Prosopometamorphopsia and Visual Field Defect Improved by Valproic acid in a CADASIL Patient

Persistent aura without infarction is defined as an aura persisting for 1 week or more without evidence of infarction on neuroimaging. It is difficult to differentiate persistent visual aura without infarction from occipital lobe epilepsy. We report a Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy patient with prosopometamorphopsia and visual field defect improved by valproic acid. We also review ambiguity between visual aura in migraine and occipital lobe epilepsy.

Clinical Characteristics of Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Patients with R544C Mutation Aged 90 or Older

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy is an inherited small vessel diseases caused by mutations in the Notch3 gene. In Caucasian patients, the average life expectancy was 65 years for men and 71 years for women. However, this does not seem to be the case in patient with R544C mutation, which is a rare mutation in Caucasian patients. Herein we report two patients with R544C mutation who were older than 90 years who were not previously reported.

CADASIL with clinical manifestations of lumbago, hunchback and Parkinson's syndrome / 中华医学遗传学杂志

OBJECTIVE@#To report a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) manifesting as lumbago, hunchback and Parkinson's syndrome.@*METHODS@#A 49-years-old male CADASIL patient was reported. Results of clinical examination, neuroimaging and genetic testing were analyzed. His family members were also subjected to genetic testing. Related literature was reviewed.@*RESULTS@#The patient had no typical symptoms of CADASIL such as headache, repeated stroke, dementia and emotional disorders, but progressive Parkinson's syndrome, late onset lumbago, hunchback, dysphagia, and diplopia. Brain MRI showed left basal ganglia and external capsule lacunar infarction. Genetic testing revealed a point mutation c.1630C>T (p.R544C) in exon 11 of the NOTCH3 gene. A heterozygous mutation was detected in the same gene in his mother, elder sister and younger brother, all of whom showed different clinical phenotypes.@*CONCLUSION@#The clinical features of CADASIL are heterogeneous. Lumbago, humpback, and Parkinson's syndrome may be a rare clinical phenotype of CADASIL.

Clinical and image features for 12 cases of cerebral autosomal dominant arteriopathy with the subcortical infarcts and leukoencephalopathy / 中南大学学报(医学版)

To analyze the clinical and image features for 12 patients of cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy (CADASIL).
 Methods: A total of 12 CADASIL patients were collected in Xiangya Hospital of Central South University from January 2013 to December 2018. The clinical manifestation, risk factors, MRI imaging data and NOTCH3 mutations were analyzed retrospectively.
 Results: The mean age of 12 patients was (47.25±9.49) years. The clinical manifestation was most common in cognitive impairment (75%) and stroke events (58.3%), and 2 cases showed cerebral hemorrhage. Migraine was only seen in 25% patients. All MRI showed white matter hyperintensity (WMH), lacune and enlarged perivascular space (PVS). WMH mainly occurred in the frontal parietal lobe (100%), temporal lobe (83.3%), external capsule (66.7%), occipital lobe (41.6%), callosum 41.6% and the temporal pole (33.3%), while lacune mainly appeared in frontal lobe (91.6%), parietal lobe(83.3%), temporal lobe(66.7%), basal ganglia (66.7%), brain stem (41.6%), occipital lobe (33.3%), cerebellum (8.3%). Enlarged PVS located in the basal ganglia (100%), partly under the cortex (45.4%). WMH of the patient with intracerebral hemorrhage was mild (Fezakas score 1-2), which was not found in external capsule. 16.7% of the patients had intracranial arterial stenosis. In 12 patients, 8 different Notch3 mutations were detected. The c1013G>c p.(Cys338Ser) located in exon 6, which was a new pathogenic mutation of CADASIL.
 Conclusion: The patients with cerebral hemorrhage have mild WMH and specific genotype, indicating that the clinical characteristics of CADASIL with cerebral hemorrhage may be related to image features and genotype.

