Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Evaluation of Brain SPECT with 99mTc-TRODAT-1 in the Differential Diagnosis of Parkinsonism.

Introduction: Brain SPECT with 99mTc-TRODAT-1 (SPECT-TRODAT) may be a useful tool in the differential diagnosis of Parkinsonism. Objective: To compare results of SPECT-TRODAT with clinical findings in patients with Parkinsonism. Methods: We evaluated 153 outpatients. SPECT-TRODAT results were visually analyzed into normal, abnormal, symmetric, and asymmetric, and according to the degree of impairment into mild, moderate, marked, and severe (1-4). Results: A direct relationship was found between motor scores severity (MDS-UPDRS-III) and SPECT-TRODAT-reduced binding in general, in the group of patients with synucleinopathies (rho = 0.258, p=0.005), especially in patients with Parkinson's disease (rho = 0.204, p=0.049). Changes in SPECT-TRODAT had high correspondence with symmetry in all Parkinsonism. When comparing groups to the correspondence predominantly bilateral or unilateral impairment in SPECT, there was a difference between patients with SNP (p=0.041) and between this group and patients with secondary Parkinsonism (SP) (p < 0.0001). It was handy in differentiating drug-induced Parkinsonism from synucleinopathies. In the group of drug-induced Parkinsonism, younger people were the ones who showed the most significant reductions in radiotracer uptake. In this group, nonmotor signs resulted in examinations with more significant reductions in radiotracer uptake. When the scans without alterations and those that did not correspond to the symmetry were considered negative, SPECT-TRODAT's accuracy and specificity to differentiate PD from other forms of Parkinsonism were low. There was an inverse correlation between the severity of the SPECT-TRODAT result and the absence of nonmotor signs in patients with drug-induced Parkinsonism. Conclusion: The authors concluded that the SPECT with 99mTc-TRODAT-1 was mainly useful in differentiating between synucleinopathies and secondary Parkinsonism.

Increased frequency and range of sexual behavior in a patient with Parkinson's disease after use of pramipexole: a case report.

INTRODUCTION: Several recent reports have linked the use of dopamine agonists (DAs) to a variety of compulsive behaviors in patients with Parkinson's disease (PD). These inappropriate behaviors may include pathological gambling, compulsive shopping, and hypersexuality. AIM: To report the case of a patient with increased range of sexual behavior after use of pramipexole, a DA. METHODS: A 67-year-old man with a 7-year diagnosis of PD treated with levodopa and pramipexole presented with a dramatic change in sexual behavior after an increase in DA dose. RESULTS: The patient, who historically was a very shy and conservative person, started to present increased frequency of sexual intercourse with his wife, during which he began speaking obscenities with an extreme preference for anal intercourse, preferences never requested before. After pramipexole was withdrawn, complete remission was observed with return to his usual sexual behavior. CONCLUSIONS: Hypersexuality and paraphilias are complications not uncommonly found in patients with PD under dopaminergic treatment. Further studies are needed for the understanding of this complex complication, and particularly the most prevalent relationship between pathological hypersexuality and use of DAs.

Cognitive and psychiatric changes as first clinical presentation in Sneddon syndrome.

Sneddon syndrome (SS) is a rare progressive non-inflammatory thrombotic vasculopathy affecting small/medium-sized blood vessels of unknown origin. It is strongly associated with the presence of antiphospholipid antibodies (AA). The presence of livedo reticularis and cerebrovascular disease are hallmark features. The condition is far more common in young women. We report a case of SS in a 43 year-old male with a two-year history of progressive cognitive impairment consistent with dementia syndrome, and major personality changes, besides livedo reticularis and cerebral angiographic pattern of vasculitis. AA were borderline. The recognition of skin blemishes that precede strokes should raise the hypothesis of SS. AA are elevated in more than half of cases, but their role in the pathogenesis or association of positive antibodies and SS remains unclear. Dementia syndrome in young patients should be extensively investigated to rule out reversible situations. Typical skin findings, MRI and angiography may aid diagnosis.

