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In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) the vascular smooth muscle cells are destroyed and granular osmiophilic material is deposited followed by fibrosis of the arterial wall. To verify whether true stenosis of the fibrotic white matter arteries is a key pathogenic event in CADASIL, we analyzed the thickness of walls (expressed as sclerotic index) and luminal diameters of penetrating arterioles in both grey matter and white matter of four CADASIL patients due to the C475T (R133C) mutation in the Notch3 gene and in 9 age-matched controls. We also reconstructed 9 arterioles from 1000 serial sections in two CADASIL patients. The thickness of the arteriolar walls in both grey matter and white matter was significantly increased in the CADASIL patients compared with controls. Furthermore, in CADASIL patients the arteriolar walls were significantly thicker in the white matter than in the grey matter. The distribution curve of arteriolar internal diameters in CADASIL patients shifted towards smaller sizes. In serial sections, the marked increase in the thickness of the white matter penetrating arterioles or their branches did not occur until the internal diameters had decreased to about 20 to 30 pm and external diameters to about 100 to 130 microm. In conclusion, long penetrating arterioles and their branches supplying subcortical structures in CADASIL are stenosed and their walls are thickened. This conforms to the abundance of infarcts and primary ischemic damage in CADASIL patients' white matter.

Background and Purpose— Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) causes repeated ischemic attacks leading to subcortical vascular dementia. The aim of this study was to characterize cognitive function in subjects with a C475T (R133C) mutation in the Notch3 gene, leading to CADASIL. Methods— Prestroke (n=13) and poststroke (n=13) mutation carriers and mutation carriers with dementia (n=8) were compared with healthy noncarriers from the same families using a comprehensive set of neuropsychological tests. Results— Changes in working memory and executive function were observed in the very early phase of the disease before transient ischemic attack (TIA) or stroke. Later, in the poststroke phase, the cognitive impairment concerned also mental speed and visuospatial ability. Finally, the subjects with dementia had multiple cognitive deficits, which engaged even verbal functions, verbal episodic memory, and motor speed. The 2 mutation carrier groups without dementia and the controls could be reliably distinguished using 3 tests that assessed working memory/attention, executive function, and mental speed. Episodic memory was relatively well-preserved late in the disease. Conclusion— A deterioration of working memory and executive function was already observed in the prestroke phase, which means that cognitive decline may start insidiously before the first onset of symptomatic ischemic episodes.

Whitefish eggs were confirmed by pulsed-field gel electrophoresis to cause type E foodborne botulism in a 54-year-old patient in Finland. Botulinum neurotoxin and/or nonproteolytic Clostridium botulinum type E organisms were detected in fecal and gastric samples from the patient and in suspected whitefish eggs. Apart from C. botulinum type E, proteolytic type B organisms were detected in the patient's gastric content. This was considered to be insignificant with respect to the clinical disease, suggesting botulinal spores to be occasionally present in the human gastrointestinal tract without any apparent clinical significance. This is the first domestic case of foodborne botulism in Finland.

Purpose: To describe the magnetic resonance imaging (MRI) findings of four patients with proven tick‐borne encephalitis (TBE). These are the most northern cases reported from Scandinavia. Experience of turbo fluid‐attenuated inversion recovery (FLAIR) and diffusion‐weighted imaging (DWI) has not previously been published in this context. Material and Methods: The MRI findings of four consecutive patients with TBE treated in our hospital during the year 2002 were evaluated. MRI was done during the first week of illness, and follow‐up scans were available in three cases. Results: In T2‐weighted and turbo FLAIR images, thalamic hyperintensity was equally evident in three of the four patients. One of them also showed hyperintensity in the left putamen and the internal capsule and another patient in the peduncles and the hypothalamus. T1‐weighted images without contrast were normal in all patients, and leptomeningeal enhancement was detected in only one patient. The two patients who underwent DW images did not show any restricted diffusion. Follow‐up MR images showed no atrophy or necrotic foci, and the signal abnormalities disappeared during 16–34 weeks of follow‐up. Conclusion: T2‐weighted and turbo FLAIR sequences proved equally effective in detecting and delineating the thalamic, brainstem, and basal ganglia pathologies. According to our results, mechanisms other than cytotoxic edema contribute to the signal pathology. Radiologists should be familiar with the MR findings of TBE even in non‐endemic areas.

