A 5-Minute Delay From Bolus Injection to Infusion Halves Plasma Concentration of Tissue Plasminogen Activator.

BACKGROUND: Reducing the time between onset of cerebral infarction and treatment with tissue plasminogen activator improves the prognosis of patients with cerebral infarction. Diverse dosing protocols have been developed with the aim of reducing the time to bolus injection; however, only a few studies have investigated the methods and effects of the interrupted time between bolus and post-bolus infusion. OBJECTIVE: We evaluated the impact of the interrupted time on pharmacokinetic parameters. METHODS: We calculated the changes in alteplase concentration after a bolus injection with high precision, in relation to different interval times. Simulations were performed using the linpk package of the statistical analysis software R. Post-bolus infusion was initiated at 0-, 5-, 15-, and 30-min intervals after bolus dosing. The calculation interval was set as 6 s. RESULTS: Alteplase concentration rose to 1.23 mg/mL after bolus dosing. However, it dropped to 0.53 mg/mL (43.4%) during a 5-min interval, 0.27 mg/mL (22.23%) during a 15-min interval, and 0.10 mg/mL (8.38%) during a 30-min interval. CONCLUSIONS: Because of the short half-life of alteplase, even a short delay in initiating post-bolus infusion can cause a significant reduction in serum alteplase concentration.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): Estimation of pathological lesion stage from brain images.

BACKGROUND: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a disease responsible for cognitive impairment in adult humans. It is caused by mutations in the colony stimulating factor 1 receptor gene (CSF1R) or alanyl-transfer (t) RNA synthetase 2 (AARS2) gene and affects brain white matter. Settlement of stages of the pathological brain lesions (Oyanagi et al. 2017) from the findings of brain imaging will be inevitably essential for prognostication. METHODS: MRI images of eight patients with ALSP were analyzed semiquantitatively. White matter degeneration was assessed on a scale of 0 to 4 (none, patchy, large patchy, confluent, and diffuse) at six anatomical points, and brain atrophy on a scale 0 to 4 (none, slight, mild, moderate, and severe) in four anatomical areas. The scores of the two assessments were then summed to give total MRI scores of 0-40 points. Based on the scores, the MRI features were classified as Grades (0-4). Regression analysis was applied to mutual association between mRS, white matter degeneration score, brain atrophy score, the total MRI score and disease duration. RESULTS: White matter degeneration score, brain atrophy score, and the total MRI score were significantly correlated with the disease duration. MRI Grades (2-4) based on the total MRI scores and the features of the images were well correlated with the pathological lesion stages (II - IV); i.e., 'large patchy' white matter degeneration in the frontal and parietal lobes (MRI Grade 2) corresponded to pathological Stage II, 'confluent' degeneration (Grade 3) to Stage III, and 'diffuse' degeneration (Grade 4) to Stage IV. CONCLUSION: MRI Grades (2-4) resulted from the total MRI scores were well correlated with the pathological lesion Stages (II - IV).

Lung Lobectomy Is an Embolic Risk Factor for Cerebral Infarction, Even in the Long-term Postoperative Phase.

The vein stump created after lung lobectomy has been reported to cause thrombus and subsequently cerebral infarction. However, its assessment after a long-term postoperative course remains unreported. The pulmonary vein stump is a structure near the left atrial appendage; therefore, such patients may be at a constant risk of thrombus formation. We herein report two cases of cerebral infarction associated with lung lobectomy. Transesophageal echocardiography revealed mobile thrombi in the pulmonary vein stump. Both patients had cancer recurrence, and hypercoagulability may have contributed to thrombus formation. This vein stump should be investigated as an embolic source, even after a long postoperative duration.

Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant of HTRA1.

Objective: To investigate the clinical effect of a heterozygous missense variant of HTRA1 on cerebral small vessel disease (CSVD) in a large Japanese family with a p.A252T variant. Methods: We performed clinical, laboratory, radiologic, and genetic evaluations of members of a previously reported family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Results: Two family members were previously reported patients with CARASIL. Among 6 uniallelic p.A252T carriers, 2 had neurologic symptoms with brain MRI abnormalities, 2 showed CSVD on the MRI only, and the other 2 were unaffected. Clinical phenotypes of 2 heterozygous patients were comparable with those of patients with CARASIL, whereas the other 3 heterozygous patients had developed milder and later-onset CSVD. One heterozygous carrier was asymptomatic. Discussion: Previous studies have suggested that uniallelic p.A252T causes disease. However, our study revealed that patients with uniallelic p.A252T can have severe and young-onset CSVD. The clinical manifestations of uniallelic variant carriers were highly variable, even within the same family. Male and atherosclerotic risk factors were considered to be additional factors in the severity of neurologic symptoms in uniallelic p.A252T carriers, suggesting that strict control of vascular risk factors can prevent vascular events in uniallelic HTRA1 carriers.

Two Cases of Alice in Wonderland Syndrome with a Right Occipital Lobe Lesion Caused by Isolated Cortical Venous Thrombosis.