A síndrome de Sneddon (SS) é uma vasculopatia trombótica não inflamatória progressiva rara que afeta os vasos sanguíneos de pequeno e médio tamanho com origem desconhecida. Está fortemente associada à presença de anticorpos antifosfolipídios (AA). A presença de livedo reticularis e doença cerebrovascular são a marca registrada. É muito mais comum em mulheres jovens. Relatamos um caso de SS em um homem de 43 anos de idade com dois anos de história de comprometimento cognitivo progressivo compatível com síndrome demencial e mudanças graves de personalidade, além de livedo reticular e padrão angiográfico cerebral de vasculite. AA eram limítrofes. O reconhecimento das manchas da pele que precedem eventos isquêmicos cerebrovasculares deve reforçar a hipótese de SS. Os AA são elevados em mais da metade dos casos, mas seu papel na patogênese ou associação de anticorpos positivos e SS permanece obscuro. A síndrome demencial em pacientes jovens deve ser amplamente investigada para se descartarem situações reversíveis. Achados típicos da pele, ressonância magnética e angiografia podem ajudar no diagnóstico.

Liver transplantation in a patient with rapid onset parkinsonism-dementia complex induced by manganism secondary to liver failure.

Bilateral and symmetric globus-pallidus hyperintensities are observed on T1-weighted MRI in most of the patients with chronic liver failure, due to manganese accumulation. We report a 53-year-old man, with rapid onset parkinsonism-dementia complex associated with accumulation of manganese in the brain, secondary to liver failure. A brain MRI was performed and a high signal on T1-weighted images was seen on globus-pallidus, as well as on T2-weighted images on the hemispheric white-matter. He was referred to a liver-transplantation. The patient passed away on the seventh postoperative day. Our findings support the concept of the toxic effects of manganese on the globus-pallidus. The treatment of this form of parkinsonism is controversial and liver-transplantation should not be considered as first line treatment but as an alternative one.

Parkinsonism and other movement disorders in outpatients in chronic use of cinnarizine and flunarizine.

The purpose of this study is to determine the prevalence and the patterns of movement disorders (MD) in outpatients submitted to the chronic use of cinnarizine (cz) or flunarizine (fz), and to establish the main risk factors for MD development. Over a period of 3 months, data were collected from outpatients who were chronic users of cz or fz in a municipal health institute. A total of 26 outpatients were included and all of them were submitted to a protocol that included DSM-4 diagnosis criteria for drug-induced movement disorders, parkinsonism (PK) and depression. Parkinsonism was diagnosed in 34% of the patients, PK plus akathisia, PK plus akathisia and bucco-linguo-masticatory syndrome (BLMS), isolated BLMS and dystonia were found in 4% patients each. Patients with BLMS had the highest median age and the longest average period in which they used the drugs. The affected group, when compared to the non-affected one, presented with higher rates of depression. This study demonstrates the existence of a direct relationship between the time of use of cz and fz, the age and the prevalence of PK and other MD. It also suggests that these drugs increase the incidence of depression.

[Peripheral neuropathy and myositis in idiopathic hypereosinophilic syndrome: case report]. / Neuropatia periférica e miosite na síndrome hipereosinofílica idiopática: relato de caso.

We describe a case of idiopathic hypereosinophilic syndrome manifested by an axonal sensory-motor polyneuropathy (ASMP) and signals of myositis. A 20 year old woman began with progressive gait impairment with drops and presented with subacute lower limb edema associated with paresthesis and cramps. She showed hypotonia in the lower limbs, absence of knee and ankle jerks, steppage gait, and decreased sensation on both legs. Examinations of stools were negative. Blood examination showed 7700 leukocytes with 24% (1848/mm(3)) eosinophils. Electrodiagnostic studies showed axonal lesion in sensory and motor nerves. Muscle biopsy showed type 2 muscle fibers atrophy with discrete inflammatory cells, predominantly lymphocytic in perivascular and interstitial locations. She was treated with prednisone and all the symptoms subsided after two months.

[Clinical response to long action propranolol in 40 patients diagnosed with essential tremor with no previous treatment: an open, non-controlled study]. / Uso do propranolol de ação prolongada em 40 pacientes com tremor essencial e virgens de tratamento: um ensaio clínico não controlado.

