Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes.

BACKGROUND: Spinal cord has been considered the main target of damage in hereditary spastic paraplegias (HSPs), but mounting evidence indicates that the brain is also affected. Despite this, little is known about the brain signature of HSPs, in particular regarding stratification for specific genetic subtypes. OBJECTIVE: We aimed to characterize cerebral and cerebellar damage in five HSP subtypes (9 SPG3A, 27 SPG4, 10 SPG7, 9 SPG8, and 29 SPG11) and to uncover the clinical and gene expression correlates. METHODS: We obtained high-resolution brain T1 and diffusion tensor image (DTI) datasets in this cross-sectional case-control study (n = 84). The MRICloud, FreeSurfer, and CERES-SUIT pipelines were employed to assess cerebral gray (GM) and white matter (WM) as well as the cerebellum. RESULTS: Brain abnormalities were found in all but one HSP group (SPG3A), but the patterns were gene-specific: basal ganglia, thalamic, and posterior WM involvement in SPG4; diffuse WM and cerebellar involvement in SPG7; cortical thinning at the motor cortices and pallidal atrophy in SPG8; and widespread GM, WM, and deep cerebellar nuclei damage in SPG11. Abnormal regions in SPG4 and SPG8 matched those with higher SPAST and WASHC5 expression, whereas in SPG7 and SPG11 this concordance was only noticed in the cerebellum. CONCLUSIONS: Brain damage is a conspicuous feature of HSPs (even for pure subtypes), but the pattern of abnormalities is genotype-specific. Correlation between brain structural damage and gene expression maps is different for autosomal dominant and recessive HSPs, pointing to distinct pathophysiological mechanisms underlying brain damage in these subgroups of the disease. © 2021 International Parkinson and Movement Disorder Society.

Randomized Trial of Botulinum Toxin Type A in Hereditary Spastic Paraplegia - The SPASTOX Trial.

BACKGROUND: Hereditary spastic paraplegia presents spasticity as the main clinical manifestation, reducing gait quality and producing incapacity. Management with botulinum toxin type A (BoNT-A) is not well elucidated. The objective of the current study was to evaluate the efficacy and safety of BoNT-A in patients with hereditary spastic paraplegias. METHODS: This was a double-blind, randomized, placebo-controlled crossover trial. Each participant was randomly assigned to receive 1 injection session of either BoNT-A (100 IU/2 mL of Prosigne in each adductor magnus and each triceps surae) or saline 0.9% (2 mL). The primary outcome measure was change from baseline in maximal gait velocity, and secondary outcome measures included changes in gait at self-selected velocity, spasticity, muscle strength, Spastic Paraplegia Rating Scale, pain, fatigue, and subjective perception of improvement. We also looked at adverse events reported by the patients. RESULTS: We enrolled 55 patients, 36 of whom were men and 41 with the pure phenotype. Mean age was 43 ± 13.4 years (range, 19-72 years), mean age of onset waws 27 ± 13.1 years (range, <1 to 55 yars), and mean disease duration was 17 ± 12.7 years (range, 1-62 years). Compared with baseline, we did not find significant differences between groups in primary and secondary outcomes, except for reduction in adductor tone (P = 0.01). The adverse events were transient and tolerable, and their incidence did not significantly differ between treatments (P = 0.17). CONCLUSIONS: BoNT-A was safe in patients with hereditary spastic paraplegias and reduced the adductor tone, but it was not able to produce functional improvement considering the doses, injection protocol, measures, and instruments used. © 2021 International Parkinson and Movement Disorder Society.

Botulinum toxin for hereditary spastic paraplegia: effects on motor and non-motor manifestations.

Motor and non-motor manifestations are common and disabling features of hereditary spastic paraplegia (HSP). Botulinum toxin type A (Btx-A) is considered effective for spasticity and may improve gait in these patients. Little is known about the effects of Btx-A on non-motor symptoms in HSP patients. Objective To assess the efficacy of Btx-A on motor and non-motor manifestations in HSP patients. Methods Thirty-three adult patients with a clinical and molecular diagnosis of HSP were evaluated before and after Btx-A injections. Results Mean age was 41.7 ± 13.6 years and there were 18 women. Most patients had a pure phenotype and SPG4 was the most frequent genotype. The Btx-A injections resulted in a decrease in spasticity at the adductor muscles, and no other motor measure was significantly modified. In contrast, fatigue scores were significantly reduced after Btx-A injections. Conclusion Btx-A injections resulted in no significant functional motor improvement for HSP, but fatigue improved after treatment.

Translation and validation into Brazilian Portuguese of the Spastic Paraplegia Rating Scale (SPRS).