Diferenciación clínica del déficit cognitivo del CADASIL con respecto a otras demencias vasculares / Clinical differentiation of the cognitive deficit of CADASIL whit respect to the other vascular dementias

En el mundo hay unos 47 millones de personas que padecen demencia, y cada año se registran cerca de 10 millones de nuevos casos. La demencia es una de las principales causas de discapacidad y dependencia entre las personas mayores de 65 años. La demencia vascular constituye la segunda causa de demencia en adultos mayores y en ocasiones su diagnóstico es poco asertivo por la variedad y similitud de síntomas entre las diferentes enfermedades que originan demencia vascular, incluyendo CADASIL (acrónimo inglés de Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy); particularmente el déficit cognitivo es de los síntomas más complejos de diagnóstico, teniendo en cuenta que su manifestación clínica depende de la magnitud y localización de la lesión. La enfermedad de CADASIL, aunque se constituye como una infrecuente causa de demencia vascular de naturaleza hereditaria a nivel mundial, representa una patología de gran importancia en el ámbito nacional, dado que en familias colombianas se ha reportado mutaciones que conllevan a dicha patología. Por lo tanto, su diagnóstico y tratamiento constituyen un reto para el personal clínico, sabiendo que la identificación temprana y precisa es la mejor estrategia para evitar la progresión precoz de la enfermedad y el mejoramiento de la calidad de vida del paciente. De acuerdo con lo anterior, se realizó una revisión de la diferenciación clínica del déficit cognitivo del CADASIL con respecto a las demás demencias vasculares, con el fin de generar una herramienta que apoye la diferenciación clínica de dicha patología.

In the world, there are approximately 47 million people who have dementia, and every year they register near 10 million new cases. The dementia is one of the principal reasons for disability and dependence between people older than 65 years old. Vascular dementia constitutes the second reason of dementia in the elders, and sometimes the diagnosis is slightly assertive because of the variety and similarity of symptoms between the different diseases that originate vascular dementia, including CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). Particularly, the cognitive deficit is one of the most complex symptoms of diagnosis, bearing in mind that its clinical manifestation depends on the magnitude and location of the injury. CADASIL disease, though it constituted as an infrequent reason of vascular dementia of hereditary nature worldwide, represents a pathology of great importance in the national area, because, in Colombian families, there have been reported mutations that carry to the above-mentioned pathology. Therefore, its diagnosis and treatment constitute a challenge for the clinical personnel, knowing that the early and precise identification is the best strategy to avoid the rapid progression of the disease and the improvement of the quality of life of the patient. In agreement with the previous information, there was made a review of the clinical differentiation of the cognitive deficit of CADASIL regarding other vascular dementias, to generate a tool that supports the clinical differentiation of the pathology mentioned above.

Heterozygous HTRA1 missense mutation in CADASIL-like family disease

The aim of this study was to find related pathogenic genes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in (CADASIL)-like patients. The direct sequencing and high-throughput multiplex polymerase chain reaction (PCR) was performed to screen for related genes. The clinical and imaging data of a CADASIL-like patient (the pro-band) and his family members were collected. At first, the known hereditary cerebral vascular genes of the pro-band were screened with direct sequencing to find candidate gene mutations. High-throughput multiplex PCR was then used to analyze the single nucleotide polymorphism of the candidate gene in the family members. The results showed that there was missense mutation of the high temperature requirement protease A1 (HTRA1) gene in the pro-band, which may be a pathogenic factor according to the biological software analysis. The following SNP results revealed that the other family members also had the HTRA1 gene mutation. Thus, the CADASIL-like family disease may be caused by heterozygous HTRA1 gene mutation, which leads to autosomal dominant hereditary cerebral small vessel disease.

Updates on Prevention of Hemorrhagic and Lacunar Strokes / 대한뇌졸중학회지

Intracerebral hemorrhage (ICH) and lacunar infarction (LI) are the major acute clinical manifestations of cerebral small vessel diseases (cSVDs). Hypertensive small vessel disease, cerebral amyloid angiopathy, and hereditary causes, such as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), constitute the three common cSVD categories. Diagnosing the underlying vascular pathology in these patients is important because the risk and types of recurrent strokes show significant differences. Recent advances in our understanding of the cSVD-related radiological markers have improved our ability to stratify ICH risk in individual patients, which helps guide antithrombotic decisions. There are general good-practice measures for stroke prevention in patients with cSVD, such as optimal blood pressure and glycemic control, while individualized measures tailored for particular patients are often needed. Antithrombotic combinations and anticoagulants should be avoided in cSVD treatment, as they increase the risk of potentially fatal ICH without necessarily lowering LI risk in these patients. Even when indicated for a concurrent pathology, such as nonvalvular atrial fibrillation, nonpharmacological approaches should be considered in the presence of cSVD. More data are emerging regarding the presentation, clinical course, and diagnostic markers of hereditary cSVD, allowing accurate diagnosis, and therefore, guiding management of symptomatic patients. When suspicion for asymptomatic hereditary cSVD exists, the pros and cons of prescribing genetic testing should be discussed in detail in the absence of any curative treatment. Recent data regarding diagnosis, risk stratification, and specific preventive approaches for both sporadic and hereditary cSVDs are discussed in this review article.

