belgrade MG Registry (1993-2008). Incidence and prevalence were standardized by the direct method (using the world standard population). A time-trend analysis of MG incidence was performed using a linear regression model. RESULTS: During the study period 562 cases (316 women, 246 men) were registered. On December 31st, 2008, the standardized prevalence (according to the world standard population) was 188.3/1,000,000 (women: 237.8/1,000,000; men: 139.4/1,000,000). The average annual standardized incidence rate was 13.3/1,000,000 (women: 14.1/1,000,000; men: 12.2/1,000,000). The incidence rates tended to increase significantly in both sexes during the study period (y = 3.299 + 14.363x, p = 0.002). Age-specific incidence rates for women demonstrated a bimodal pattern, with the first peak in the 20- to 29-year age group and the second one in the ≥70-year group. For both genders, an increase in age-specific incidence rates was registered for all age groups, although this was significant (p = 0.001) only for an MG onset of ≥60 years of age. CONCLUSIONS: The study confirms an increase in the incidence of MG in the area of Belgrade during the study period, especially for those with MG onset after 60 years of age.

The predictive value of the presence of different antibodies and thymus pathology to the clinical outcome in patients with generalized myasthenia gravis.

OBJECTIVES: To analyze the predictive value of anti-acetylcholine receptor antibodies (anti-AChR Ab) and anti-muscle specific kinase antibodies (anti-MuSK Ab), as well as the thymus pathology to the clinical outcome in patients with generalized myasthenia gravis (MG). METHODS: We analyzed 138 patients with generalized MG, who were thymectomized and assayed for anti-AChR Ab and anti-MuSK Ab. RESULTS: Anti-AChR Ab were detected in 84% of patients, while anti-MuSK Ab were present in 36% of the AChR Ab negative patients. Severe forms of the disease were more frequent in MuSK Ab positive, compared to the AChR Ab positive and complete seronegative patients. Thymic lymphoid follicular hyperplasia (LFH) was present in 60%, thymoma in 23%, atrophic thymus in 9% and the normal thymus in 8% of patients. LFH was more frequent among women, while thymoma and atrophic thymus were more frequent in men. The younger patients mainly had LFH and normal thymus, while thymoma and atrophic thymus were more frequent in older patients. The mildest clinical presentation was present in patients with normal thymus, while severe forms of the disease were registered in the patients with thymoma. The AChR Ab positive patients had more often LFH and thymoma, while within MuSK Ab positive patients atrophic thymus was most common. CONCLUSION: The best disease outcome was observed in patients with normal thymus or LFH with anti-AChR Ab or without both types of antibodies.

Amyotrophic lateral sclerosis immunoglobulins G enhance the mobility of Lysotracker-labelled vesicles in cultured rat astrocytes.

AIM: We examined the effect of purified immunoglobulins G (IgG) from patients with amyotrophic lateral sclerosis (ALS) on the mobility and exocytotic release from Lysotracker-stained vesicles in cultured rat astrocytes. METHODS: Time-lapse confocal images were acquired, and vesicle mobility was analysed before and after the application of ALS IgG. The vesicle counts were obtained to assess cargo exocytosis from stained organelles. RESULTS: At rest, when mobility was monitored for 2 min in bath with Ca(2+), two vesicle populations were discovered: (1) non-mobile vesicles (6.1%) with total track length (TL) < 1 µm, averaging at 0.33 ± 0.01 µm (n = 1305) and (2) mobile vesicles (93.9%) with TL > 1 µm, averaging at 3.03 ± 0.01 µm (n = 20,200). ALS IgG (0.1 mg mL(-1)) from 12 of 13 patients increased the TL of mobile vesicles by approx. 24% and maximal displacement (MD) by approx. 26% within 4 min, while the IgG from control group did not alter the vesicle mobility. The mobility enhancement by ALS IgG was reduced in extracellular solution devoid of Ca(2+), indicating that ALS IgG vesicle mobility enhancement involves changes in Ca(2+) homeostasis. To examine whether enhanced mobility relates to elevated Ca(2+) activity, cells were stimulated by 1 mm ATP, a cytosolic Ca(2+) increasing agent, in the presence (2 mm) and in the absence of extracellular Ca(2+). ATP stimulation triggered an increase in TL by approx. 7% and 12% and a decrease in MD by approx. 11% and 1%, within 4 min respectively. Interestingly, none of the stimuli triggered the release of vesicle cargo. CONCLUSION: Amyotrophic lateral sclerosis-IgG-enhanced vesicle mobility in astrocytes engages changes in calcium homeostasis.