Herpes simplex virus type 2 (HSV-2) as a cause of post-neonatal meningoencephalitis is very rare. We present a 50-year-old patient with proven HSV-2 encephalitis, which preceded herpetic genital vesicles. This is the first report on HSV-2 encephalitis where the turbo-Flair-sequence was used for both diagnosis and follow-up.

Background and Purpose — CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation. Methods — The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically. Results — The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient’s heterozygous son had his first transient ischemic attack–like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient. Conclusions — Our homozygous patient’s phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.

Tick-borne encephalitis is a significant concern in endemic regions, and in rare cases it may even be fatal. There is no specific treatment for the disease. Vaccines from two manufacturers are available against tick-borne encephalitis, both considered effective and safe. Severe adverse effects due to tick-borne encephalitis vaccine are rare. We describe the first severe myelitis detected in Finland following vaccination against tick-borne encephalitis.

The number of cases with tick-borne encephalitis in Europe has increased particularly in the 1990's, and new regions have become endemic. Ixodes persulcatus, i.e. the taiga tick, is found on the west coast of Finland along the Närpiö-Simo axis. This tick has not been encountered in other parts of Western Europe. In Kokkola archipelago it transmits the Siberian subtype of tick-borne encephalitis virus. We describe the first and fatal case of tick-borne encephalitis transmitted by the "taiga tick" in Finland.

Background and Purpose— In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) the arteriopathy leads to recurrent infarcts in cerebral white matter (WM) and deep gray matter (GM), whereas cortex is spared. To assess the pathogenesis of deep GM infarcts, we analyzed structural changes in arterioles of the lenticular nucleus (LN) in 6 CADASIL patients. Methods— Five elderly and one 32-year-old deceased CADASIL patients were studied. Seven elderly and 4 young deceased persons without cerebrovascular diseases served as controls. In addition to immunohistochemical analysis the external and luminal diameters of arterioles in the LN, cerebral cortex and WM were measured. The thickness of arteriolar wall and sclerotic index were calculated. Results— In CADASIL patients, LN arterioles were immunoreactive for the extracellular domain of Notch3 and collagen I, whereas α-smooth muscle actin staining was irregular or negative. No major leakage of plasma fibrinogen or fibronectin was observed. Although in patients the walls of LN arterioles were significantly thicker than in controls, definite stenosis was not observed. Arteriolar lumina in the LN were not only significantly larger than in the WM, where most lacunar infarcts in CADASIL occur, but also larger than in cortical GM, where infarcts virtually never exist. Conclusions— Fibrotic thickening of the arteriolar walls without consequent stenosis occurs in the LN of CADASIL patients. The pathogenesis of lacunar infarcts in the WM and LN seem to be different, stenosis in the former and probably hemodynamic disturbances in the latter.

Based on a structured questionnaire and medical records, the authors found that 12 of 25 mothers with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with the R133C NOTCH3 mutation had had neurologic symptoms in 17 of their 43 pregnancies, most commonly hemiparesthesia (76%), hemiparesis (36%), aphasia (65%), and visual disorders (47%). In 82% of the patients, the symptoms were the first manifestation of CADASIL. The symptoms were most common during puerperium and in patients older than age 30.

To determine the ophthalmologic findings, especially the nature of retinal vascular changes, and their clinical significance in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a disease that causes migraine, recurrent strokes, and finally subcortical vascular dementia.Cross-sectional study.Thirty-eight CADASIL patients (19 to 61 years old; 20 in a prestroke group, 15 in a stroke group, and 3 in a dementia group), all with the R133C NOTCH3 mutation and including one homozygous patient, underwent a detailed ophthalmologic examination.Common cardiovascular risk factors were evaluated. Ophthalmologic examination included best-corrected visual acuity, anterior- and posterior-segment biomicroscopy, and measurement of intraocular pressure. In 33 patients and 16 healthy controls (20-64 years old), retinal fundus photographs were taken. Diameters of all arterioles and venules located in the area from 0.5 to 1.0 disc diameters from the optic disc margin were measured with a computer-based program and arteriole-to-venule (A/V) ratios were calculated from digitized photographs.General arterial narrowing and arteriovenous nickings were common. Straightening of the retinal arterioles and a marked wall reflex (n = 6) occurred. The A/V ratio of CADASIL patients was significantly (P0.001) lower than that of controls. One patient had one retinal microinfarct and hemorrhages. The homozygous patient had a chorioretinal scar as a sign of circulatory deficiency. Anterior-segment changes included mild iris atrophy (n = 5) and various degrees of lens opacities. Visual acuity was normal in all but 2 patients, who had cataract and amblyopia.The generalized arteriopathy of CADASIL causes a wide variety of changes in retinal arterioles but only minimal functional disturbances. These findings are consistent with alterations in arterioles in the cerebral cortex with which the retina and its arterioles are analogous, but contrast with the severe damage of cerebral white matter arterioles.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease characterized by brain infarcts, cognitive decline and dementia. The disease is caused by at least 91 missense mutations, four deletions and one splice site mutation in the NOTCH3 gene, which maps to 19p13.1. In 18 out of the 21 Finnish CADASIL families so far identified, the causative mutation is an arginine to cysteine substitution in position 133 (R133C). Most of the families carrying this mutation originate from the western coast of Finland, thus suggesting a founder effect. No previous reports of a founder effect in CADASIL have been published. We haplotyped 60 patients from these 18 families for 10 microsatellite markers in order to determine whether the families descend from a common ancestor. We found a similar haplotype linked to the mutation in all 18 pedigrees, which indicates a single common ancestor for all the Finnish R133C families. The age analysis of the founder mutation places the introduction of the mutation in the late 1600s or early 1700s.

