INVESTIGATION OF INCIDENCE AND CAUSES OF ACUTE VISION LOSS DURING ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION DURING A FOUR-YEAR FOLLOW-UP.

PURPOSE: To investigate the incidence, risk factors, and outcomes of patients with age-related macular degeneration who experienced acute vision loss despite periodic injections of anti-vascular endothelial growth factor treatment for 4 years. METHODS: This retrospective cohort study included patients who were diagnosed with treatment-naive neovascular age-related macular degeneration and completed a 4-year follow-up. The incidence and risk factors for the occurrence of three or more lines of visual loss at every checkup were investigated. RESULTS: The analysis included 76 eyes of 76 patients. Acute vision loss occurred in 30 eyes (39.5%) over 4 years. Lower baseline best-corrected visual acuity and disrupted ellipsoid zone were independent predictors of vision loss occurrence. Although the causes and timing of visual acuity loss varied, retinal pigment epithelium tears were observed only in the first year. Most patients (86.7%) who experienced vision loss recovered their vision to pre-loss levels at least once; however, the final best-corrected visual acuity was worse than that in the group that did not experience acute vision loss. CONCLUSION: Approximately half of the patients with age-related macular degeneration experienced acute vision loss during a 4-year follow-up, despite continuous anti-vascular endothelial growth factor treatment. Most patients recovered from vision losses temporarily; however, they experienced worse visual outcomes subsequently.

Venous Cerebral Infarction Due to Thrombosis of an Isolated Intraventricular Cerebral Varix: A Case Report.

OBJECTIVES: An isolated intraventricular cerebral varix is a rare entity. Although it is generally asymptomatic, there have been reports of symptomatic cases. Here, we report a case of right hemiplegia and aphasia due to venous infarction caused by thrombosis of the intraventricular varix. CASE PRESENTATION: A 79-year-old woman presented with right-sided hemiplegia and aphasia accompanied by conjugate eye deviation to the left. She had a history of hypertension, dyslipidemia, and asymptomatic isolated cerebral varix located in the left lateral ventricle. Blood analysis indicated no abnormalities in coagulation or fibrinolysis. Plain head computed tomography showed an intraventricular varix in the form of a high-density mass, indicating acute phase thrombosis, and contrast-enhanced computed tomography depicted a filling defect in the varix. In addition, fluid-attenuated inversion recovery imaging showed hyperintense lesions in the deep white matter of the frontal-parietal lobe, indicating venous infarction due to occlusion of the varix of the thalamostriate vein. Glycerol and prophylactic levetiracetam were administered, and she was transferred to another hospital for rehabilitation 23 days after treatment initiation. CONCLUSION: This is the first reported case in which a typically asymptomatic condition, intraventricular cerebral varix, caused venous infarction due to thrombosis and occlusion of the varix of the thalamostriate vein. Careful selection of the treatment strategy is required on a case-by-case basis because an intraventricular varix can cause both bleeding and infarction, which are treated differently.

Propionibacterium acnes-associated chronic hypertrophic pachymeningitis followed by refractory otitis media: a case report.

BACKGROUND: Hypertrophic pachymeningitis (HP) is a rare disorder that involves localized or diffuse thickening of the dura mater. HP is associated with various inflammatory, infectious, and malignant diseases, such as rheumatic arthritis, sarcoidosis, anti-neutrophil cytoplasmic antibody-associated vasculitis, IgG4-related disorders, syphilis, tuberculosis, bacterial and fungal infections, cancer, and idiopathic diseases, when evaluation fails to reveal a cause. Among them, chronic infection with Propionibacterium acnes is a rare etiology of HP, and its pathology remains unclear. CASE PRESENTATION: An 80-year-old man having refractory otitis media with effusion of the right ear presented with progressive right-sided headache and nausea. Post-contrast brain magnetic resonance imaging revealed right mastoiditis and remarkable thickening of the dura mater and enhancement of pia mater extending from the right middle cranial fossa to the temporal lobe. HP secondary to middle ear infection was suspected, and a biopsy of the right mastoid was performed. An anaerobic culture of the biopsied right mastoid showed the growth of P. acnes, and histopathological examination using P. acnes-specific monoclonal antibody (PAB antibody) revealed the infiltration of inflammatory cells with P. acnes. Moreover, using PAB antibody, P. acnes was detected in the biopsy specimen of the thickening dura mater. No granulomas were identified in either specimen. HP was resolved with long-term administration of antibiotics and steroids. CONCLUSION: This is the first documentation of pathologically demonstrated chronic HP associated with P. acnes infection followed by refractory otitis media. This report showed that chronic latent P. acnes infection induces chronic inflammation.

