Spinal Cord Gray and White Matter Damage in Different Hereditary Spastic Paraplegia Subtypes.

BACKGROUND AND PURPOSE: Spinal cord damage is a hallmark of hereditary spastic paraplegias, but it is still not clear whether specific subtypes of the disease have distinctive patterns of spinal cord gray (GM) and white (WM) matter involvement. We compared cervical cross-sectional GM and WM areas in patients with distinct hereditary spastic paraplegia subtypes. We also assessed whether these metrics correlated with clinical parameters. MATERIALS AND METHODS: We analyzed 37 patients (17 men; mean age, 47.3 [SD, 16.5] years) and 21 healthy controls (7 men; mean age, 42.3 [SD, 13.2] years). There were 7 patients with spastic paraplegia type 3A (SPG3A), 12 with SPG4, 10 with SPG7, and 8 with SPG11. Image acquisition was performed on a 3T MR imaging scanner, and T2*-weighted 2D images were assessed by the Spinal Cord Toolbox. Statistical analyses were performed in SPSS using nonparametric tests and false discovery rate-corrected P values < .05. RESULTS: The mean disease duration for the hereditary spastic paraplegia group was 22.4 [SD, 13.8] years and the mean Spastic Paraplegia Rating Scale score was 22.8 [SD, 11.0]. We failed to identify spinal cord atrophy in SPG3A and SPG7. In contrast, we found abnormalities in patients with SPG4 and SPG11. Both subtypes had spinal cord GM and WM atrophy. SPG4 showed a strong inverse correlation between GM area and disease duration (ρ = -0.903, P < .001). CONCLUSIONS: Cervical spinal cord atrophy is found in some but not all hereditary spastic paraplegia subtypes. Spinal cord damage in SPG4 and 11 involves both GM and WM.

Sensory neuronopathy is a specific and disabling neurological manifestation of autoimmune hepatitis.

BACKGROUND AND PURPOSE: Neurological manifestations have been identified in the context of autoimmune hepatitis (AIH). Previous case reports highlighted the association between AIH and sensory neuronopathy (SN). Despite that, little is known about the frequency of AIH-related SN and its clinical/neurophysiological profile. Moreover, it is not clear whether SN is an AIH-specific manifestation or related to chronic liver damage. METHODS: Seventy consecutive AIH patients were enrolled and their characteristics were compared with 52 consecutive patients with chronic active hepatitis B. All subjects underwent clinical and neurophysiological evaluation. Further comparisons were performed between AIH SN and AIH non-SN patients. RESULTS: Mean ages and male:female proportions in the AIH and chronic active hepatitis B groups were 42.2 ± 16.3/51.7 ± 13.6 years and 14:56/29:23, respectively. The frequencies of carpal tunnel syndrome, radiculopathy and polyneuropathy were similar between groups. In contrast, SN was identified only in AIH patients (5/70 vs. 0/52, P = 0.04); the overall prevalence of AIH-related SN was 7% with an average profile of a woman in her 40s with asymmetric onset of sensory deficits that chronically evolved to disabling proprioceptive ataxia associated with marked dysautonomia. Neurological disability and hepatocellular damage did not follow in parallel. Anti-fibroblast growth factor receptor type 3 antibodies were found in 3/5 (60%) of the patients with AIH-related SN. Clinical or demographic predictors of SN in the context of AIH could not be identified. CONCLUSION: Sensory neuronopathy, but not other peripheral nervous system diseases, is a specific AIH neurological manifestation. It is often disabling and, in contrast to hepatocellular injury, does not respond to immunosuppression.

Autonomic dysfunction in hereditary spastic paraplegia type 4.