Serum Neurofilament Light Chain Levels Are Related to Small Vessel Disease Burden / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) is a blood marker for neuroaxonal damage. We assessed the association between serum NfL and cerebral small vessel disease (SVD), which is highly prevalent in elderly individuals and a major cause of stroke and vascular cognitive impairment. METHODS: Using a cross-sectional design, we studied 53 and 439 patients with genetically defined SVD (Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [CADASIL]) and sporadic SVD, respectively, as well as 93 healthy controls. Serum NfL was measured by an ultrasensitive single-molecule array assay. We quantified magnetic resonance imaging (MRI) markers of SVD, i.e., white matter hyperintensity volume, lacune volume, brain volume, microbleed count, and mean diffusivity obtained from diffusion tensor imaging. Clinical characterization included neuropsychological testing in both SVD samples. CADASIL patients were further characterized for focal neurological deficits (National Institutes of Health stroke scale [NIHSS]) and disability (modified Rankin scale [mRS]). RESULTS: Serum NfL levels were elevated in both SVD samples (P < 1e-05 compared with controls) and associated with all SVD MRI markers. The strongest association was found for mean diffusivity (CADASIL, R2=0.52, P=1.2e-09; sporadic SVD, R2=0.21, P < 1e-15). Serum NfL levels were independently related to processing speed performance (CADASIL, R2=0.27, P=7.6e-05; sporadic SVD, R2=0.06, P=4.8e-08), focal neurological symptoms (CADASIL, NIHSS, P=4.2e-05) and disability (CADASIL, mRS, P=3.0e-06). CONCLUSIONS: We found serum NfL levels to be associated with both imaging and clinical features of SVD. Serum NfL might complement MRI markers in assessing SVD burden. Importantly, SVD needs to be considered when interpreting serum NfL levels in the context of other age-related diseases.

NOTCH3 gene mutations in two Chinese families featuring cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To analyze potential mutations of the NOTCH3 gene in two Chinese families featuring cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy (CADASIL).</p><p><b>METHODS</b>The two probands and related family members and 100 healthy controls were recruited. Potential mutations of the NOTCH3 gene were screened by PCR and direct sequencing. PolyPhen-2 and SIFT software were used to predict the protein function.</p><p><b>RESULTS</b>The conditions of both probands were adult-onset, with main clinical features including recurrent transient ischemic attacks and/or strokes, cognitive impairment. MRI findings suggested multiple cerebral infarcts and severe leukoencephalopathy. A heterozygous mutation c.328C>T (p.Arg110Cys), which was located in exon 3 of the NOTCH3 gene and known as a causative mutation, was identified in proband 1. A novel heterozygous mutation c.1013 G>C (p.Cys338Ser) located in exon 6 of the NOTCH3 gene was identified in the proband 2, which was not reported previously. The same mutations were not detected among the 100 unrelated healthy controls. Function analysis suggested that heterozygous mutation c.1013G>C can severely affect the functions of NOTCH3 protein.</p><p><b>CONCLUSION</b>Two heterozygous missense mutations in the NOTCH3 gene have been identified in two families affected with CADASIL. The novel heterozygous Cys338Ser mutation in exon 6 of the NOTCH3 gene probably underlies the CADASIL.</p>

CADASIL with clinical manifestations of baldness, lumbago and Parkinson's symptoms / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate a cerebral autosomal dominant arteriopathy with the subcortical infarcts and leukoencephalopathy (CADASIL) case with clinical manifestations of baldness, lumbago and Parkinson's symptoms.</p><p><b>METHODS</b>Clinical and imaging data of the patient were analyzed. The patient and his family members were also subjected to genetic testing.</p><p><b>RESULTS</b>The symptoms of the patient included recurrent stroke, dementia, and mood disturbance, in addition with lumbago, baldness and Parkinson's symptoms but no migraine. Cranial MRI of the patient showed bilateral symmetric leukoencephalopathy and multiple small subcortical lacunar infarcts. A point mutation in exon 11 of the NOTCH3 gene (R558C) was discovered in the proband and four asymptomatic relatives.</p><p><b>CONCLUSION</b>CADASIL is characterized by recurrent subcortical ischemic stroke, dementia, pseudobulbar palsy, and mood disturbance. Baldness, lumbago and Parkinson's symptoms may also be seen in such patients.</p>