Left Atrial Spinning Ball Thrombus in a Patient with Cardioembolic Stroke: A Case Report.

A left atrial movable ball thrombus is unusual and may cause fatal systemic emboli or left ventricular inflow obstruction. Among movable ball thrombi, a spinning ball thrombus is a rare and devastating occurrence that results in cardioembolic stroke. Here, we report the case of an 88-year-old woman with a large spherical thrombus spinning in the left atrium when a catastrophic cardioembolic stroke recurred. She had a history of atrial fibrillation but was unable to continue anticoagulation therapy due to hemorrhagic complications and developed an initial cerebral embolism with a large thrombus attached to the left atrium. Twelve days after the initiation of anticoagulation therapy, an extensive cerebral embolism throughout the bilateral frontal lobe recurred with disturbance of consciousness. Transthoracic echocardiography revealed a large detached spherical thrombus spinning in the left atrium. She did not recover consciousness and was moved to another hospital for palliative care three months later. Movable type left atrial thrombi are regarded as a high risk for thromboembolic events, but those with spinning movements may have a worse prognosis.

Paradoxical Cerebral Embolism as Initial Manifestation of Chronic Thromboembolic Pulmonary Hypertension: A Case Report.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by chronic thrombi in the pulmonary arteries, causing pulmonary hypertension and right heart failure. Early and accurate diagnosis are essential for successful treatment but are often difficult because clinical signs and symptoms can be nonspecific and risk factors, such as history of venous thromboembolism, may not always be present. Here, we report a case involving a 76-year-old woman who demonstrated paradoxical cerebral embolism as the initial manifestation of CTEPH. She developed right hemiplegia without dyspnea or edema. Brain magnetic resonance imaging revealed multiple fresh infarctions, while transesophageal echocardiography revealed a patent foramen ovale. Based on these findings, she was diagnosed as having paradoxical cerebral embolism. During the search for the embolic source, right heart catheterization showed significant pulmonary hypertension and pulmonary angiography revealed chronic thrombi in the peripheral pulmonary arteries, consistent with a diagnosis of CTEPH. To our knowledge, this is the first case of CTEPH to be diagnosed with the onset of paradoxical cerebral embolism. Because CTEPH is the only potentially curable form of pulmonary hypertension, clinicians should consider paradoxical cerebral embolism as a possible initial manifestation of CTEPH.

Late-onset paradoxical reactions 10 years after treatment for tuberculous meningitis in an HIV-negative patient: a case report.

BACKGROUND: Although paradoxical reactions (PRs) to anti-tuberculosis (anti-TB) therapy during treatment are well-established occurrences, PRs presenting as a new lesion after the completion of treatment are extremely rare, and little is known about the management of such cases, particularly of central nervous system (CNS) tuberculosis. CASE PRESENTATION: A 27-year-old female, with a past medical history of tuberculous meningitis 10 years ago and who completed the anti-TB treatment with asymptomatic remnant tuberculomas in the basal cistern, was admitted to our hospital because of a headache and the worsening of pre-existing visual disturbance. Contrast-enhanced T1-weighted brain magnetic resonance imaging (MRI) revealed new tuberculomas in the left sylvian fissure with a diffuse low signal around it. Because repeated polymerase chain reaction and Mycobacterium tuberculosis culture presented negative results and the patient had no laboratory data suggestive of a relapse of tuberculous meningitis, she was diagnosed with late-onset post-treatment PRs and treated with oral corticosteroids, tapered off over 1 year. Eventually, the symptoms were relieved, and the tuberculomas disappeared. CONCLUSIONS: Clinicians should consider the possibility of PRs long after the completion of tuberculous meningitis treatment. Hence, a precise MRI-based examination is imperative for the follow-up of CNS tuberculosis, and the unnecessary administration of anti-TB drugs should be avoided. The use of corticosteroids as a treatment option for post-treatment PRs is seemingly safe when the isolated M. tuberculosis is sensitive to the first-line anti-TB therapy.

Utility of Autonomic Function Tests to Differentiate Dementia with Lewy Bodies and Parkinson Disease with Dementia from Alzheimer Disease.