Background and Purpose— CADASIL causes repeated ischemic strokes leading to subcortical vascular dementia. The purpose of this study was to assess whether cerebral blood flow (CBF) and regional cerebral metabolic rates of glucose (rCMR gluc ) in CADASIL patients are affected in early adulthood. Methods— CBF and rCMR gluc were examined with positron emission tomography in correlation with magnetic resonance imaging (MRI) in 14 adult (19 to 41 years) CADASIL patients with the Notch3 R133C mutation. Seven patients had experienced transient ischemic attack and 3 had experienced ≥1 strokes. Results— The mean CBF in the CADASIL patients was significantly lower in both frontal ( P =0.019) and occipital ( P =0.009) white matter (WM) than those in the controls. CBF decreased significantly with increased severity of the disease. The patients had lower mean rCMR gluc values than the controls, although differences were not statistically significant. Sum scores of semiquantitative MRI rating scale (Scheltens) correlated significantly with WM CBF but not with rCMR gluc . Conclusions— In CADASIL, there is an early and significant decrease in the CBF of WM associated with simultaneous MRI changes. These are obviously caused by the arteriopathy in long penetrating arteries and indicate early tissue damage, also expressed as impaired rCMR gluc in the WM.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by cerebral symptoms, but peripheral nerve or muscle involvement has not been reported. We describe a patient who had a stereotypic clinical presentation of CADASIL and, in addition, myopathy with ragged-red fibers, suggesting a mitochondrial disorder. Therefore we determined the nucleotide sequence in the entire coding region of the patient's mtDNA by conformation-sensitive gel electrophoresis and sequencing. Sequence of the exon 4 in the Notch3 gene was determined in a similar fashion. We found that the patient had myopathy with ragged-red fibers, and ultrastructural examination revealed mitochondrial aberrations. CADASIL was due to an R133C mutation in Notch3; in addition, we found a novel mutation 5650GA in the tRNAAla gene in mtDNA. The mutation was heteroplasmic, with the proportions of the mutant genome being 99% in muscle, 96% in the buccal epithelium, 95% in the skin, and 65% in the blood. The absence of the mutation in a maternal cousin four times removed indicated that it was new in the pedigree. We suggest that the mtDNA mutation is pathogenic, as it was associated with a relevant clinical phenotype, it was not found among controls, and it altered a structurally important segment in the amino acid acceptor stem in the tRNAAla. Furthermore, its absence in nine patients from five families with R133C suggests that its relationship with the Notch3 mutation is coincidental.

The present study focuses on semantic deficits in Alzheimer's disease (AD). We distinguish three different levels of semantic knowledge: (1) lexical, (2) semantic-conceptual, (3) conscious understanding. We devised methods that tap levels (2) and (3). Our aim was to determine how much guidance AD patients need to consciously access a given semantic-conceptual field and how well they can understand the meanings of concepts and semantic relations. Four different tasks were used to tap different kinds of concepts, the relationships between concepts and their attributes, and the hierarchical structure among different concepts. The retrieval demands of the tasks were eased by presenting guiding questions. The results revealed that AD patients have deficient voluntary access to semantic-conceptual representations. The deficits persist even in passive recognition and forced-choice tasks. We conclude that AD patients have a generalized access deficit, although some aspects of the results are suggestive of storage deficit.

Ophthalmologic findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy : a cross-sectional study.