BACKGROUND AND PURPOSE: SPAST mutations are the most common cause of hereditary spastic paraplegia (SPG4-HSP), which is characterized by progressive lower limb weakness, spasticity and hyperreflexia. There are few studies about non-motor manifestations in this disease and none about autonomic involvement. Therefore, the aim was to determine the frequency and pattern of autonomic complaints in patients with SPG4-HSP, as well as to determine the clinical relevance and the possible factors associated with these manifestations. METHODS: Thirty-four molecularly confirmed SPG4 patients were recruited in a multicenter cross-sectional study, of whom 26 underwent detailed neurophysiological testing (heart rate variability, sympathetic skin response and the Quantitative Sudomotor Axonal Reflex Test). The Scales for Outcomes in Parkinson's Disease - Autonomic Questionnaire (SCOPA-AUT) was applied to quantify the severity of autonomic symptoms. Results were compared with 44 age- and gender-matched healthy controls using non-parametric tests. P values <0.05 were considered significant. RESULTS: In the SPG4-HSP group, there were 18 men with a mean age of 47.7 ± 12.6 years. SCOPA-AUT scores were similar between patients and controls (P = 0.238). Only the urinary domain subscore was significantly higher amongst patients (4 vs. 2.5, P = 0.05). Absent sympathetic skin response in the hands and feet was more frequent amongst patients (20% vs. 0%, P < 0.001, and 64% vs. 0%, P = 0.006, respectively). Quantitative Sudomotor Axonal Reflex Test responses were also smaller throughout all recording regions in the SPG4-HSP group. CONCLUSION: Our results indicate that SPG4-HSP patients have sudomotor dysfunction caused by damaged small post-ganglionic cholinergic fibers. Damage in SPG4-HSP extends to the peripheral nervous system.

Genetic profile of Brazilian patients with dystrophinopathies.

Different types of mutations in the DMD gene underlie Duchenne muscular dystrophies (DMD) and Becker muscular dystrophies (BMD). Large deletions and duplications are the most frequent causative genetic alterations worldwide, but little is known about DMD/BMD genetic profile in Brazil. Hence, we recruited patients with DMD and BMD from 8 neuromuscular reference centers along the country, and performed a comprehensive molecular investigation that included Multiplex Ligation-dependent Probe Amplification and Next generation sequencing (NGS) analyses. We evaluated 199 patients from 177 unrelated families: 166 with DMD, 32 with BMD and 1 1.5 years old asymptomatic patient with persistent hiperCKemia. Overall, large deletions (58.2%) followed by nonsense mutations (12.4%) and large duplications (11.3%) were the most frequent variants in Brazilian families. Large deletions were less frequent in BMD than in DMD (44.8% vs 60.8%). We identified 19 new DMD variants. Nonsense mutations were significantly more frequent in patients from northeastern region than from southern/southeastern regions of Brazil (27.7% vs 8.5%, P < .05). Genetic profile of Brazilian patients with DMD/BMD is similar to previously reported cohorts, but it is not uniform across the country. This information is important to plan rational clinical care for patients in face of the new coming mutation-specific therapies.

Phonoarticulation in spinocerebellar ataxia type 3.

Phonoarticulation is characterized by changes in resonance, diadochokinesis, prosody, sound frequency, vocal quality, and intraoral pressure. The main aim of this study was to characterize the phonoarticulation in spinocerebellar ataxia type 3 (SCA3) and correlate it with clinical and genetic factors. Thirty-one patients with SCA3 who were subjected to spontaneous speech recordings and phonoarticulatory diadochokinesis (DDK) participated in the study. Speech analyses were performed starting after 10 s of spontaneous speech, by three experienced speech therapists, using a protocol for dysarthria adapted from the Mayo Clinic. The intra-evaluator reliability was analyzed. The lower the patient's age at disease onset was, the more frequent the occurrences of monofrequency and altered speech rhythm were. Articulation, DDK, resonance, and prosody showed a moderate correlation with the number of "CAG" triplet repeats. We conclude that the phonoarticulation of patients with Machado-Joseph disease (MJD) is characterized by mixed dysarthrophonia with cerebellar and hypokinetic components, and that there is a tendency toward higher frequency of dysarthrophonia symptoms with lower age of disease onset, longer time since onset and higher number of "CAG" triplet repeats.

Non-motor symptoms in patients with hereditary spastic paraplegia caused by SPG4 mutations.