Respiratory onset in an ALS family with L144F SOD1 mutation.

Familial amyotrophic lateral sclerosis (FALS) cases linked to SOD1 mutations may sometimes present with unusual clinical features such as pure lower motor neuron involvement or sensory signs. The authors describe a FALS pedigree with the L144F SOD1 mutation in which all cases had respiratory involvement as a first symptom. Although atypical clinical features are not rare in ALS families, this is the first pedigree with respiratory-onset in three affected members. This unusual presentation led to delayed diagnosis in the proband and highlights the fact that respiratory-onset can occur in familial ALS cases carrying SOD1 mutation.

Health-related quality of life in patients with myotonic dystrophy type 1 and amyotrophic lateral sclerosis.

The aim was to assess factors that might influence health-related quality of life (HRQoL) in patients with two different neuromuscular disorders - myotonic dystrophy type 1 (DM1) and amyotrophic lateral sclerosis (ALS). A cross-sectional study was performed on 79 patients with DM1 and 74 with ALS. The HRQoL was evaluated by SF-36, Serbian version. Depressive and anxiety symptoms were assessed using the Hamilton rating scale for depression and the Hamilton rating scale for anxiety respectively. Severity of muscular involvement in DM1 was measured with MRC scale and severity of ALS with ALSFRSr score. The mean total score as well as all domain scores of SF-36 were similar in DM1 and ALS patients (p > 0.05), except that ALS patients experienced less bodily pain (p < 0.05). Depressiveness was found in 51% and marked anxiety in 38% of DM1 patients. Emotional status and severity of muscular involvement emerged as significant independent contributing factors to the total SF-36 in DMI patients (p < 0.05). Only 3% of ALS patients showed depressiveness and 4% anxiety symptoms. The factors found to contribute to HRQoL in ALS patients were severity of disease and educational level ofpatients (p < 0.05). We found significant percentage of potentially treatable emotional disturbances which together with severity of disease significantly contributed to HRQoL in DM1 patients. On the other hand, in ALS patients depressiveness and anxious symptoms were uncommon and the factors found to contribute to HRQoL were severity of disease and educational level.

Leptin and the metabolic syndrome in patients with myotonic dystrophy type 1.

OBJECTIVES: To evaluate serum leptin concentration and its relation to metabolic syndrome (MSy) in non-diabetic patients with myotonic dystrophy type 1 (DM1). MATERIALS AND METHODS: This study included 34 DM1 patients, and the same number of healthy subjects matched for age, sex and body mass index (BMI). RESULTS: DM1 patients had increased BMI and insulin resistance, and increased leptin and insulin concentrations, but the other features of MSy such as diabetes, glucose intolerance and hypertension were not detected in DM1 patients. Serum leptin levels were higher in patients with DM1 than in healthy controls (8.5 +/- 6.6 ng/ml vs 3.6 +/- 2.9 ng/ml in men, and 13.9 +/- 10.0 ng/ml vs 10.9 +/- 6.9 ng/ml in women, respectively). In DM1 patients, leptin levels correlated with BMI, fasting insulin and insulin resistance (HOMA) (P < 0.01). CONCLUSIONS: The leptin overproduction correlated with insulin resistance in DM1 patients but the significance of this finding remains unclear.

Validation of Serbian version of the disease-specific myasthenia gravis questionnaire.