UNLABELLED: Essential tremor (ET) is the most common movement disorder and betablockers are still considered the first line of treatment. The aim of our study is to report the clinical response to long action propranolol (LAP) of 40 patients diagnosed with essential tremor with no previous treatment. METHOD: 40 patients with ET were evaluated with rating scales for severity of tremor and clinical classification of ET. All patients were evaluated at least twice, at enrollment and one month after starting treatment. RESULTS: thirty-six patients (90%) had type 2 ET and types 3 and 4 occurred in two patients each (10%). Familiar history was positive in 25 patients (62.5%). Mean age at first evaluation was 43.1 years and mean age at onset was 27.4 years. Of all patients, 33 (82.5%) had some degree of benefit and in 52.5 % this benefit was either good or excellent. CONCLUSION: LAP seems to be a good treatment option for ET in our series of 40 patients.

Cognitive and psychiatric changes as first clinical presentation in Sneddon Syndrome / Alterações cognitivas e psiquiátricas como primeira apresentação clínica na Síndrome de Sneddon

ABSTRACT Sneddon syndrome (SS) is a rare progressive non-inflammatory thrombotic vasculopathy affecting small/medium-sized blood vessels of unknown origin. It is strongly associated with the presence of antiphospholipid antibodies (AA). The presence of livedo reticularis and cerebrovascular disease are hallmark features. The condition is far more common in young women. We report a case of SS in a 43 year-old male with a two-year history of progressive cognitive impairment consistent with dementia syndrome, and major personality changes, besides livedo reticularis and cerebral angiographic pattern of vasculitis. AA were borderline. The recognition of skin blemishes that precede strokes should raise the hypothesis of SS. AA are elevated in more than half of cases, but their role in the pathogenesis or association of positive antibodies and SS remains unclear. Dementia syndrome in young patients should be extensively investigated to rule out reversible situations. Typical skin findings, MRI and angiography may aid diagnosis.

RESUMO A síndrome de Sneddon (SS) é uma vasculopatia trombótica não inflamatória progressiva rara que afeta os vasos sanguíneos de pequeno e médio tamanho com origem desconhecida. Está fortemente associada à presença de anticorpos antifosfolipídios (AA). A presença de livedo reticularis e doença cerebrovascular são a marca registrada. É muito mais comum em mulheres jovens. Relatamos um caso de SS em um homem de 43 anos de idade com dois anos de história de comprometimento cognitivo progressivo compatível com síndrome demencial e mudanças graves de personalidade, além de livedo reticular e padrão angiográfico cerebral de vasculite. AA eram limítrofes. O reconhecimento das manchas da pele que precedem eventos isquêmicos cerebrovasculares deve reforçar a hipótese de SS. Os AA são elevados em mais da metade dos casos, mas seu papel na patogênese ou associação de anticorpos positivos e SS permanece obscuro. A síndrome demencial em pacientes jovens deve ser amplamente investigada para se descartarem situações reversíveis. Achados típicos da pele, ressonância magnética e angiografia podem ajudar no diagnóstico.

Reversible parkinsonian syndrome in systemic and brain vasculitis.

A young female patient with chronic renal failure due to a systemic vasculitis and a parkinsonian syndrome secondary to brain vasculitis, most likely systemic lupus erythematosus, is described. The patient had a dramatic response to a pulse of methylprednisolone, with remission of her parkinsonian symptoms.

Liver transplantion in a patient with rapid onset parkinsonism-dementia complex induced by manganism secondary to liver failure

Bilateral and symmetric globus-pallidus hyperintensities are observed on T1-weighted MRI in most of the patients with chronic liver failure, due to manganese accumulation. We report a 53-year-old man, with rapid onset parkinsonism-dementia complex associated with accumulation of manganese in the brain, secondary to liver failure. A brain MRI was performed and a high signal on T1-weighted images was seen on globus-pallidus, as well as on T2-weighted images on the hemispheric white-matter. He was referred to a liver-transplantation. The patient passed away on the seventh postoperative day. Our findings support the concept of the toxic effects of manganese on the globus-pallidus. The treatment of this form of parkinsonism is controversial and liver-transplantation should not be considered as first line treatment but as an alternative one.

