RESUMO
We report the case of a 63-year-old female with definite unilateral Ménière disease, osteoarthritis of the distal finger joints with mucous cysts and Heberden's nodes, and constipation with recurrent abdominal pain whose symptoms remitted after 6months of a restrictive gluten-free diet.
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Doença Celíaca/complicações , Dieta Livre de Glúten , Doença de Meniere/dietoterapia , Doença de Meniere/etiologia , Doença Celíaca/diagnóstico , Doença Celíaca/terapia , Feminino , Seguimentos , Glutens/efeitos adversos , Glutens/imunologia , Humanos , Pessoa de Meia-Idade , Medição de Risco , Resultado do TratamentoRESUMO
The purpose of this study was to investigate how non-verbal visual reinforcement provided by the audiologist during speech testing influences performance in the elderly. Thirty-two volunteers with age-related hearing loss with or without dual sensory-impairment (DSI), were administered a speech audiometry test in which they repeated lists of ten disyllabic words in two different conditions, namely with and without visual reinforcement. In the conditions of "with visual reinforcement", the tester provided non-verbal cues to acknowledge the response of each participant. The "visual reinforcement" condition did not apparently provide any significant variation in the results. However, when we considered the group of patients without DSI, the non-verbal "visual reinforcement" resulted in better scores (p < 0.001). Non-verbal visual reinforcement may influence speech audiometry results in the elderly. During speech testing of elderly people with age-related hearing loss, audiologists should always remember to administer visual reinforcement to the patients in order to remove a possible confounding factor from audiological evaluation.
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Audiometria da Fala/métodos , Retroalimentação Sensorial , Comunicação não Verbal , Presbiacusia/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Audiometria da Fala/estatística & dados numéricos , Limiar Auditivo , Comorbidade , Feminino , Humanos , Presbiacusia/complicações , Presbiacusia/reabilitação , Presbiopia/complicações , Presbiopia/diagnóstico , Estatísticas não ParamétricasRESUMO
UNLABELLED: Despite the numerous works published, static posturography has still a limited clinical use due to its intrinsic inter-individual high variability. For this reason, foam pads have been introduced but their use is still not standardized. Aim of the study was to define the variability of static posturography parameters in standard and foam standing. METHODS: 50 healthy subjects were studied with static posturography in four standing conditions: eyes open (EO) and eyes closed (EC), with and without foam pads. Unstable tests have been performed with two different types of rubber foam pads placed on the force platform. "Sensory ratios" have been calculated by the ratio of sway length among the four different conditions, adapted from dynamic posturography, in order to measure the relative contributions of vestibular, visual and somatosensory inputs. RESULTS: Static posturography in standard conditions showed unacceptable coefficients of variation (>than 15%) for all the parameters. The use of foam pads reduced the high intrinsic variability, in particular for LFS (12.6-15.4%). The use of "sensory ratios" led to decrease the inter-subject coefficient of variation of this measurement to about 9.47-14.42% using the bilayer foam pads. CONCLUSIONS: Further studies are needed to confirm these data by applying the ratio formulas in clinical practice.
Assuntos
Equilíbrio Postural/fisiologia , Postura/fisiologia , Adulto , Análise de Variância , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , BorrachaRESUMO
The aim of this article was to evaluate the time course of paroxysmal positioning vertigo (PPV) and to investigate correlations with environmental and seasonal factors through a retrospective statistical analysis spanning 4 years (2001-2004). Applying rigorous diagnostic criteria, we selected 575 patients (429 women and 146 men; age range, 17-94 years; mean age, 55 years for men and 56 years for women). Statistical analysis included events per month and per year. We conducted a descriptive statistical analysis to investigate the correlation between vertigo events and main environmental factors: air pollution as expressed by daily concentration of nitric monoxide and ultrafine particles; air pressure; mean temperature and sun radiation; and humidity. We referred the environmental data, collected by Regione Lombardia (the regional government of Lombardy), to the greater Milan homogeneous area. We performed an analysis of variance test and observed that PPV is more frequent in middle-aged women (in or around their fifties) and on the right side. PPV is clearly negatively correlated with temperature, and frequency of attacks depends on temperature variations. The role of air pollution, especially particles, is suspected, but it is not yet clearly identified. Factors that link climate and otoconia metabolism require further investigation.