AIM: The aim of this study was to validate translated and cross-cultural adapted Italian version of myasthenia gravis-specific questionnaire (MGQ) in Serbian MG patients. MATERIALS AND METHODS: The questionnaire was validated in 140 consecutive MG patients from Belgrade. In each patient association between the total MGQ score and form and severity of the disease was determined. Also, correlation between regional domain scores of MGQ and main clinical findings according to Besinger's clinical score was analyzed. RESULTS: Patients' participation in the assessment was satisfactory with excellent internal consistency and reproducibility. Total MGQ score, as well as domain scores, correlated with highly significant inverse relationship with the disease severity and clinical status of patients at the moment of completing the questionnaire. Furthermore, the bulbar domain of the questionnaire appeared more specific and sensitive than clinical history and examination. CONCLUSION: We concluded that the Serbian version of the MGQ may be useful as a measure of clinical outcome in patients with MG.

Hereditary motor and sensory neuropathy Lom type in a Serbian family.

Hereditary motor and sensory neuropathy Lom type (HMSNL), also called CMT 4D, a hereditary autosomal recessive neuropathy, caused by mutation in N-Myc downstream regulated gene 1 (NDRG1 gene), was first described in a Bulgarian Gypsy population near Lom and later has been found in Gypsy communities in Italy, Spain, Slovenia and Hungary. We present two siblings with HMSNL, female and male, aged 30 and 26, respectively in a Serbian non-consanguineous family of Gypsy ethnic origin. They had normal developmental milestones. Both had symptoms of lower limb muscle weakness and walking difficulties with frequent falls, which began at the age of seven. At the age of 12, they developed hearing problems and at the age of 15 hand muscle weakness. Neurological examination revealed sensorineural hearing loss, dysarthria, severe distal and mild proximal muscle wasting and weakness, areflexia and impairment of all sensory modalities of distal distribution. Electrophysiological study revealed denervation with severe and early axonal loss. Sensorineural hearing loss was confirmed on electrocochleography and brainstem evoked potentials. Molecular genetic testing confirmed homozygote C564t (R148X) mutation in NDRG1 gene.

Cardiac autonomic nervous system in patients with myotonic dystrophy type 1.

The purpose of the present study was to evaluate cardiac autonomic nervous system (ANS) in patients with myotonic dystrophy type 1 (DM1). The function of ANS was studied in 20 patients with DM1 and 15 healthy controls. All subjects were investigated by a battery of six cardiovascular autonomic tests and power spectral analysis of heart rate variability (HRV). Only one patient had normal autonomic function. Two (10%) patients had mild, 10 (50%) moderate and 7 (35%) severe autonomic dysfunction. Thirteen (65%) patients had vagal and 4 (20%) sympathetic hyperactivity. Seven (35%) patients had vagal and 15 (75%) sympathetic dysfunction. Eighteen (90%) patients had orthostatic hypotension. The 24-hour time domain parameters of SDNN (SD of the NN interval) and total power were significantly lower in DM1 patients than in healthy controls (p < 0.05). However, other parameters of HRV, such as SDANN (SD of the mean NN, 5-minute interval), low frequency (LF), high frequency (HF) power and the LF/HF ratio were somewhat lower in patients with DM1 than in controls, but this was not statistically significant. There was no significant relationship between autonomic dysfunction and the severity of the disease or CTG repeat length. There was also no correlation between HRV and age. Our findings suggest that sympathetic dysfunction and vagal predominance may both occur in patients with DM1.

Cyclosporine in the treatment of myasthenia gravis.

Cyclosporine A (CsA) treatment was evaluated in 52 patients with severe generalized myasthenia gravis (MG) whose illness was not controlled by anticholinesterase drugs, thymectomy, corticosteroids, and azathioprine. The efficacy of CsA treatment was expressed by mean disability score quotient (MDSQ), which was obtained by comparing mean disability score (MDS) at the beginning of the treatment with the MDS at the end of the follow-up period. For the entire group of patients MDSQ was 53.3%, indicating moderate improvement. Analyzing individual cases, eight patients (15%) did not improve, 17 (33%) showed moderate improvement, 20 (38%) showed remarkable improvement, and seven patients (14%) achieved complete remission. The most common side effects were rise of serum creatinine (seven), hypertension (two), gingival hyperplasia (two), hypertrichosis (six), myalgia (10), and 'flu-like' symptoms (10 patients). The results of this study suggest that CsA is efficacious and safe treatment in severe and resistant forms of MG.

Increased levels of the pro-inflammatory prostaglandin PGE2 in CSF from ALS patients.