Alice in Wonderland syndrome (AIWS) is extremely rare, occurring more often in young individuals than in older adults. Symptoms of this syndrome typically include an altered body image, size perception, and time perception. However, the pathophysiology and lesions responsible for this syndrome remain unclear. In most cases, specific lesions cannot be identified using computed tomography or magnetic resonance imaging. Two patients with isolated cortical venous thrombosis in the right occipital area experienced transient visual symptoms of AIWS. Furthermore, a literature search indicated that AIWS with visual distortions is associated with right occipital lobe lesions, supporting the findings of our study.

Hypertrophic pachymeningitis in polyarteritis nodosa: a case-based review.

Hypertrophic pachymeningitis (HP) is a rare neurological disorder with focal or diffuse thickening of the dura mater, which usually causes headache, cranial neuropathies, seizures, and motor or sensory impairments. The development of HP is attributed to an immune-mediated mechanism, and some autoimmune diseases have been implicated in the development of HP. Herein, we describe the case of a 73-year-old woman with persistent headache ascribable to HP, which developed approximately 3 years after a diagnosis of polyarteritis nodosa (PAN). She was treated with high-dose corticosteroid and cyclophosphamide that resulted in immediate disappearance of headache and improved radiological findings of thickened dura mater. In addition, she was subsequently administered methotrexate, ultimately resulting in maintenance of remission and regular reduction of prednisolone. In our review of published English articles, only two cases of HP in patients with PAN have been reported to date, suggesting that HP is a rare complication in PAN. However, it should be recognized that HP may develop as a neurological involvement related to PAN.

Delayed Detection of Hydrocephalus following Mildly Traumatic Subarachnoid Hemorrhage in Corticobasal Degeneration: A Case Report.

A 65-year-old woman presented with slowly progressive aphasia with gait disturbance associated with parkinsonism. She experienced a fall that resulted in a brain trauma. Brain imaging revealed a small amount of subarachnoid hemorrhage (SAH) with intraventricular bleeding. Despite conservative therapy, gait disturbance and hyporesponsiveness gradually deteriorated following that brain trauma. One month later, she was transferred to our hospital, and magnetic resonance imaging revealed prominent communicating hydrocephalus. A ventriculoperitoneal shunt and brain biopsy were performed. Neurosurgical intervention did not improve the patient's neurological condition. Clinical-pathological analysis confirmed the diagnosis of corticobasal degeneration (CBD) as an underlying disease relating to parkinsonism and aphasia. In patients with parkinsonism with high risks of falling, attention should be paid to neurological deterioration due to traumatic SAH-related hydrocephalus. Particularly, in patients with aphasia such as in those with CBD, delayed detection of posttraumatic complications might cause poor responsiveness to surgical intervention.

Pathologic basis of the preferential thinning of thecorpus callosum in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

BACKGROUND: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an early onset dementia characterized by axonal loss in the cerebral white matter with swollen axons (spheroids). It had been reported that the preferential thinning and "focal lesions" of the corpus callosum were observed on T2-weighted MRI in ALSP patients. The present study aimed to reveal the pathologic basis of them in relation to brain lesion staging (I ~ IV: Oyanagi et al. 2017). METHODS: Seven autopsied brains of ALSP and five controls were neuropathologically examined. RESULTS: Even at Stage I, corpus callosum body showed evident atrophy, and the atrophy advanced with stage progression. Spheroid size and density were maximal at Stage II in both centrum semiovale and corpus callosum body, but spheroids were larger in corpus callosum body than in centrum semiovale. Microglia in the body at Stage II had a larger cytoplasm than those in centrum semiovale. But spheroids and microglia in the "focal lesions" were identical with those of centrum semiovale. CONCLUSION: Preferential thinning of corpus callosum was considered to be formed in relation to peculiar morphological alteration of microglia there in ALSP. Instead, "focal lesions" were formed in connection with the lesions in centrum semiovale.

Development of Arthritis as the Initial Involvement in Adult-Onset Cutaneous Polyarteritis Nodosa: Two Cases and Literature Review.

Articular symptoms are commonly present in polyarteritis nodosa (PAN). Meanwhile, they may occur as the initial and main involvement of PAN, raising a concern of a delay in a definitive diagnosis of disease unless the histological evidence is obtained. Herein, we report two cases of cutaneous PAN (c-PAN) in which arthritis developed as the initial clinical episode of disease and we argued, through a review of the literature, the clinical feature of patients presenting with arthritis as the initial symptom of PAN. To our knowledge, only six cases have been reported in the English literature, and all six patients were categorized as having c-PAN. Of those patients, four had arthritis with indicating destructive changes. A median of 9 years elapsed prior to the induction of immunosuppressive treatment despite the fact that the other reviewed cases as well as our two patients, who received treatment significantly earlier, showed no evidence of joint destruction. Taken together, this report suggests that the early induction of therapy based on the definitive diagnosis of PAN may be required for preventing joint disruption even though it is not easy to make a diagnosis of PAN unless biopsied tissue can provide the evidence of necrotizing vasculitis.

Intrafamilial phenotypic variation in spinocerebellar ataxia type 23.