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Poluição do Ar/efeitos adversos , Clima , Estações do Ano , Vertigem/epidemiologia , Fatores Etários , Causalidade , Estudos Transversais , Feminino , Humanos , Umidade , Itália , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Temperatura , Vertigem/etiologiaRESUMO
From 2001 to 2006, we performed a retrospective study of patients suffering from chronic unilateral or bilateral tinnitus that was previously ineffectively treated by oral drugs [betahistine (Betaserc), extract of Ginkgo biloba (EGb 761), tanakan (Tebokan), and cinnarizine-dimenhydrinate (Arlevert), singly or in combination]. We divided 150 tinnitus patients (80 men, 70 women) into seven treatment groups. Treatments consisted of application of intravenous pentoxifylline, lidocaine, or vinpocetine (Cavinton) and combination of these agents with physiotherapy and soft laser. Mean duration (+/- standard deviation) of tinnitus in these patients was 7.4 +/- 6.0 years; their mean age was 55.6 +/- 12.5 years. The aim of our study was to compare treatment modalities and define their effectiveness for tinnitus relief. The most effective treatment was defined as a combination of Cavinton and physiotherapy. We evaluated pure lidocaine infusion therapy as ineffective. None of the treatment modalities had an objective correlate of improvement, though improvement was reported by a visual analog scale.
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Zumbido/reabilitação , Adulto , Idoso , beta-Histina/uso terapêutico , Doença Crônica , Cinarizina/uso terapêutico , Terapia Combinada , Dimenidrinato/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Ginkgo biloba , Humanos , Lidocaína/uso terapêutico , Terapia com Luz de Baixa Intensidade , Masculino , Pessoa de Meia-Idade , Pentoxifilina/uso terapêutico , Modalidades de Fisioterapia , Extratos Vegetais/uso terapêutico , Estudos Retrospectivos , Alcaloides de Vinca/uso terapêuticoRESUMO
SCA17 is a rare type of autosomal dominant spinocerebellar ataxia caused by a CAG/CAA expansion in the gene encoding the TATA-binding protein (TBP). We screened for triplet expansion in the TBP gene 110 subjects with progressive cerebellar ataxia and 94 subjects with Huntington-like phenotype negative at specific molecular tests. SCA17 mutation-positive subjects were found in both groups of patients. Expanded alleles with > or = 44 CAG/CAA repeats were identified in 11 individuals and in 4 non-symptomatic relatives. Eleven de novo diagnosed patients and four patients previously reported underwent extensive clinical, neuroradiological and oculographic examination. Cerebellar signs and symptoms were present in all cases; 80% of the patients had mild to severe cognitive deficits; 66% of patients showed choreic movements; pyramidal signs, bradykinesia and dystonia were observed in approx 50% of the cases. MRI demonstrated cortical and cerebellar atrophy in all patients, whereas neurophysiological examination excluded signs of peripheral nervous system involvement. Oculographic examinations were performed in 9 out of 15 patients and showed a distinct pattern of oculomotor abnormalities, characterized by impairment of smooth pursuit, defects in the saccade accuracy, normal saccade velocity, hyperreflexia of vestibuloocular reflexes, and absence of nystagmus. In summary, this study presents one of the largest series of SCA17 patients in Europe. In our group of patients, SCA17 represents the third most frequent SCA genotype. Our clinical data confirm the large variability in SCA17 phenotypic presentation, and indicate that a peculiar combination of neuroradiological, electrophysiological and oculomotor findings is recognizable in SCA17.
