Marco A. Chieia

The frequency of CD127low expressing CD4+CD25high T regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1) proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis

BackgroundCD4+CD25high regulatory T (TReg) cells modulate antigen-specific T cell responses, and can suppress anti-viral immunity. In HTLV-1 infection, a selective decrease in the function of TReg cell mediated HTLV-1-tax inhibition of FOXP3 expression has been described. The purpose of this study was to assess the frequency and phenotype of TReg cells in HTLV-1 asymptomatic carriers and in HTLV-1-associated neurological disease (HAM/TSP) patients, and to correlate with measures of T cell activation.ResultsWe were able to confirm that HTLV-I drives activation, spontaneous IFNγ production, and proliferation of CD4+ T cells. We also observed a significantly lower proportion of CTLA-4+ TReg cells (CD4+CD25high T cells) in subjects with HAM/TSP patients compared to healthy controls. Ki-67 expression was negatively correlated to the frequency of CTLA-4+ TReg cells in HAM/TSP only, although Ki-67 expression was inversely correlated with the percentage of CD127low TReg cells in healthy control subjects. Finally, the proportion of CD127low TReg cells correlated inversely with HTLV-1 proviral load.ConclusionTaken together, the results suggest that TReg cells may be subverted in HAM/TSP patients, which could explain the marked cellular activation, spontaneous cytokine production, and proliferation of CD4+ T cells, in particular those expressing the CD25highCD127low phenotype. TReg cells represent a potential target for therapeutic intervention for patients with HTLV-1-related neurological diseases.

Amyotrophic lateral sclerosis: considerations on diagnostic criteria

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, compromising the motor neuron, characterized by progressive muscle weakness, with reserved prognosis. The diagnosis is based on inclusion and exclusion clinical criteria, since there is no specific confirmation test. The objective of this research is to critically examine the main diagnosis instrument - El Escorial revisited, from the World Federation of Neurology (1998). Of the 540 patients with initial ALS diagnosis, either probable or definite, seen at UNIFESP-EPM, 190 underwent thorough investigation, following regular clinical and therapeutic treatment for over two years. Thirty patients (15.78%) had their diagnosis completely changed. The false-positive diagnoses were related to: early age, clinical presentation of symmetry, weakness greater than atrophy, symptomatic exacerbation. In addition, three patients with myasthenia gravis developed framework for ALS, suggesting the post-synaptic disability as a sign of early disease.

MUNIX: Reproducibility and clinical correlations in Amyotrophic Lateral Sclerosis

OBJECTIVE To study the reproducibility, diagnostic yield to detect denervation, and clinical correlations of the Motor Unit Number Index (MUNIX) in subjects with Amyotrophic Lateral Sclerosis (ALS). METHODS MUNIX evaluation was performed in three muscles twice on the same day to assess reproducibility. Cut-off values for the MUNIX were based on data from 51 healthy subjects (controls) to evaluate the sensitivity of the technique to detect denervation in 30 subjects with ALS. RESULTS The method had good reproducibility. The variability was greater in the ALS group. In 23 ALS subjects (77%), low MUNIX values were detected. Most of the muscles with low MUNIX had also low compound muscle action potential (CMAP) and strength, but these parameters were normal in 9% of muscles. According to ROC curve analysis, MUNIX was generally accurate (AUC=0.9504) for discriminating between healthy individuals and subjects with at least one denervated muscle. CONCLUSIONS MUNIX variability was higher in the ALS group. The method showed good diagnostic performance for the detection of denervation in a sample of patients with ALS. SIGNIFICANCE This study demonstrated that in addition to being a quantitative tool MUNIX can detect denervation in subjects with ALS.

LATE-ONSET HEXOSAMINIDASE A DEFICIENCY MIMICKING PRIMARY LATERAL SCLEROSIS

The GM2 gangliosidosis are a group of metabolic disorders in which deficiency of a lysosomal enzyme, hexosaminidase A (Hex A), leads to an abnormal intracellular accumulation of lipids in neurons and glia. Total deficiency is responsible for a fatal infantile disorder, Tay-Sachs disease, characterized by involution in motor abilities, hypotonia, seizures and cortical blindness, with death around 5 or 6 years-old. Partial deficiency of enzyme activity is associated with a variety of late-onset (teenagers and young adults) neurological phenotypes, characterized by upper and lower motor neuron signs, cerebellar disturbances, parkinsonism, and psychosis or dementia in different combinations. Macular cherry red spots, which are typical for Tay-Sachs, are not apparent in these patients. All of the GM2 gangliosidosis subtypes are inherited in an autosomal recessive fashion and the differences in age at onset and disease course may be partly attributed to the underlying Hex A gene defect. Patients with infantile onset tend to be homozygous or compound heterozygote for severe, deleterious (“null”) alleles, whereas patients with late-onset disease have a combination of one severe and another allele associated with residual Hex A activity. Late onset GM2 gangliosidosis (LOGM2) is commonly included in the differential diagnosis of amyotrophic lateral sclerosis (ALS), due to the involvement of anterior horn cell, causing weakness, atrophy, cramps and fasciculations. We report a patient with unusual clinical features of isolated upper motor neuron (UMN) involvement, resembling primary lateral sclerosis (PLS).