BACKGROUND: Spinocerebellar ataxia type 23 (SCA23) is an autosomal dominant cerebellar ataxia caused by pathogenic variants in the prodynorphin gene (PDYN). The frequency of PDYN variants is reportedly very low (~ 0.1%) in several ataxia cohorts screened to date. CASE PRESENTATIONS: We found five cases of SCA23 in two families (mean age at onset: 37.8 ± 5.5 years; mean age at examination: 64.2 ± 12.3 years) with a novel PDYN variant (c.644G > A:p.R215H). We identified marked heterogeneity in the clinical features in Family 1: the proband showed clinical and neuroimaging features suggestive of multiple system atrophy with predominant parkinsonism (MSA-P). Conversely, the proband's mother with the PDYN p.R215H variant had no subjective symptoms; she had not come to medical attention before our survey, although she showed apparent cerebellar atrophy on brain magnetic resonance imaging (MRI). The other two patients in Family 1 and a patient in Family 2 showed slowly progressive cerebellar ataxia. CONCLUSIONS: We here report two Japanese families with SCA23, one of which showed considerable phenotypic variation in affected members. Our findings support that SCA23 can phenotypically overlap with MSA.

Recurrent Painful Ophthalmoplegic Neuropathy with Residual Mydriasis in an Adult: Should it Be Classified as Ophthalmoplegic Migraine?

Recurrent painful ophthalmoplegic neuropathy (RPON) is a rare condition that manifests as headache and ophthalmoplegia. It typically occurs in children. Although migraine or neuropathy have been suggested as etiologies, the precise etiology remains unclear. In the International Classification of Headache Disorders 3rd edition-beta version (ICHD3ß) (code 13.9), RPON was categorized into painful cranial neuropathies and other facial pains. We encountered a 48-year-old woman who had diplopia and right ptosis. The administration of prednisolone led to the immediate improvement of her oculomotor palsy, but residual mydriasis remained. Based on this case, the pathophysiology of RPON may involve temporary nerve inflammation with migraine. Repeated and severe migraine attacks may cause irreversible nerve damage. Thus, medication for migraine prophylaxis might be needed to prevent RPON.

Protein-losing Gastroenteropathy Related to Mixed Connective Tissue Disease: A Case Report of a Successful Outcome and Literature Review.

We herein report the case of a 44-year-old woman who developed protein-losing gastroenteropathy (PLGE) with hypoalbuminemia as the first manifestation of mixed connective tissue disease (MCTD). Albumin leakage from the stomach and intestinal tract was demonstrated by 99mTc-labeled human serum albumin scintigraphy. The patient's response to prednisolone therapy was insufficient; therefore, additional cyclosporin A (CsA) treatment was administered, and clinical remission was achieved. We concluded that although PLGE is a rare complication of MCTD, it may manifest as an initial clinical episode of MCTD. Furthermore, CsA can be a useful treatment option for refractory PLGE related to MCTD.

Corpus callosum atrophy in patients with hereditary diffuse leukoencephalopathy with neuroaxonal spheroids: an MRI-based study.

OBJECTIVE: Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is an adult-onset white matter disease that presents clinically with cognitive, mental and motor dysfunction. Several autopsy reports have indicated that the corpus callosum (CC), the largest bundle of white matter, is severely affected in patients with HDLS. The aim of this study was to evaluate corpus callosum atrophy (CCA) quantitatively in HDLS patients. METHODS: We assessed CCA in six genetically-proven HDLS patients (HDLS group), in comparison with that observed in 20 patients with vascular dementia (VaD group) and 24 age-matched patients without organic central nervous system (CNS) disease (non-CNS group). Using midsagittal MR images, five measurements of the CC were obtained: the width of the rostrum (aa'), body (bb') and splenium (cc'), the anterior to posterior length (ab) and the maximum height (cd). Next, the corpus callosum index (CCI) was calculated as (aa' + bb' + cc')/ab. RESULTS: All HDLS patients had white matter lesions in the CC and frontoparietal lobes on the initial MRI scans. Compared with that observed in the VaD and age-matched non-CNS groups, the CCI was significantly decreased in the HDLS group (with VaD group, p<0.01; with non-CNS group, p<0.01). CONCLUSION: This study showed significant atrophy of the CC in all HDLS patients on the initial MRI scans obtained 6-36 months after onset. We propose that the early appearance of CCA, frequently accompanied by high-intensity in the genu and/or splenium, on T2 images is an important diagnostic clue to HDLS.

Early involvement of the corpus callosum in a patient with hereditary diffuse leukoencephalopathy with spheroids carrying the de novo K793T mutation of CSF1R.

We herein report the case of a 41-year-old Japanese man with hereditary diffuse leukoencephalopathy with spheroids (HDLS) who carried the de novo K793T mutation in the colony-stimulating factor 1 receptor gene (CSF1R). He showed a gradual decline of his cognitive and mental functions over the following six months. On brain MRI, a thin corpus callosum with T2- and FLAIR-high signal intensity in the splenium was conspicuous, whereas cerebral deep and periventricular white matter lesions were mild. We propose that a diagnosis of HDLS should be considered in patients with presenile dementia presenting with corpus callosum lesions on MRI, even in cases with a lack of any apparent family history.