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Mutação/genética , Transtornos da Motilidade Ocular/etiologia , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/genética , Proteína de Ligação a TATA-Box/genética , Expansão das Repetições de Trinucleotídeos , Adulto , Idoso , Análise Mutacional de DNA/métodos , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Nistagmo Fisiológico/fisiologia , Transtornos da Motilidade Ocular/patologia , Fenótipo , Reflexo Vestíbulo-Ocular/genética , Reflexo Vestíbulo-Ocular/fisiologia , Ataxias Espinocerebelares/patologiaRESUMO
Stress is a significant factor influencing the clinical course of tinnitus. The auditory system is particularly sensitive to the effects of various stress factors (chemical, oxidative, emotional, etc.). Different stages of reaction (alarm, resistance, exhaustion) lead to different characteristics of tinnitus and to different therapeutic approaches. Individual characteristics of stress reaction may explain different aspects of tinnitus in various patients with different responses to treatment, despite similar audiological and etiological factors. A model based on individual reactions to stress factors (stress-reaction tinnitus model, or SRTM) could explain tinnitus as an alarm signal. In each patient, stressors have to be identified during the alarm phase to prevent an evolution toward the resistance and exhaustion phases. In the exhaustion phase, chronic tinnitus is due to the organization of a paradoxical auditory memory and a pathologically shifted attention to tinnitus. The aim of our study is to describe a therapeutic proposal based on the SRTM by taking an educational approach to management of chronic tinnitus. The educational aspect is emphasized; thus, we named our approach tinnitus school. Selection of appropriate patients and follow-up is based on psychometrics of tinnitus and stress questionnaires, including a tinnitus reaction questionnaire, a tinnitus cognitive questionnaire, and a 20-item perceived stress questionnaire. Tinnitus school is a three-phase program: counseling, training, and home training. Training is based on a tinnitus-fitted physiotherapeutic protocol.
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Aconselhamento , Educação de Pacientes como Assunto , Modalidades de Fisioterapia , Estresse Psicológico/complicações , Zumbido/terapia , Nível de Alerta , Atenção , Doença Crônica , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Inventário de Personalidade , Prática Psicológica , Psicometria , Zumbido/psicologiaRESUMO
Ménière's disease (MD) is an idiopathic inner-ear disorder characterized by fluctuating hearing loss, episodic vertigo, and tinnitus. Though MD's etiology is unknown, growing evidence suggests that autoimmunity may be involved in its development. The aim of this prospective study was to investigate the presence of anti-heat shock protein 70 (anti-HSP70) antibodies during the acute phase of MD and to relate its presence to the antibody pattern. We examined the sera of 13 patients by Western blot immunoassays for reactivity to bovine inner-ear antigen (anti-HSP70) antibodies. The presence of viral antibodies and autoantibodies (herpes simplex, types 1, 2; herpes zoster; cytomegalovirus; Epstein-Barr; IgM; IgG; cardiolipin; thyroglobulin and thyroperoxidase; and antinuclear, antimitochondrial, and anti-smooth-cell antibodies) were also tested. We found reactivity to HSP70 in only 1 of the 13 MD patients (7.7%), and it occurred during herpes zoster reactivation. We found no relationship between the presence of antibodies to HSP70 and immunological or viral testing.
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Anticorpos Antivirais/imunologia , Proteínas de Choque Térmico HSP70/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Doença de Meniere/sangue , Doença de Meniere/imunologia , Viroses/sangue , Viroses/imunologia , Adulto , Autoanticorpos/imunologia , Western Blotting , Feminino , Herpes Zoster/sangue , Herpes Zoster/imunologia , Herpes Zoster/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RecidivaRESUMO
OBJECTIVE: We aimed to study postural balance in preclinical Spinocerebellar ataxia type 1 (SCA1) mutation carriers to identify and observe specific motor functional deficit before evident clinical manifestation. METHODS: Participants were 9 asymptomatic SCA1 mutation carriers (6M/3F), aged 31.8±7years (range 22-44), and 17 age-matched non-carrier controls (5M/12F) (age 18-42). Subjects underwent postural tests on a force platform (Tetrax®-IBS, Sunlight Medical Ltd.) with and without visual feedback. Amount of body sway was represented by stability index (ST). Tests were repeated after 2- and 4-years. Estimated years to onset were calculated. RESULTS: In controls, ST was unchanged from baseline to 4-year evaluations in all standing conditions. SCA1 mutation carriers performed similarly to controls in the postural tasks with open eyes, whereas in conditions without visual feedback SCA1 carriers had significantly higher ST than controls at all longitudinal evaluations. Close-to-disease onset carriers (≤7years) showed more prominent time-dependent stance abnormalities (p<0.0001 for all comparisons). CONCLUSIONS: Traceable and progressive postural abnormalities can be observed in preclinical close-to-onset SCA1 carriers. Quantitative analysis of stance could represent a promising outcome measure in clinical trials including preclinical subjects.
