Masahiro Uemura

Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL.

Objective: To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals. Methods: We recruited 113 unrelated index patients with clinically diagnosed cerebral small vessel disease. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. Results: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. The mean age at cognitive impairment onset was 51.1 years. Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases; an autopsied case with p.G283E showed arteriopathy in their cerebral small arteries. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer-associated HTRA1 activation. Conclusions: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.

Identification of internal carotid artery dissection by transoral carotid ultrasonography.

Background and Purpose: Conventional transsurface carotid ultrasonography (TSCU) via the cervical surface often fails to detect dissection of the extracranial internal carotid artery (ICA). The role of transoral carotid ultrasonography (TOCU) in the detection of ICA dissection was examined. Method: Patients with unilateral extracranial ICA dissection identified by digital subtraction angiography (DSA) from our database of patients with ischemic stroke or transient ischemic attack (TIA) were reviewed. Findings of dissection were compared between TSCU and TOCU. Results: Eight patients (7 men, 37–69 years old), including 7 with ischemic stroke and 1 with TIA, had ICA dissection. By DSA, dissection was identified between the first and third vertebrae in 4 patients and from the third cervical vertebra to the intracranial level in the remaining 4. TOCU images revealed an intimal flap as definite evidence of dissection in all patients. In 7 patients, color flow signals were not seen in false lumens, indicating thrombosed lumens. Four patients showed morphological changes of dissection on follow-up TOCU, including a patient with recovery of color flow signals in false lumens. The diameter of the dissected ICA was 7.3 ± 0.7 mm and that of the contralateral ICA was 4.9 ± 0.6 mm (p = 0.008). In contrast, TSCU did not enable any conclusive findings of ICA dissection to be made in any patient. Six patients had intramural hematoma on T1-weighted MRI, and 2 had an intimal flap with a double lumen on magnetic resonance angiography. Conclusion: TOCU has advantages over TSCU in achieving an accurate diagnosis and follow-up evaluation of ICA dissection.

Dropped head syndrome in amyotrophic lateral sclerosis.

Dropped head syndrome (DHS), which is characterized by severe neck flexion without thoracic or lumbar curvature, limits activities of daily living (ADL) because the patient can only look downward. ...

Pituitary apoplexy during treatment with dabigatran

Pituitary apoplexy is known as an uncommon complication of pituitary adenoma, and anticoagulant therapy has been reported as one of the precipitating factors. We report an 85‐year‐old man who developed pituitary apoplexy during treatment with dabigatran. His medical history included a non‐functioning pituitary adenoma and non‐valvular atrial fibrillation. Headache occurred 4 days after changing the anticoagulant from warfarin to dabigatran; and other neurological symptoms, such as ptosis and ophthalmoplegia, subsequently developed. On admission, laboratory examination showed a prolonged activated partial thromboplastin time and moderately decreased kidney dysfunction. Emergency magnetic resonance imaging (MRI) showed pituitary hemorrhage in the tumor. Although dabigatran was reported to cause intracranial hemorrhage less commonly than warfarin, it could cause uncommon bleeding like in the present case.

Spontaneous Middle Cerebral Artery Dissection Demonstrated by High-Resolution T1-Weighted 3D Image

Case Report A 39-year-old, right-handed man was admitted to our hospital because of sudden onset of right hemiparesis and aphasia. His medical history included atopic dermatitis, and included no episodes of trauma. He was alert on admission; however, his speech and comprehension were impaired, and was assessed a National Institutes of Health Stroke Scale score of 15. Brain computed tomography showed obscuration of the lentiform nucleus on the left side. Computed tomography angiography (CTA) demonstrated an occlusion of the left MCA at the horizontal segment. Laboratory examination yielded unremarkable results. Administration of intravenous recombinant tissue plasminogen activator (IV rtPA) was started at 164 min after symptom onset (alteplase, 0.6 mg/ kg). However, no neurological improvement was observed. Transcranial color-coded flow velocity measurements demonstrated reperfusion of the left MCA just after IV rt-PA administration, and 1.5T MRI detected an acute infarction in the left putamen, insular cortex, and corona radiata ( fig. 1 a). Magnetic resonance angiography results could not be evaluated because of motion artifacts. On day 4, CTA showed dilatation of the left MCA ( fig. 1 b) and the double lumen sign ( fig. 1 c), on the basis of which spontaneous MCAD was strongly suggested. However, atherothrombic occlusion, while unlikely given the circumstances, could not be completely ruled out at the time, since the fat-saturated T1-weighted imaging [4] needed to make an unambiguous diagnosis of MCAD was not performed. On day 17, fast spoiled gradient-echo images Spontaneous cervicocephalic arterial dissection is an uncommon cause of stroke [1] . Segments of the middle cerebral artery (MCA) are rarely involved, and the incidence of MCA dissection (MCAD) is reported to be 4% of the spontaneous cervicocephalic arterial dissections in Japan [2] . A previous report suggests that magnetic resonance imaging (MRI) may be useful for detecting intracranial vertebrobasilar artery dissection [3] , although the applicability in MCAD patients is unknown. Here, we report a patient who had MCAD with characteristic lesions, which was demonstrated by high-resolution T1-weighted 3D images obtained using a 3-tesla MRI (3T MRI) system. Published online: October 12, 2013