Study of Enhanced Depth Imaging Optical Coherence Tomography in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small artery disease caused by NOTCH3 gene mutation. We performed enhanced depth imaging optical coherence tomography (EDI-OCT) to evaluate the retinal vessel changes in CADASIL patients and assessed their consonance with brain magnetic resonance imaging (MRI) findings.</p><p><b>METHODS</b>Of 27 genetically confirmed patients and an equal number of controls were recruited at the Peking University First Hospital from January 2015 to August 2016. All patients underwent 7T-MRI of the brain. Fazekas score, number of small infarcts and microbleeds were evaluated. All patients and controls underwent EDI-OCT to measure subfoveal choroidal thickness (SFCT), inner and outer diameters as well as arterial and venous wall thickness, and arterial venous ratio of the inner (AVRin) and outer diameters (AVRout). The relation between retinal vessel changes and Fazekas scores, numbers of small infarcts, or microbleeds was analyzed. Paired t-test was used to compare the SFCT and retinal vessel measurement data between patients and controls. Spearman's correlation was used to investigate the correlation between retinal vessel changes and MRI lesions.</p><p><b>RESULTS</b>In CADASIL patients, mean SFCT (268.37 ± 46.50 μm) and mean arterial inner diameter (93.46 ± 9.70 μm) were significantly lower than that in controls (P < 0.001,P = 0.048, respectively). Mean arterial outer diameter (131.74 ± 10.87 μm), venous inner (128.99 ± 13.62 μm) and outer diameter (164.82 ± 14.77 μm), and mean arterial (19.13 ± 1.85 μm) and venous (17.91 ± 2.76 μm) wall thickness were significantly higher than that in controls (P = 0.023,P = 0.004,P < 0.001,P < 0.001, respectively). Arterial inner diameter (rs= -0.39, P= 0.044), AVRin (rs= -0.65,P < 0.001), and AVRout (rs= -0.56, P= 0.002) showed a negative correlation with the number of small infarcts. Venous inner diameter (rs = 0.46, P= 0.016) showed a positive correlation with the number of small infarcts. Venous inner diameter (rs = 0.59, P= 0.002), outer diameter (rs = 0.47, P= 0.017), showed a positive correlation with the number of cerebral microbleeds (CMBs). AVRin (rs= -0.52, P= 0.007) and AVRout (rs= -0.40, P= 0.048) showed a negative correlation with the number of CMBs.</p><p><b>CONCLUSIONS</b>Measurement of retinal vessels using EDI-OCT correlates moderately well with MRI parameters. EDI-OCT might be a useful evaluation tool for CADASIL patients.</p>

Tratamiento neurorehabilitador en paciente con arteriopatía cerebral hereditaria / Neurorehabilitation treatment in a patient with hereditary cerebral arteriopathy