OBJECTIVE: To translate and validate the Spastic Paraplegia Rating Scale (SPRS) into Brazilian-Portuguese. METHOD: Two experienced and English-fluent neurologists translated SPRS into Portuguese, creating SPRS-BR. We then assessed inter and intra-rater reliability of this version using coefficients of correlation and variability in a cohort of 30 patients. RESULTS: Mean age of patients and disease duration were 47.7 ± 10.5 and 17.0 ± 10.6 years, respectively. Twenty-one had pure HSP and SPG4 was the most frequent genotype. Mean Rankin and SPRS-BR scores were 2.2 ± 0.9 and 19.9 ± 9.9, respectively. Mean intra and inter-rater correlation coefficients of SPRS-BR scores were 0.951 and 0.934, whereas coefficients of variation were 11.5% (inter-rater) and 9.9% (intra-rater). Cronbach's alpha for the whole SPRS-BR scale was 0.873. CONCLUSION: SPRS-BR is a useful, reliable and valid clinical instrument.

Clinical features and management of hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

Botulinum toxin for hereditary spastic paraplegia: effects on motor and non-motor manifestations / Toxina botulínica nas paraplegias espásticas hereditárias: efeitos nas manifestações motoras e não-motoras

ABSTRACT Motor and non-motor manifestations are common and disabling features of hereditary spastic paraplegia (HSP). Botulinum toxin type A (Btx-A) is considered effective for spasticity and may improve gait in these patients. Little is known about the effects of Btx-A on non-motor symptoms in HSP patients. Objective To assess the efficacy of Btx-A on motor and non-motor manifestations in HSP patients. Methods Thirty-three adult patients with a clinical and molecular diagnosis of HSP were evaluated before and after Btx-A injections. Results Mean age was 41.7 ± 13.6 years and there were 18 women. Most patients had a pure phenotype and SPG4 was the most frequent genotype. The Btx-A injections resulted in a decrease in spasticity at the adductor muscles, and no other motor measure was significantly modified. In contrast, fatigue scores were significantly reduced after Btx-A injections. Conclusion Btx-A injections resulted in no significant functional motor improvement for HSP, but fatigue improved after treatment.

RESUMO Manifestações motoras e não motoras são comuns e incapacitantes nas paraparesias espásticas hereditárias (PEH). Toxina botulínica do tipo A (TB-A) é considerada eficaz no tratamento da espasticidade e pode melhorar a marcha nesses pacientes. Pouco se sabe sobre os efeitos da TB-A sobre sintomas não-motores. Objetivo avaliar a eficácia da TB-A sobre manifestações motoras e não-motoras nas PEH. Método trinta e três pacientes adultos com PEH foram avaliados antes e depois das aplicações de TB-A. Resultados A média de idade foi 41,7 ± 13,6 anos e havia 18 mulheres. A maioria dos pacientes portava a forma pura e o genótipo mais comum foi SPG4. Houve diminuição da espasticidade dos músculos adutores da coxa sem melhora da marcha. A pontuação da fadiga reduziu após as injeções. Conclusão As aplicações de TB-A não melhoraram a marcha nos pacientes mas a redução da fadiga foi significativa após o tratamento.

Translation and validation into Brazilian Portuguese of the Spastic Paraplegia Rating Scale (SPRS) / Tradução e validação da escala de classificação de paraplegia espástica (SPRS) para a versão brasileira

ABSTRACT Hereditary spastic paraplegias (HSP) are characterized by progressive lower limb weakness and spasticity. There are no validated instruments to quantify disease severity in Portuguese. Objective To translate and validate the Spastic Paraplegia Rating Scale (SPRS) into Brazilian-Portuguese. Method Two experienced and English-fluent neurologists translated SPRS into Portuguese, creating SPRS-BR. We then assessed inter and intra-rater reliability of this version using coefficients of correlation and variability in a cohort of 30 patients. Results Mean age of patients and disease duration were 47.7 ± 10.5 and 17.0 ± 10.6 years, respectively. Twenty-one had pure HSP and SPG4 was the most frequent genotype. Mean Rankin and SPRS-BR scores were 2.2 ± 0.9 and 19.9 ± 9.9, respectively. Mean intra and inter-rater correlation coefficients of SPRS-BR scores were 0.951 and 0.934, whereas coefficients of variation were 11.5% (inter-rater) and 9.9% (intra-rater). Cronbach’s alpha for the whole SPRS-BR scale was 0.873. Conclusion SPRS-BR is a useful, reliable and valid clinical instrument.