Hiperintesidades simétricas e bilaterais dos gânglios da base são observadas em imagens de ressonância magnética encefálica (RM) ponderadas em T1 na maioria dos pacientes com insuficiência hepática crônica devidas ao acúmulo de manganês. Nós relatamos o caso de um homem, com 53 anos de idade, com um complexo parkinsonismo-demência rapidamente progressivo associado com o acúmulo de manganês no cérebro, secundariamente a insuficiência hepática. Uma RM encefálica foi realizada e foram observadas imagens hiperintensas/hipersinal nas imagens ponderadas em T1 no globo pálido e, também, na substância branca dos hemisférios cerebrais ponderadas em T2. Devido à falta de resposta ao tratamento clinico optamos pelo transplante hepático. O paciente faleceu no 7° dia de PO. Nossos achados corroboram o conceito dos efeitos tóxicos do manganês nos gânglios da base/globo pálido. O tratamento desta forma de parkinsonismo é controverso e o transplante hepático não deverá ser considerada uma opção terapêutica de primeira linha, porém como um tratamento alternativo considerando-se os riscos-benefícios dessa escolha.

Aspectos clínicos e terapêuticos em 135 pacientes com distonia: esperiência do setor de distúrbios do movimento do Hospital das Clínicas da Universidade Federal do Paraná / Clinical and therapeutical features in 135 patients with dystonia: experience of movement disorders unity of the Hospital de Clínicas of the Universidade do Paraná

Este estudo visa descrever aspectos clínicos e respostas terapêuticas de 135 pacientes com distonia. Quanto à classificação, 54 por cento apresentava distonia focal, 17,8 por cento segmentar, 8,1 por cento hemidistonia, 1,5 por cento multifocal e 18,6 por cento generalizada. Vinte e seis por cento apresentavam distonia secundária; e 5,9 por cento tinham história familiar. O tratamento das distonias idiopáticas divide-se em específico e sintomático, podendo ser local, com toxina botulínica; ou sistêmico, com drogas orais. As drogas utilizadas foram anticolinérgicos e benzodiazepínicos, com resposta pobre em formas generalizadas. A toxina botulínica foi utilizada em 54 pacientes com distonia focal ou segmentar. Na distonia cervical o início do efeito (IE) ocorreu em oito dias; obtendo-se efeito máximo (EM) em 25,2 dias, e duração média do efeito (DME) de 76,8 dias. Na síndrome de Meige e blefaroespasmo obtivemos resultados encorajadores: IE=4,5 dias; EM=17,6 dias; DME=87,6 dias. Conclui-se que a toxina botulínica A é a primeira escolha para distonias focais e segmentares, enquanto formas generalizadas apresentam resposta pobre às drogas utilizadas.

Parkinsonism and other movement disorders in outpatients in chronic use of cinnarizine and flunarizine

O objetivo deste estudo foi determinar a prevalência e os padrões de distúrbios do movimento (DM) em pacientes ambulatoriais sob uso crônico de cinarizina (cz) ou flunarizina (fz), além de estabelecer os principais fatores de risco para o seu aparecimento. Durante três meses foram coletados dados de pacientes ambulatoriais em uso de cz ou fz. Todos esses pacientes foram submetidos a protocolo pré-estabelecido que incluía critérios diagnósticos do DSM-IV para distúrbios do movimento induzido por drogas e critérios para diagnostico de depressão maior. Parkinsonismo (PK) puro foi diagnosticado em 34% dos pacientes, PK com acatisia, PK com acatisia e síndrome mastigatória bucolingual (SMBL), SMBL isoladamente e distonia, foram encontrados em 4% dos pacientes. Os pacientes com SMBL apresentavam a média de idade mais avançada, o maior tempo médio de uso das drogas, configurando-se o grupo de maior risco ao aparecimento dos DM. O grupo dos pacientes com DM apresentou maior incidência de depressão quando comparados com os não afetados. O estudo demonstra uma relação direta entre o tempo de uso da droga, a idade avançada do paciente e o surgimento dos DM. Os resultados também sugerem que estas drogas aumentam a incidência de depressão.