La arteriopatía cerebral autosómica dominante con infartos subcorticales y leucoencefalopatía, es poco frecuente y con escasos informes en la literatura médica y tiene una mayor prevalencia en el continente europeo. Este cuadro clínico se caracteriza por migrañas con aura, enfermedad cerebrovascular isquémica, demencia y alteraciones psiquiátricas. Su diagnóstico se confirma cuando se detecta una alteración genética característica y/o por cambios anatomopatológicos ocurridos en la piel. Se presenta el caso de un paciente del sexo masculino, de 49 años de edad que ha presentado manifestaciones neurológicas episódicas de cefalea tipo migraña y hemiparesia derecha. Se realizó biopsia de piel, encontrándose alteraciones típicas de esta enfermedad. Se describe la evolución clínica detallada a través del tratamiento neurorehabilitador en un paciente con arteriopatía cerebral hereditaria. Se aplica este tratamiento por 21 días, basado en técnicas de ejercicios neurológicos, cuidados posturales, terapia ocupacional, acupuntura, ozonoterapia, psicológicos, para obtener una mayor independencia en las actividades de la vida diaria, restablecer funciones y mejorar la discapacidad que presenta el paciente. Se describen los cambios ocurridos en las actividades de la vida diaria del paciente y su evolución favorable después del tratamiento neurorehabilitador. La arteriopatía cerebral autosómica dominante con infartos subcorticales y leucoencefalopatía es un terreno poco transitado por los centros de rehabilitación. La ausencia de un tratamiento etiológico hace que la rehabilitación aplicada y practicada permita mantener -periódicamente- un grado mayor de independencia con una mejora de la calidad de vida del paciente y sus familiares. El diagnóstico precoz y la fisioterapia brindan nuevas oportunidades al paciente(AU)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is rare and there are few reports in the literature, with a higher prevalence in Europe. This clinical condition is characterized by migraine with aura, ischemic cerebrovascular disease, dementia and psychiatric disorders. It is done a detailed clinical description of the evolution and diagnosis of this hereditary disease. Diagnosis is confirmed by detecting a characteristic and / or pathological changes in the skin. We present the case of a 49-year-old male patient who has presented episodic neurological manifestations of migraine-type headache and right hemiparesis. A skin biopsy was performed, finding typical alterations of this disease. Detailed clinical course is described through neuro-rehabilitating treatment in a patient with hereditary cerebral arteriopathy. This treatment is applied for 21 days, based on techniques of neurological exercises, postural care, occupational therapy, acupuncture, ozone therapy, psychological, to obtain greater independence in daily living activities, restore functions and improve the disability in this patient. This paper describes the changes that occurred in the patient daily life activities and his favorable evolution after the neuraorehabilitator treatment. Autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy is a gray area for rehabilitation centers. The absence of an etiological treatment means that the rehabilitation applied and practiced allows greater degree of independence to be maintained periodically with an improvement in the quality of life of the patient and family. Early diagnosis and physiotherapy offer new opportunities for the patient(AU)

Phenotypic Features of Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Subjects with R544C Mutation

BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most-common single gene disorder of cerebral small vessel disease. There is no definite evidence of genotype-phenotype correlation in CADASIL. However, recent studies have shown the unique phenotypic feature of NOTCH3 R544C mutation. METHODS: We investigated the phenotypic spectrum of NOTCH3 R544C mutation in 73 CADASIL patients in Jeju between April 2012 and January 2014. RESULTS: Of the 73 subjects from 60 unrelated families included in this study, 40 (55%) were men. The mean age of the subjects was 62.2±12.2 (range 34-86 years). Cerebral infarction was the most frequent manifestation (37%), followed by cognitive impairment (32%), headache (17%), psychiatric symptom (16%), intracerebral hemorrhage (12%), transient ischemic attack (7%), and seizure (1%). The mean age of the subjects with ischemic or hemorrhagic episodes was 64.9±10.9 (range 41-86 years). A diagnosis of dementia was made in 12 subjects (16%). The mean age of the subjects with dementia was 75.6±6.5 (range 62-86 years). About 3% of subjects were unable to walk without assistance at assessment. Only one subject had developed chronic headache before the 40s. CONCLUSIONS: Our data support the hypothesis that CADASIL patients with R544C mutation in Jeju have relatively late onset disease.

Possible Role of a Missense Mutation of p.P167S on NOTCH3 Gene Associated with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder caused by mutations in the NOTCH3 gene, located on chromosome 19p13. NOTCH3 encodes a transmembrane receptor which plays a role in cellular differentiation and cell cycle regulation. CASE REPORT: A 71-year-old female showing headache and memory impairment, familial history of stroke and having a missense mutation from proline to serine at codon 167 in the exon 4 on NOTCH3 gene. Five family members revealed the same mutation (c.499C>T), who presented migrainous headache and stroke. In this study, we have uncovered a novel NOTCH3 mutation at the nucleotide position 499 (c.499C>T; p.P167S) in a family with CADASIL. CONCLUSIONS: We suggested a missense mutation of proline to serine at codon 167 in exon 4 of the NOTCH3 gene, which resulted in the substitution of cytosine to thymine (c.499C>T) resulting migraine, stroke and vascular cognitive impairment.