RESUMO As paraparesias espásticas hereditárias (PEH) apresentam progressiva espasticidade e fraqueza dos membros inferiores. Não existem escalas validadas em língua portuguesa para quantificar a gravidade da doença. Objetivo Traduzir e validar para o português do Brasil a Spastic Paraplegia Rating Scale (SPRS). Método Dois neurologistas experientes em neurogenética e fluentes em inglês traduziram a SPRS para o português, criando a SPRS-BR. Em seguida, checamos a reprodutibilidade da escala usando coeficientes de correlação e variabilidade em um grupo de 30 pacientes. Resultados As médias de idade e duração de doença foram de 47,7 ± 10,5 e 17,0 ± 10,6 anos, respectivamente. Vinte e um eram portadores da forma pura de PEH, sendo que SPG4 foi o genótipo mais frequente. A pontuação das escalas Rankin e SPRS-BR foi, respectivamente, 2,2 ± 0,9 e 19,9 ± 9,9. Os coeficientes de correlação inter e intraexaminador da SPRS-BR foram 0,934 e 0,951, enquanto que os coeficientes de variação foram de 11,5% (interexaminador) e 9,9% (intraexaminador). O coeficiente alfa de Cronbach’s para a escala SPRS-BR foi de 0.873. Conclusão A SPRS-BR é uma escala útil clinicamente, fácil de aplicar e que apresentou boa reprodutibilidade e validade.

Clinical features and management of hereditary spastic paraplegia / Aspectos clinicos e manejo das paraplegias espasticas hereditarias

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

Paraplegias espásticas hereditárias (PEH) constituem um grupo de desordens geneticamente determinadas caracterizadas por espasticidade e paraparesia de progressão insidiosa. Paraplegia espástica aparentemente esporádica de início no adulto constitui problema frequente na prática neurológica. Evidências recentes sugerem que uma proporção significativa destes casos é geneticamente determinada. O grupo das PEH é dividido clinicamente em formas puras e complicadas de acordo com a concomitância de outras manifestações clinicas e neurológicas. Até o momento 60 tipos genéticos foram identificados. Todos os modos de herança monogênica já foram descritos: autossômica dominante, autossômica recessiva, ligada ao X e mitocondrial. Avanços recentes indicam que alterações do transporte axonal estão implicadas na degeneração dos longos axônios motores no sistema nervoso central na PEH. Nesta revisão abordamos recentes avanços na área com ênfase nos aspectos clínicos chave que ajudam o neurologista geral no diagnóstico e manejo correto deste grupo de doenças.

Aplicação da escala SF-36 em pacientes operados de tumores da base do crânio / Application of SF-36 scale in patients operated on skull base tumors

Introdução: A base do crânio é uma região que pode ser afetada por diferentes tipos de tumores. Os tumores dessa região podem ser benignos ou malignos e se localizarem na cavidade anterior, média ou posterior do crânio. Embora relativamente raras, essas lesões podem afetar significativamente os pacientes em virtude de sua localização anatômica complexa e riscos próprios do manejo cirúrgico. A qualidade de vida de pacientes operados de tumores da base do crânio pode ser prejudicada não somente pelo comprometimento neurológico resultante da lesão anatômica, mas também por problemas psicossociais tais como diminuição da autoconfiança e autoestima, mudança nas atividades de vida diária, dependência, estigma, discriminação, dificuldade de interação social, desemprego, entre outras. Dessa forma, o objetivo deste estudo foi avaliar a qualidade de vida dos pacientes operados de tumores da base do crânio. Método: O estudo incluiu 38 indivíduos que foram avaliados entre seis meses e um ano após a cirurgia usando a escala de qualidade de vida SF-36. Resultados: Todos os pacientes tiveram pontuação acima de 50. Em seis dos oito domínios, nos componentes físico e mental, mulheres pontuaram melhor que homens, especialmente em LAF (limitação por aspectos físicos). Quando comparadas as idades, pacientes acima de 50 anos pontuaram melhor. Quando comparados os sexos, mulheres até 50 anos pontuaram melhor que os homens. Por outro lado, homens com idade superior a 50 anos pontuaram melhor que as mulheres. Conclusão: Embora haja diferenças, estas não foram estatisticamente significantes. Assim, não houve melhora significativa nos quesitos social, físico, psicológico e funcional quando idade e sexo foram comparados.

Background: The skull base is a region that may be affected by different types tumors. Tumors in this region can be benign or malignant and are located in the anterior fossa, middle or posterior fossa. Although relatively rare, they are potentially harmful, because of the complex anatomic features of these regions and the inherent risk of a surgical procedure. The quality of life of patients can be hampered not only by neurological impairment, but also by psychosocial problems such as decreased self-confidence and self-esteem, change in daily activities, dependency, stigma and discrimination, difficulty in social interaction and unemployment. Thus, the aim of this study was to assess the quality of life of patients operated on for tumors of the skull base. Method: The study included 38 individuals who were evaluated between six months and one year after surgery, using the SF-36. Results: All patients had scores above 50 when all domains were summed up. In six out of eight domains (physical and mental components) women scored better than men, especially in LAF (limitation due to physical abilities). When compared to age, patients older than 50 years scored better. When compared with gender, women until 50 years had a better score. On the other hand, men aged over 50 years scored better than women. Conclusion: Although there are slight differences, these were not statistically significant. We concluded that no significant improvement occurred in social, physical, psychological and functional outcome when age and sex were compared.