BACKGROUND AND PURPOSE: Non-motor manifestations are frequently overlooked in degenerative disorders and little is known about their frequency and clinical relevance in SPG4 hereditary spastic paraplegia (SPG4-HSP). METHODS: Thirty patients with SPG4-HSP and 30 healthy controls answered the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, Brief Pain Inventory and Beck Depression Inventory. Student's t test was used to compare groups and linear regression was used to assess correlations. RESULTS: Patients had higher fatigue scores than controls (31.0 ± 16.5 vs. 14.5 ± 16.0, P = 0.002) as well as pain (3.4 ± 2.7 vs. 1.0 ± 1.6, P = 0.001) and depression (12.7 ± 8.9 vs. 4.4 ± 3.8, P < 0.001, respectively). Fatigue was associated with depression and possibly with disease severity (P = 0.008 and 0.07, respectively). CONCLUSIONS: Fatigue, pain and depression are frequent and often severe manifestations in patients with SPG4-HSP.

MRI Texture Analysis Reveals Bulbar Abnormalities in Friedreich Ataxia.

BACKGROUND AND PURPOSE: Texture analysis is an image processing technique that can be used to extract parameters able to describe meaningful features of an image or ROI. Texture analysis based on the gray level co-occurrence matrix gives a second-order statistical description of the image or ROI. In this work, the co-occurrence matrix texture approach was used to extract information from brain MR images of patients with Friedreich ataxia and a control group, to see whether texture parameters were different between these groups. A longitudinal analysis was also performed. MATERIALS AND METHODS: Twenty patients and 21 healthy controls participated in the study. Both groups had 2 sets of T1-weighted MR images obtained 1 year apart for every subject. ROIs chosen for analysis were the medulla oblongata and pons. Texture parameters were obtained for these ROIs for every subject, for the 2 sets of images. These parameters were compared longitudinally within groups and transversally between groups. RESULTS: The comparison between patients and the control group showed a significant differences for the medulla oblongata (t test, P < .05, Bonferroni-corrected) but did not show a statistically significant difference for the pons. Longitudinal comparison of images obtained 1 year apart did not show differences for either patients or for controls, in any of the analyzed structures. CONCLUSIONS: Gray level co-occurrence matrix-based texture analysis showed statistically significant differences for the medulla oblongata of patients with Friedreich ataxia compared with controls. These results highlight the medulla as an important site of damage in Friedreich ataxia.

Cerebral cortex involvement in Machado-Joseph disease.

BACKGROUND AND PURPOSE: Machado-Joseph disease (MJD/SCA3) is the most frequent spinocerebellar ataxia, characterized by brainstem, basal ganglia and cerebellar damage. Few magnetic resonance imaging based studies have investigated damage in the cerebral cortex. The objective was to determine whether patients with MJD/SCA3 have cerebral cortex atrophy, to identify regions more susceptible to damage and to look for the clinical and neuropsychological correlates of such lesions. METHODS: Forty-nine patients with MJD/SCA3 (mean age 47.7 ± 13.0 years, 27 men) and 49 matched healthy controls were enrolled. All subjects underwent magnetic resonance imaging scans in a 3 T device, and three-dimensional T1 images were used for volumetric analyses. Measurement of cortical thickness and volume was performed using the FreeSurfer software. Groups were compared using ancova with age, gender and estimated intracranial volume as covariates, and a general linear model was used to assess correlations between atrophy and clinical variables. RESULTS: Mean CAG expansion, Scale for Assessment and Rating of Ataxia (SARA) score and age at onset were 72.1 ± 4.2, 14.7 ± 7.3 and 37.5 ± 12.5 years, respectively. The main findings were (i) bilateral paracentral cortex atrophy, as well as the caudal middle frontal gyrus, superior and transverse temporal gyri, and lateral occipital cortex in the left hemisphere and supramarginal gyrus in the right hemisphere; (ii) volumetric reduction of basal ganglia and hippocampi; (iii) a significant correlation between SARA and brainstem and precentral gyrus atrophy. Furthermore, some of the affected cortical regions showed significant correlations with neuropsychological data. CONCLUSIONS: Patients with MJD/SCA3 have widespread cortical and subcortical atrophy. These structural findings correlate with clinical manifestations of the disease, which support the concept that cognitive/motor impairment and cerebral damage are related in disease.