Assuntos
Ataxina-1/genética , Equilíbrio Postural/fisiologia , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/fisiopatologia , Adolescente , Adulto , Doenças Assintomáticas , Estudos de Casos e Controles , Progressão da Doença , Feminino , Seguimentos , Marcadores Genéticos , Heterozigoto , Humanos , Masculino , Mutação , Estudos Prospectivos , Ataxias Espinocerebelares/genética , Adulto JovemRESUMO
Patients affected with multiple sclerosis (MS) frequently suffer from vestibular disorders due to vestibulospinal involvement. The vestibulospinal reflexes in these subjects can be well investigated through vestibular evoked myogenic potentials (VEMPs). Evoked by the acoustic stimulation of the saccular macula and mediated by the vestibulocollic reflex pathway, they are recorded using surface electromyographic electrodes from the ipsilateral sternocleidomastoid muscle tonically contracted. Abnormal findings (e.g., absence of response, prolonged latencies) disclose a lesion anywhere in the pathway. We examined VEMPs in 19 patients with definite MS (5 men, 14 women; age range, 31-59 years; mean age, 45 years) and compared them to VEMPs in 10 subjects with onset MS (2 men, 8 women; age range, 24-35 years; mean age, 29 years). VEMPs in definite MS subjects were abnormal in 14, absent (on the left side only) in 1, and normal in the remaining 4. In patients with onset MS, VEMPs were abnormal in 6. These results suggest that latencies of vestibulospinal reflexes can be remarkably delayed in MS at different stages of disease, whereas vestibulospinal involvement is more frequent in definite cases. To date, no study has yet investigated different VEMPs involvement at different stages of MS.
Assuntos
Potenciais Evocados Auditivos/fisiologia , Esclerose Múltipla/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Tempo de Reação , Valores de Referência , Núcleos Vestibulares/fisiologiaRESUMO
OBJECTIVES: The aim of this study was to focus on patients suffering from cochleo-vestibular disorder with and without Ménière disease (MD) in order to verify whether chronic cerebrospinal drainage abnormalities could play a role in the etiopathogenesis of endolymphatic hydrops. METHODS: Fifty-two volunteers were enrolled and subdivided into two groups: 24 definite MD and 28 not-MD. Both magnetic resonance venography imaging with contrast-enhanced imaging of the venous cerebrospinal system (MRV) and venous echo-color Doppler (ECD) were performed. RESULTS: MRV showed abnormalities in 83% of MD and 57% of not-MD subjects (p < 0.001). Asymmetrical cervical venous flow, assessed by MRV, was confirmed by ECD in 62.5% of MD but in only 21.5% of not-MD subjects (p<0.001). CONCLUSION: Chronic cerebrospinal venous insufficiency might be the anatomical background, which provides a predisposing factor for the development of endolymphatic hydrops in MD patients.