Cadasil - genetic and ultrastructural diagnosis: case report / Cadasil - diagnóstico genético e ultraestrutural: relato de caso

ABSTRACT Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary disorder which affects the cerebral vasculature due to mutations in the NOTCH 3 gene. The diagnosis may be established through genetic testing for detection of these mutations and/or by skin biopsy. We report a case of the disorder in a female patient, who presented recurrent transient ischemic attacks that evolved to progressive subcortical dementia. Neuroimaging disclosed extensive leukoaraiosis and lacunar infarcts. The genetic analysis for NOTCH 3 was confirmatory. The ultrastructural examination of the skin biopsy sample, initially negative, confirmed the presence of characteristic changes (presence of granular osmiophilic material inclusions [GOM]), after the analysis of new sections of the same specimen. The present findings indicate that negative findings on ultrastructural examinations of biopsy should not exclude the diagnosis of the disease and that further analyses of the sample may be necessary to detect the presence of GOM.

ABSTRACT Arteriopatia Cerebral Autossômica Dominante com Infartos Subcorticais e Leucoencefalopatia (CADASIL) é uma desordem hereditária que acomete a vasculatura cerebral devido a mutações no gene do NOTCH 3. O diagnóstico pode ser estabelecido através de testes genéticos para a detecção das mutações e/ou de biópsia de pele. É relatado um caso da desordem em paciente feminino, que apresentou ataques isquêmicos transitórios recorrentes, evoluindo para um quadro progressivo de demência subcortical. A neuroimagem mostrou extensa leucoaraiose e infartos lacunares. A análise genética para NOTCH 3 foi confirmatória. O exame ultraestrutural de biópsia de pele, inicialmente negativa, confirmou a presença de alterações características (presença de material granular osmiofílico [GOM]), após a análise de novos cortes do mesmo material. Os presentes achados indicam que achados negativos de exames ultraestruturais de biópsia não deveriam excluir o diagnóstico da doença e que análise adicional da amostra pode ser necessária para detectar a presença de GOM.

Friedrich Nietzsche: the wandering and learned neuropath under Dionisius / Friedrich Nietzsche: o neuropata culto e vagante sob Dionísio

Friedrich Nietzsche (1844-1900) was a remarkable philologist-philosopher while remaining in a condition of ill-health. Issues about his wandering/disruptive behavior that might be a consequence and/or protection against his cognitive decline and multifaceted disease are presented. The life complex that raises speculations about its etiology is constituted by: insight, creativity and wandering behavior besides several symptoms and signs of disease(s), mainly neurological one. The most important issue to be considered at the moment is not the disease diagnosis (Lissauer’s general paresis or CADASIL, e.g.), but the probable Nietzsche’s great cognitive reserve linked to the multifactorial etiology (genetic and environmental), and shared characteristics both to creativity and psychopathology. This makes any disease seems especial regarding Nietzsche, and whichever the diagnostic hypothesis has to consider the Nietzsche’s unique background to express any disease(s).

Friedrich Nietzsche (1844-1900) foi um notável filólogo-filósofo enquanto mantinha-se em uma condição de saúde precária. São apresentadas questões sobre seu comportamento errante/disruptivo que podem ser uma consequência e/ou protecção contra seu declínio cognitivo e doença multifacetada. O complexo de vida que levanta especulações sobre sua etiologia é constituído por: insight, criatividade e comportamento errante, além de vários sintomas e sinais de doença(s) principalmente neurológicas. A questão mais importante a ser considerada no momento não é o diagnóstico da doença (Paralisia geral de Lissauer ou CADASIL, por exemplo), mas a grande reserva cognitiva de Nietzsche ligada à etiologia multifatorial (genética e ambiental) e as características comuns tanto para criatividade ou psicopatologia. Isso faz com que qualquer doença do filósofo se expresse de forma especial, e qualquer que seja a hipótese diagnóstica tem que considerar a base especial de Nietzsche para expressar qualquer doença(s).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Argentina / Arteropatia cerebral autosomal dominante com infartos subcorticais e leucoencefalopatia (CADASIL) na Argentina

CADASIL is the most common cause of hereditary stroke and vascular dementia. Published information about this disease in South America is scant. We describe clinical and demographic characteristics of 13 patients (10 families) with CADASIL from Argentina.Methods Medical records, diagnostic tests and family history of patients with CADASIL were reviewed.Results Thirteen patients with CADASIL (10 families) were included. All patients had European ancestry. Initial presentation was stroke in most patients (n = 11). Stroke patients later developed cognitive complaints (n = 9), migraine with aura (n = 1), apathy (n = 4) and depression (n = 6). External capsule and temporal lobe involvement on MRI were characteristic imaging findings. Two patients died after intracerebral hemorrhage.Conclusion This is the first report of non-related patients with CADASIL in South America addressing ancestry. Since European ancestry is not highly prevalent in all South American countries, there may be variable incidence of CADASIL within this region.