Dentate nuclei T2 relaxometry is a reliable neuroimaging marker in Friedreich's ataxia.

BACKGROUND AND PURPOSE: In Friedreich's ataxia (FRDA), frataxin deficiency results in iron redistribution in the dentate nuclei (DNC). Clusters of iron cause inhomogeneities in a magnetic field and result in a reduction in T2 relaxation time (T2). METHODS: T2 was prospectively evaluated in DNC, putamen, substantia nigra (SN), cerebellar white matter (CWM) and caudate and the correlation with clinical parameters was investigated. Thirty-five patients (range 9-51 years) and 44 controls (12-49 years) underwent T2 multi-echo sequence in a 3T scanner. Twenty-three patients (12-50 years) and 19 controls (14-49 years) were reassessed after 1 year. T2 was evaluated using specialized software (Aftervoxel) and severity of disease was quantified with the Friedreich Ataxia Rating Scale (FARS). RESULTS: T2 of both DNC was significantly shorter in the FRDA group at baseline (right, 58.6 ± 8.3 ms vs. 63.7 ± 8.1 ms, P = 0.013; left, 56.7 ± 7.7 ms vs. 62.6 ± 6.8 ms, P = 0.001). No significant difference was found between groups regarding the SN, putamen, CWM and caudate T2. DNC T2 values correlated with age, FARS total score and FARS III subscore on both sides. Prospectively, there was a significant reduction of T2 in FRDA patients in right and left DNC (P = 0.001 and 0.009) but not in other structures. Amongst controls, none of the regions significantly changed after 1 year. DNC T2 change over time correlated with GAA expansions and clinical deterioration (expressed by a change in FARS scores). CONCLUSIONS: DNC T2 values are abnormal in FRDA, progress over time and correlate with ataxia severity. These results strongly suggest that DNC relaxometry can be a useful neuroimaging marker in FRDA.

Zinc pharmacokinetic parameters in the determination of body zinc status in children.

BACKGROUND/OBJECTIVES: Serum or tissue zinc concentrations are often used to assess body zinc status. However, all of these methods are relatively inaccurate. Thus, we investigated three different kinetic methods for the determination of zinc clearance to establish which of these could detect small changes in the body zinc status of children. SUBJECTS/METHODS: Forty apparently healthy children were studied. Renal handling of zinc was investigated during intravenous zinc administration (0.06537 mg Zn/kg of body weight), both before and after oral zinc supplementation (5 mg Zn/day for 3 months). Three kinetic methods were used to determine zinc clearance: CZn-Formula A and CZn-Formula B were both used to calculate systemic clearance; the first is a general formula and the second is used for the specific analysis of a single-compartment model; CZn-Formula C is widely used in medical practices to analyze kinetic routine. RESULTS: Basal serum zinc values, which were within the reference range for healthy children, increased significantly after oral zinc supplementation. The three formulas used gave different results for zinc clearance both before and after oral zinc supplementation. CZn-Formula B showed a positive correlation with basal serum zinc concentration after oral supplementation (R2=0.1172, P=0.0306). In addition, CZn-Formula B (P=0.0002) was more effective than CZn-Formula A (P=0.6028) and CZn-Formula C (P=0.0732) in detecting small variations in body zinc status. CONCLUSIONS: All three of the formulas used are suitable for studying zinc kinetics; however, CZn-Formula B is particularly effective at detecting small changes in body zinc status in healthy children.

Clinical correlates of autonomic dysfunction in patients with Machado-Joseph disease.