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Veia Ázigos/fisiopatologia , Circulação Cerebrovascular , Veias Jugulares/fisiopatologia , Doença de Meniere/complicações , Medula Espinal/irrigação sanguínea , Insuficiência Venosa/etiologia , Adulto , Idoso , Veia Ázigos/diagnóstico por imagem , Veias Cerebrais/diagnóstico por imagem , Doença Crônica , Doenças Cocleares/fisiopatologia , Hidropisia Endolinfática/etiologia , Feminino , Humanos , Veias Jugulares/diagnóstico por imagem , Angiografia por Ressonância Magnética , Masculino , Doença de Meniere/fisiopatologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Ultrassonografia Doppler em Cores , Insuficiência Venosa/diagnóstico , Insuficiência Venosa/diagnóstico por imagem , Insuficiência Venosa/fisiopatologia , Doenças Vestibulares/fisiopatologiaRESUMO
In this report, we summarize our clinical experience with intratympanic dexamethasone treatment (IDT) for control of tinnitus. From March 2000 through February 2001, we observed 54 patients (23 women, 31 men; mean age, 49.6 +/- 7.2 years; range, 24-71 years) suffering from subjective idiopathic tinnitus (SIT). After common audiological tests had been performed; all patients underwent specific topodiagnostic tests to verify the cochlear SIT genesis. The 50 subjects with positive results from a furosemide test and negative results from caraverine and carbamazepine tests were selected for the IDT, consisting of transtympanic perfusion of 4 mg dexamethasone to the round window via the middle ear. The treatment was repeated three times daily for 3 consecutive months. Its short-term effects were evaluated 2 weeks after the last perfusion. In 17 of 50 of these patients (34%), the SIT disappeared; 20 of the 50 (40%) reported a significant decrease of the symptom; and the remaining 13 of the 50 (26%) did not experience any improvement. Therefore, we believe that IDT represents an effective drug delivery system for SIT control, as long as the condition arises from inner ear disorders only and treatment occurs within 3 months of symptom onset.
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Anti-Inflamatórios/uso terapêutico , Dexametasona/uso terapêutico , Zumbido/tratamento farmacológico , Adulto , Idoso , Anti-Inflamatórios/administração & dosagem , Dexametasona/administração & dosagem , Sistemas de Liberação de Medicamentos , Orelha Interna/efeitos dos fármacos , Orelha Média , Feminino , Humanos , Injeções , Líquidos Labirínticos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Retrospectivos , Janela da Cóclea/metabolismo , Resultado do TratamentoRESUMO
The difficulty of accurately localizing the source of subjective tinnitus is well-known. Anamnesis and traditional audiological tests can often suggest a source if its origin as peripheral or merely central (or both). Therefore, several authors, such as Risey, Denk, and Shulman, recently proposed identifying the source of subjective tinnitus through the evaluation of the responses reported by patients to adequate pharmacological treatments. Our study presents a useful plan to perform tinnitus topodiagnosis, which consists of specific audiological tests evaluating the characteristics of symptoms (annoyance, pitch, loudness, hyperacusis) and of several pharmacological tests carried out through the administration of particular drugs, the pharmacodynamic mechanisms and meaningful side effects of which are described. On the basis of pharmacological effects on tinnitometry, some drugs will be combined.
Assuntos
Amantadina , Carbamazepina , Furosemida , Quinoxalinas , Zumbido/diagnóstico , Anticonvulsivantes , Audiometria/métodos , Percepção Auditiva/fisiologia , Diuréticos , Humanos , Hiperacusia/complicações , Hiperacusia/diagnóstico , Hiperacusia/fisiopatologia , Zumbido/complicações , Zumbido/fisiopatologiaRESUMO
The objective of this study was verification, through suitable hematochemical tests, of the supposition that central-systemic microtoxicosis plays a role either in the etiopathogenesis of Ménière's syndrome or in labyrinthine pathological processes or hypoacusis. We did not, therefore, exclude other well-known hypotheses in the causality of these pathologies. Nonetheless, one finds, particularly in the Ménière's cases, a constant homogeneous distribution of the metabolic products of this microtoxicosis, such as a high concentration of free radicals and low natural defenses (e.g., antioxidant plasmatic capacity). Therefore, there exists a kind of dangerous central and systemic presence of reactive molecules, aimed toward the polyunsaturated fatty acids and homeostatic complex enzymes, that is not compensated for by the natural antioxidant defense. The presence of this lack of balance, verified by suitable tests, has shown the rationality of use of a product made from reduced glutathione, thioctic acid, cysteine, and other antioxidants as a multipurpose antidote to this element of etiopathogenesis. Patients were divided into three groups (control, conventional therapy, and antioxidant treatment), and those in the antioxidant treatment group, especially those with Ménière's syndrome, demonstrated a net and more significant improvement. Also, parallel clinical and instrument evaluations of this new therapeutic solution, the efficacy of which has already been positively demonstrated, are expected to provide further evidence to support the primary hypothesis.