CADASIL é a causa mais frequente de acidente vascular cerebral e demência hereditários. São poucas as publicações sobre esta doença na América do Sul. Aqui descrevemos dados clínicos e demográficos de 13 pacientes (10 famílias) da Argentina com CADASIL.Métodos Prontuários médicos testes diagnósticos e história familiar de pacientes com CADASIL foram revisados.Resultados Treze pacientes com CADASIL (10 famílias) foram incluídos. Todos os pacientes tinha ancestralidade europeia. A apresentação inicial foi acidente vascular cerebral na maioria dos pacientes (n = 11). Pacientes com acidente vascular cerebral depois desenvolveram alterações cognitivas (n = 9), enxaqueca com aura (n = 1), apatia (n = 4) e depressão (n = 6). Os achados de imagem característicos da RM foram na cápsula externa e no lobo temporal. Dois pacientes morreram por hemorragia intracerebral.Conclusão Este é o primeiro relato de série de casos de pessoas não relacionadas entre si que apresentavam CADASIL na América do Sul, discutindo ancestralidade. Uma vez que a ascendência europeia tem prevalência variada em diferentes países da América do Sul, é possível que esta seja uma variável de incidência de CADASIL nesta região.

Lacunar Infarction and Small Vessel Disease: Pathology and Pathophysiology / 대한뇌졸중학회지

Two major vascular pathologies underlie brain damage in patients with disease of small size penetrating brain arteries and arterioles; 1) thickening of the arterial media and 2) obstruction of the origins of penetrating arteries by parent artery intimal plaques. The media of these small vessels may be thickened by fibrinoid deposition and hypertrophy of smooth muscle and other connective tissue elements that accompanies degenerative changes in patients with hypertension and or diabetes or can contain foreign deposits as in amyloid angiopathy and genetically mediated conditions such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These pathological changes lead to 2 different pathophysiologies: 1) brain ischemia in regions supplied by the affected arteries. The resultant lesions are deep small infarcts, most often involving the basal ganglia, pons, thalami and cerebral white matter. And 2) leakage of fluid causing edema and later gliosis in white matter tracts. The changes in the media and adventitia effect metalloproteinases and other substances within the matrix of the vessels and lead to abnormal blood/brain barriers in these small vessels. and chronic gliosis and atrophy of cerebral white matter.

Genetics of Cerebral Small Vessel Disease / 대한뇌졸중학회지

Cerebral small vessel disease (SVD) is an important cause of stroke and cognitive impairment among the elderly and is a more frequent cause of stroke in Asia than in the US or Europe. Although traditional risk factors such as hypertension or diabetes mellitus are important in the development of cerebral SVD, the exact pathogenesis is still uncertain. Both, twin and family history studies suggest heritability of sporadic cerebral SVD, while the candidate gene study and the genome-wide association study (GWAS) are mainly used in genetic research. Robust associations between the candidate genes and occurrence of various features of sporadic cerebral SVD, such as lacunar infarction, intracerebral hemorrhage, or white matter hyperintensities, have not yet been elucidated. GWAS, a relatively new technique, overcomes several shortcomings of previous genetic techniques, enabling the detection of several important genetic loci associated with cerebral SVD. In addition to the more common, sporadic cerebral SVD, several single-gene disorders causing cerebral SVD have been identified. The number of reported cases is increasing as the clinical features become clear and diagnostic examinations are more readily available. These include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, COL4A1-related cerebral SVD, autosomal dominant retinal vasculopathy with cerebral leukodystrophy, and Fabry disease. These rare single-gene disorders are expected to play a crucial role in our understanding of cerebral SVD pathogenesis by providing animal models for the identification of cellular, molecular, and biochemical changes underlying cerebral small vessel damage.