BACKGROUND: Autonomic dysfunction is a usual feature of several neurological conditions characterized by either extra-pyramidal and/or peripheral damage, such as those seen in Machado-Joseph disease (MJD). AIMS OF THE STUDY: We used clinical evaluation and sympathetic skin responses (SSR) to assess autonomic function in a large series of patients with MJD. METHODS: A total of 50 patients were enrolled in this study and all of them had the molecular confirmation of MJD by DNA genotyping. In addition, a group of 20 control subjects was included. RESULTS: Overall, autonomic complaints were more frequent in patients than in control subjects, especially those related to the genitourinary and sudomotor systems. Eighteen patients (36%) presented abnormal SSR. Age at onset, duration of disease and length of expanded (CAG)(n) were not different between patients with and without dysautonomia. However, severe dysautonomia was significantly associated with polyneuropathic or parkinsonian phenotypes in patients with MJD. CONCLUSION: Autonomic symptoms are common, but possibly under recognized in patients with MJD; therefore, we believe that autonomic complaints should be sought in patients with MJD, especially in those with parkinsonian or polyneuropathic phenotypes.

Protective effect of locally applied carvacrol gel on ligature-induced periodontitis in rats: a tapping mode AFM study.

The aims of this study were to test a locally applied carvacrol gel and determine its efficacy preventing alveolar bone loss in experimental periodontitis in rats by regular methodology to validate applicability the atomic force microscopy (AFM) as a novel morphology method on this model. Wistar rats were subjected to ligature around second, upper-left molars. Animals were treated carvacrol gel topically (CAG), immediately after Experimental Periodontitis Disease induction for 1' three-times/day for 11 days. A vehicle gel was utilized as control. The periodontium and the surrounding gingivae were examined at regular histopathology and by AFM method; the neutrophil influx into the gingivae was also assayed using myeloperoxidase activity. The bacterial flora was assessed through culture of the gingival tissue. Alveolar bone loss was significantly inhibited by CAG group compared to the Vehicle (V) group, the carvacrol gel treatment reduced tissue lesion at histopathology, with preservation of the periodontium, coupled to decreased myeloperoxidase activity in gingival tissue and also prevented the proliferation of periodontal microorganisms and the weight loss. The GAC treatment preserved alveolar bone resorption and showed anti-inflammatory and antibacterial activities in experimental periodontitis. Topographical changes in histological sections were seen bringing into high relief the periodontal structures, being a simple and cost-effective method for periodontal evaluation with ultrastructural resolution.

Chronic acquired sensory neuron diseases.

BACKGROUND AND PURPOSE: Sensory neuron diseases (SND) represent a specific subgroup of peripheral nervous system disorders that are becoming increasingly recognized. We aimed to analyze clinical, neurophysiological, and MRI features in patients with SND. METHODS: We reviewed clinical and electrophysiological data of 20 individuals fulfilling SND criteria. Patients underwent an additional neurological evaluation and cervical spine MRI. RESULTS: Sensory neuron diseases was associated with dysimmune conditions in six, hepatitis C in one, B12 deficiency in another, and in one patient SND was related to organophosphate intoxication. In the remaining eleven, it was considered as idiopathic. Nineteen patients experienced sensory symptoms. Worse ataxia was related with longer disease duration (P = 0.02). Early CSF assessment was related to higher protein level (P = 0.008). All patients showed widespread impairment in sensory nerve action potential amplitudes. High signal intensity in the posterior columns was observed in most patients when MRI was performed more than 3 years after disease onset. DISCUSSION: Sensory neuron diseases usually presents with sensory symptoms and ataxia. A high index of suspicion is important because inflammatory changes might be more prominent initially, a period when immunotherapy could be more valuable. Early diagnosis should be based mainly on electrophysiological and clinical grounds, as MRI may be normal initially.

Guillain-Barré syndrome in the elderly: clinical, electrophysiological, therapeutic and outcome features

There are few papers devoted to geriatric Guillain-Barré (GBS) and many related issues remain unanswered. OBJECTIVE: To describe clinical, electrophysiological and therapeutic features in this age. METHOD: Clinico-epidemiological data and therapy of GBS patients older than 60 years were reviewed. Hughes scores were used to quantify neurological deficit and define outcome. RESULTS: Among 18 patients (mean age 64.8 years), 9 had evident prodrome and 80% noticed initially sensory-motor deficit. Demyelinating GBS was found in 8 and axonal in 6 subjects. There was one Miller-Fisher and 3 unclassified cases. Plasmapheresis (PFX) was single therapy in 12 patients and intravenous immunoglobulin (IVIg) in 2. Disability scores just before therapy were similar in both groups, so as short and long term outcome. CONCLUSION: Axonal GBS seems to be more frequent in the elderly and this may have prognostic implications. PFX and IVIg were suitable options, but complications were noticed with PFX. Prospective studies are needed to better understand and manage GBS in the elderly.