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Antioxidantes/metabolismo , Radicais Livres/metabolismo , Doença de Meniere/metabolismo , Adulto , Idoso , Antioxidantes/uso terapêutico , Feminino , Humanos , Masculino , Doença de Meniere/tratamento farmacológico , Doença de Meniere/etiologia , Pessoa de Meia-Idade , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Resultado do TratamentoRESUMO
Balance disorders are commonly observed during the course of multiple sclerosis (MS). The aim of this study is to report characteristics of MS patient stance control disorders, measured by means of posturography and related to the brainstem lesions. Thirty-eight patients affected by MS, mildly to moderately disable according to Kurtzke's Expanded Disability Status Scale, underwent a complete clinical neurological and vestibular evaluation and brain MRI scanning. All patients were then tested on a static posturography platform (Tetrax, Israel) in four conditions: eyes open and eyes closed standing on a firm surface and on a foam pad. Clinical and/or magnetic resonance imaging evidence of brainstem involvement was observed in 55.3% of patients. When brainstem lesion was detected, Fourier analysis showed a typical pattern characterized by inversion of the 0-0.1 Hz and 0.1-0.25 Hz frequency bands. In conclusion, MS leads to pervasive postural disturbances in the majority of subjects, including the visuo-vestibular loops and proprioception involving vestibulo-spinal pathways in at least 55.3% of patients. Our results may also suggest the presence of Fourier inversion in patients with brainstem lesions.
RESUMO
Experimental evidence suggests that panic disorder is characterized by abnormalities in the balance system function and that these abnormalities might be related to the severity of agoraphobic avoidance. Since the balance system can be modulated by the serotonergic system, we investigated the effect of a 6-week treatment with citalopram on the balance system function in patients with panic disorder. Fifteen patients with panic disorder with/without agoraphobia underwent static posturography on days 0 and 42. Static posturography and clinical assessments were carried out by different investigators who were blind to each other. Static posturography showed high percentages of abnormal scores. Patients with no or low agoraphobic avoidance showed less abnormal posturographic measures than those with moderate to severe agoraphobia. After 6 weeks of treatment with citalopram there was a significant decrease of four out of six posturography measures in eyes-closed and neck extension conditions, whereas no significant effect was found in the eyes-open condition. This is the first report that suggests that the modulation of the serotonergic system can improve the balance system function in patients with panic disorder, particularly when visual information is lacking. In addition, our findings confirm the observation that many patients with panic disorder have abnormalities in their balance system function, supporting the idea that these abnormalities are mainly related to agoraphobic avoidance.
Assuntos
Agorafobia/tratamento farmacológico , Citalopram/administração & dosagem , Transtorno de Pânico/tratamento farmacológico , Equilíbrio Postural/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Adulto , Agorafobia/fisiopatologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Cinestesia/efeitos dos fármacos , Cinestesia/fisiologia , Masculino , Transtorno de Pânico/fisiopatologia , Inventário de Personalidade , Equilíbrio Postural/fisiologia , Postura/fisiologia , Receptores de Serotonina/fisiologia , Resultado do TratamentoRESUMO
O controle do equilíbrio corporal baseia-se na integraçäo central de inúmeras aferências periféricas: visuais, labirínticas, proprioceptivas e somato-sensoriais. O sistema vestibular é um sistema de grande plasticidade, sensível a modificaçöes funcionais por meio de diferentes tipos de reabilitaçäo: prismas visuais, estimuladores plantares, estimulaçäo paravertebral elétrica superficial, exercícios físicos etc. Em diferentes situaçöes essas diversas opçöes terapêuticas podem ser combinadas