Clinical and genetic basis of familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis represents the most common neurodegenerative disease leading to upper and lower motor neuron compromise. Although the vast majority of cases are sporadic, substantial gain has been observed in the knowledge of the genetic forms of the disease, especially of familial forms. There is a direct correlation between the profile of the mutated genes in sporadic and familial forms, highlighting the main role of C9orf72 gene in the clinical forms associated with frontotemporal dementia spectrum. The different genes related to familial and sporadic forms represent an important advance on the pathophysiology of the disease and genetic therapeutic perspectives, such as antisense therapy. The objective of this review is to signal and summarize clinical and genetic data related to familial forms of amyotrophic lateral sclerosis.

Conjugal amyotrophic lateral sclerosis in Brazil

UNLABELLED The origin of amyotrophic lateral sclerosis (ALS) remains unknown, although it seems to be multifactorial. The role of environmental factors has been frequently investigated and suspicion of its influence can be obtained when clusters of a rare disease are described. OBJECTIVE To describe conjugal cases of ALS in Brazil. METHOD We describe 2 couples in which both spouses were affected by ALS. Both couples had lived in southeast Brazil and were married for at least 20 years. RESULTS There was a great variability in clinical presentation of ALS in our patients. In both couples the interval between disease onsets was short. No precise environmental factors could be identified at the origin of these conjugal cases. CONCLUSION The occurrence of ALS in couples living in the same area may be epidemiologically important, but we cannot exclude that cases may be due to a chance association.

Restless leg syndrome exacerbated by amytriptiline in a patient with Duchenne Muscular Dystrophy

We report an unusual case of a Duchenne Muscular Dystrophy(DMD) patient who initiated a restless leg syndrome after the use of amytriptiline. The prescription and use of this medication for patients with persistent neuropathic pain is relatively common, especially for patients with DMD. Normally, this medication is well tolerated, however, we now report the occurrence of an induction or intensification of a restless leg syndrome case in a young patient with DMD, treated with amytriptiline for his chronic pain.

Treatment of sleep central apnea with non-invasive mechanical ventilation with 2 levels of positive pressure (bilevel) in a patient with myotonic dystrophy type 1

We are reporting a case of a 29 year-old female with diagnosis of myotonic dystrophy type 1 (Steinert’s disease) with excessive daytime sleepiness, muscle fatigue, snoring, frequent arousals, non-restorative sleep, and witnessed apneas. Pulmonary function tests revealed a mild decrease of forced vital capacity. Nocturnal polysomnography showed an increase of apnea/hypopnea index (85.9 events/h), mainly of central type (236), minimal oxygen saturation of 72%, and end-tidal carbon dioxide values that varied from 45 to 53 mmHg. Bi-level positive airway pressure titration was initiated at an inspiratory pressure (IPAP) of 8 and an expiratory pressure (EPAP) of 4 cm H2O. IPAP was then gradually increased to eliminate respiratory events and improve oxygen saturation. An IPAP of 12cm H20 and an EPAP of 4cm H2O eliminated all respiratory events, and the oxygen saturation remained above 90%. Bi-level positive airway pressure treatment at spontaneous/timed mode showed an improvement in snoring, apneas, and Epworth sleepiness scale decreased from 20 to 10. This case illustrates the beneficial effects of Bi-level positive airway pressure support in central sleep apnea syndrome of a patient with myotonic dystrophy type 1.

New findings in facial-onset sensory and motor neuronopathy (FOSMN) syndrome

Facial-onset sensory and motor neuronopathy (FOSMN) syndrome represents a rare, slowly progressive, lower motor neuron disease with sensory compromise, involving mainly the face, bulbar region and upper limbs. However, non-motor symptoms and neurogenetic studies have rarely been evaluated in large case series. In the present study, 10 unrelated Brazilian patients with FOSMN syndrome underwent extensive clinical, laboratory, neurophysiological and neurogenetic assessment. Median age at symptom onset was 52.1 years, and men and women were equally affected. Patients presented with hemifacial or bilateral facial paresthesia and weakness, which evolved with dysphagia, dysphonia, and facial and tongue atrophy and, finally, a dropped-head, upper limb weakness and syringomyelia-like sensory disturbances in the upper limbs. All 10 patients showed chronic diffuse neurogenic compromise of bulbar, cervical and thoracic myotomes, and abnormal blink reflex tests. A positive family history of neurodegeneration was identified in six cases, and revealed pathogenic gene variants in three families (involving VCP, TARDBP and CHCHD10). Thus, our case series has revealed new findings regarding FOSMN syndrome: (i) its clinical course is not always benign, with poorer prognoses associated with dropped-head syndrome and early bulbar compromise; (ii) FOSMN syndrome may be part of a complex familial neurodegenerative spectrum; and (iii) a definite genetic basis may be observed in some cases.

Letter re: Acute intermittent porphyria-related leukoencephalopathy

We read with interest the article by Kevelam et al.1 Current neurogenetic knowledge continues to grow with new genotypes associated with classical clinical syndromes and new phenotypes associated with shocking genetic and metabolic mechanisms, especially in inherited neurometabolic disorders and leukodystrophies. The authors defined a new clinical spectrum of neurologic phenotypes associated with mutations in the HMBS gene,1 which can be summarized as follows: (1) autosomal dominant acute intermittent porphyria2; (2) autosomal recessive severe encephalopathy with early childhood fatality3; (3) autosomal recessive early-onset leukodystrophy with spastic ataxia and optic atrophy.1