Publicações sobre a síndrome de Guillain-Barré (SGB) no idoso são escassas e várias questões sobre o tema estão abertas. OBJETIVO: Descrever aspectos clínico-eletrofisiológicos, terapêuticos e prognóstico no idoso. MÉTODO:Revisamos os prontuários de pacientes acima de 60 anos com SGB. A escala de Hughes foi usada para quantificar os déficits iniciais e finais. RESULTADOS: No total de 18 pacientes (média de idade 64,8 anos), 50% tiveram pródromo e 80% tiveram déficit sensitivo-motor no início. SGB desmielinizante foi encontrada em 8 pacientes, axonal em 6 e uma síndrome de Miller-Fisher. Três casos não puderam ser classificados. Plasmaférese (PFX) foi empregada isoladamente em 12 pacientes e imunoglobulina endovenosa (IVIg) em 2. A disfunção inicial nos dois grupos tratados era semelhante, assim como a evolução a curto e longo prazo. CONCLUSÃO: A forma axonal da SGB parece ser mais freqüente no idoso e isto pode ter implicações prognósticas. PFX e IVIg foram eficazes, mas complicações ocorreram apenas no grupo tratado com PFX. Estudos prospectivos são necessários para um melhor entendimento e manejo da SGB no idoso.

Focal status epilepticus as the first manifestation of paracoccidioidomycosis.

We report a 56-year old man with prolonged focal motor status epilepticus as the first clinical manifestation of paracoccidioidomycosis (PCM) and discuss this unusual presentation. We emphasize the need for a comprehensive work-up and increased awareness for central nervous system involvement in PCM, particularly in endemic areas.

Relação entre mortalidade adulta e indicadores socioeconômicos nas Regioes Metropolitanas do Brasil / Relation of adult mortality and socioeconomical data on metropolitan regions of Brazil

PURPOSE: To evaluate the association between the adult mortality, in the age range between 10 and 64 years old in 2000, and socioeconomic indicators for 16 metropolitan regions of Brazil. METHODS: From the datas of the Mortality System from the Ministry of Heath, were calculated the crude mortality rates (CMR) to all the causes of dead and sex, for the 16 metropolitan regions in Brazil. As a form of guarantee the spacial camparability, the CMR were standardized by age and sex, achieving the total mortality-standardized rates and for sex by the direct method of standardization. The correlation of Pearson was obtained for the 9 indicators and the analysis of cluster was used for the agroupment of the metropolitan regions. RESULTS: The matrix of correlation of Pearson showed significant correlation only between the TMSR, the urbanization degree and residence with rubbish collection. Three groups of metropolitan regions were identified. CONCLUSION: The analysis of agroupment identified three groups: 1--Porto Alegre, São Paulo, Vitória, Curitiba, Maceió, Rio de Janeiro e recife; 2--Florianópolis, Natal, Fortaleza, Brasília e São Luís e 3--Goiânia, Belo Horizonte, Salvador e Belém, that showed be significantly different by analysis of variance (P = 0.000).

Gabapentin-responsive idiopathic stabbing headache.

Idiopathic stabbing headache (ISH) is defined as the occurrence of short-lasting, painful jabs, restricted to the ophthalmic division of the trigeminal nerve. It is closely related to other forms of headache (such as migraine and tension-type headache) and has been reported among all age groups, including children and adolescents. As pathogenic mechanisms of the disease remain unclear, management decisions are empirical and limited to few options. Classically, indomethacin has been considered the first option, but therapeutic failure occurs in up to 35% of cases. In this setting, we report four patients with young-onset indomethacin-resistant ISH which had good responses to gabapentin and discuss the use of this drug in the presenting situation.