CARASIL families from India with 3 novel null mutations in theHTRA1gene

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (MIM 600142) is linked to homozygous mutations in the high-temperature requirement A serine peptidase 1 gene (HTRA1).1 The triad includes alopecia, spondylosis deformans, and young-adult onset dementia following leukoaraiosis caused by cerebral small-vessel disease (CSVD).2 Although CARASIL originally was considered to be a recessive disorder and monoethnic, restricted to Japan, there are several reports of genetically confirmed cases and a few manifest heterozygotes in other ethnicities, thus expanding the CARASIL paradigm.3–6 In this study, we describe 3 CARASIL families carrying novel null HTRA1 mutations and also the notable phenotypes among the heterozygotes.

Visualization of the Intimal Flap in Intracranial Arterial Dissection Using High-Resolution 3T MRI.

Presence of an intimal flap is a critical imaging finding in diagnosing intracranial artery dissection (ICAD). Recent reports showed that high‐resolution magnetic resonance imaging (MRI) was better at identifying intimal flaps as compared with routine MRI techniques used in clinical settings. However, no current standardized sequence for high‐resolution MRI without gadolinium enhancement produces images of satisfactory quality with clinically tolerable scanning times. This study evaluated a nonenhanced high‐resolution fast spin echo (HR‐FSE) MRI sequence for visualizing intimal flaps in patients with ICAD.

Ipsilateral hemiparesis in lateral medullary infarction: Clinical investigation of the lesion location on magnetic resonance imaging

BACKGROUND In 1946, Opalski reported two cases of Wallenberg syndrome with ipsilateral hemiparesis (IH). His hypothesis seems to be based on the view that IH is caused by post-decussating pyramidal tract damage. Afterwards, other researchers proposed a different hypothesis that ipsilateral sensory symptoms of limbs (ISSL) or ipsilateral limb ataxia (ILA) caused by lateral medullary infarction (LMI) might lead to ipsilateral motor weakness. The present study is aimed to clarify whether IH in LMI patients is attributable mainly to ISSL/ILA or disruption of ipsilateral post-decussating pyramidal tract. METHODS Thirty-two patients with acute LMI admitted during the last 13years were divided to IH Group (n=7) and Non-IH Group (n=25). Lesion location/distribution on MRI and neurological findings were compared between the two groups. RESULTS LMI involved the lower medulla in all seven IH patients and 12 of 25 Non-IH patients. The lower medullary lesion extended to the cervico-medullary junction (CMJ) in four of seven IH patients and one of 12 Non-IH patients. Definitive extension to upper cervical cord (UCC) was confirmed in none of the patients. ISSL was found in two IH and three Non-IH patients all showing only superficial sensory impairments. ILA or hypotonia was observed in 57% of IH and 60% of Non-IH patients. CONCLUSION IH in LMI appears to be due mainly to post-decussating pyramidal tract damage at the lower medulla instead of ILA or ISSL participation.

Locked‐in syndrome caused by bilateral midbrain infarctions with occlusion of the intracranial vertebral artery

Bilateral cerebral peduncles are rarely simultaneously infarcted unless the basilar artery is involved. A 60‐year‐old man developed locked‐in syndrome because of bilateral cerebral peduncle infarctions with right intracranial vertebral artery occlusion. Dysarthria occurred a day before admission. His neurological condition rapidly deteriorated, and he subsequently became quadriplegic. His left vertebral artery showed a posterior inferior cerebellar artery end pattern, and anastomosis between the anterior and posterior circulations through the hypoplastic right P1 and fine left posterior communicating artery was insufficient; therefore, severe hypoperfusion and multiple infarctions in the distribution of the posterior circulation were induced by right intracranial vertebral artery occlusion. These findings highlight the fact that large‐artery atherosclerosis represents an important cause of mesencephalic infarctions. Several neurological manifestations are caused by intracranial vertebral artery occlusion, and when collateral flow to the posterior circulation is insufficient, intracranial vertebral artery occlusion results in bilateral cerebral peduncle infarctions and locked‐in syndrome without basilar artery occlusion.