Levels of the potent pro-inflammatory prostaglandin E(2) (PGE(2)) are elevated in postmortem spinal cords from patients with ALS, and inhibition of a key PGE(2)-synthesizing enzyme, cylcooxygenase-2, is neuroprotective in an in vitro model of ALS. The authors report that 82% of the patients with ALS studied had 2 to 10 times higher PGE(2) levels in CSF compared with normal control subjects. That affected areas of the CNS are inflamed in ALS supports this. CSF PGE(2) measurement may be useful in monitoring treatment for ALS.

[Diagnostic problems in patients with myasthenia gravis]. / Dijagnosticki problemi kod bolesnika s miastenijom gravis.

Myasthenia gravis (MG) is an antigen-specific autoimmune disease in which antibodies directed against nicotinic acetylcholine receptors of the postsynaptic muscle membrane (nAChR) impair neuromuscular transmission. MG is clinically characterized by abnormal muscle fatigue and weakness. The initial symptoms and signs are often unrecognized. Therefore, we analyzed the diagnostic errors and duration of diagnostic delay in patients affected with MG (n = 444) in a ten-year period (January 1, 1983-December 31, 1992) in Yugoslavia. The initial diagnosis was correct in 44.4% of patients and erroneous in 38.4%; 17.2% of patients were admitted without an initial diagnosis. The average duration of diagnostic delay was 11 months. We present the differential diagnostic difficulties in MG and discuss the principles of diagnostic strategy which may reduce the risk of diagnostic errors in MG.

Epidemiological and clinical characteristics of myasthenia gravis in Belgrade, Yugoslavia (1983-1992).

This is the first epidemiological study of myasthenia gravis (MG) in the area of Belgrade. During the survey period (1983 1992), 124 incidental cases of MG were observed, producing an average annual incidence rate of 7.1 per million population (women, 8.3; men, 5.8). Age and sex specific incidence rates for females demonstrated a bimodal pattern, with the first peak in the age group between 20 and 40, and the second peak in the age group 70-80. The age-specific rates for males showed unimodal pattern, reaching a maximum in the age group between 60 and 80. There was a tendency of more frequent disease appearance in the urban as opposed to the suburban districts. On the prevalence day, December 31, 1992, the point prevalence rate was 121.5 per million (women, 142.5; men, 98.8). Only for incidental cases, the point prevalence rate was 77.1 (women, 83.2; men, 70.4). The average annual mortality rate was 0.47 per million (females, 0.52; males, 0.42), while cumulative lethality was 5.6 (women, 5.6; men, 5.7). Most frequently initial symptoms were ocular, occurring in 58% patients. Through the period of investigation ocular symptoms were generalized in 68%, most frequently in the first 2 years (62.5%). Thymoma was confirmed in 11.3% of patients. In this group there was equal presence of both sexes, older median age at onset, and more severe clinical course of MG. Associated autoimmune disease was found in 17 out of 124 incidental cases (13.7%). The most common were thyroid diseases (7.3%). Family history of MG was recorded in 2 cases belonging to 1 family (1.6%).

Perforating branches of the middle cerebral artery. Microanatomy and clinical significance of their intracerebral segments.

Perforating branches of the middle cerebral arteries (MCA) were examined on the forebrain hemispheres of fourteen human brains. It was noticed that their intracerebral segments arose from the MCA main trunk, and its terminal and collateral (cortical) branches. They terminated in certain parts of the basal ganglia and internal capsule. The course, direction, shape, diameters and branches of these segments were examined in detail. Classification of all the vessels was made according to caliber. It was concluded that the size of lacunar infarcts depends on the caliber and ramification zone extent of the occluded perforating vessels. Diameters of the intracerebral segments of vessels ranged from 80 to 840 microns, of their terminal branches from 80 to 780 microns, and of the collateral branches from 50 to 400 microns. The average size of the ramification zone was: 41.6 X 15.5 mm for the entire perforating artery; 37.9 X 15.5 mm for the intracerebral segment; 23 X 13 mm for the terminal branches; 8.9 X 5.5 mm for larger collateral branches; and 2.6 X 1.4 mm for the smallest branches.