OBJECTIVE: We studied autonomic disturbance in patients with dementia with Lewy bodies (DLB), Parkinson disease with dementia (PDD), Alzheimer disease (AD), to determine whether autonomic function tests can be used to distinguish these disorders. METHODS: Autonomic function was tested in 56 patients with DLB, 37 patients with PDD, and 59 patients with AD by using the sympathetic skin response, coefficient of variation in R-R interval, the head-up tilt test, serum norepinephrine concentration, and 123I-meta-iodobenzylguanidine cardiac scintigraphy. Symptoms of autonomic dysfunction, such as constipation, urinary symptoms, and orthostatic hypotension, were also noted. RESULTS: The groups did not differ on baseline characteristics other than those associated with Parkinsonism and dementia. All patients with DLB and PDD had some dysautonomia, whereas rates were much lower for patients with AD (19%). Significantly more DLB and PDD patients than AD patients showed abnormalities on autonomic function tests. CONCLUSIONS: Autonomic function tests might be quite useful to distinguish DLB and PDD from AD.

Syringomyelia due to Lumbar Spinal Fluid Drainage in the Acute Phase of Subarachnoid Hemorrhage: A Case Report.

Lumbar spinal fluid drainage is a common procedure for treating hydrocephalus and alleviating vasospasm by egesting blood in the subarachnoid cavity after subarachnoid hemorrhage. Despite being an effective and safe procedure, cerebrospinal fluid overdrainage might result in serious complications. Here we report the case of a 49-year-old man who suffered from tonsillar herniation with subsequent cervicothoracic syringomyelia in the acute phase of subarachnoid hemorrhage due to vertebral artery dissection. About 2 weeks after lumbar drainage was switched from external ventricular drainage initiated on the day of subarachnoid hemorrhage, the recovery from the disturbance of consciousness revealed tetraplegia, and magnetic resonance imaging demonstrated tonsillar herniation and syringomyelia. Removal of the spinal drain and resumption of external ventricular drainage resulted in the restoration of the herniated tonsils to the normal position and the complete disappearance of syringomyelia 11 days later. We should consider that spinal syringomyelia could develop as a complication of lumbar spinal fluid drainage in the acute phase of thick subarachnoid hemorrhage, particularly in the posterior cranial fossa.

Factors Associated with Success of Switching to Faricimab for Neovascular Age-Related Macular Degeneration Refractory to Intravitreal Aflibercept.

We investigated the factors associated with the success of switching to faricimab for type 1 macular neovascularization (MNV) refractory to intravitreal aflibercept (IVA). This retrospective cohort study included patients with type 1 MNV who were switched to faricimab because they were refractory to IVA at two centers. The primary endpoint was a more than two-week extension of the treatment interval after 6 months. In addition, factors related to the success or failure of extension and visual and anatomical outcomes were assessed. The analysis included 43 eyes from 43 patients. Extended dosing intervals of >2 weeks were identified in 14 eyes (32.6%). A short dosing interval before switching, absence of polypoidal lesions, and thin central choroidal thickness before switching were identified as factors involved in successful extension. For patients with refractory type 1 MNV, switching to faricimab is a safe and potential option to extend existing dosing intervals.

Intraperitoneal administration of AAV9-shRNA inhibits target gene expression in the dorsal root ganglia of neonatal mice.

BACKGROUND: There is considerable interest in inducing RNA interference (RNAi) in neurons to study gene function and identify new targets for disease intervention. Although short interfering RNAs (siRNAs) have been used to silence genes in neurons, in vivo delivery of RNAi remains a major challenge, especially by systemic administration. We have developed a highly efficient method for in vivo gene silencing in dorsal root ganglia (DRG) by using short hairpin RNA-expressing single-stranded adeno-associated virus 9 (ssAAV9-shRNA). RESULTS: Intraperitoneal administration of ssAAV9-shRNA to neonatal mice resulted in highly effective and specific silencing of a target gene in DRG. We observed an approximately 80% reduction in target mRNA in the DRG, and 74.7% suppression of the protein was confirmed by Western blot analysis. There were no major side effects, and the suppression effect lasted for more than three months after the injection of ssAAV9-shRNA. CONCLUSIONS: Although we previously showed substantial inhibition of target gene expression in DRG via intrathecal ssAAV9-shRNA administration, here we succeeded in inhibiting target gene expression in DRG neurons via intraperitoneal injection of ssAAV9-shRNA. AAV9-mediated delivery of shRNA will pave the way for creating animal models for investigating the molecular biology of the mechanisms of pain and sensory ganglionopathies.

Myotonic dystrophy and lipoma: a new association.

A 58-year-old man developed muscle weakness and had more than 1,000 CTG repeats in the myotonin protein kinase gene. He was diagnosed as having myotonic dystrophy. At the time of diagnosis, a large tumor was detected in his abdominal cavity on CT scan examination. He died from pneumonia 6 years later. At autopsy, the abdominal tumor was diagnosed as a lipoma. Several types of tumor have been reported to be associated with myotonic dystrophy type 1; however, this is the first detailed clinical case demonstrating the possible relationship between myotonic dystrophy and lipoma.

Recurrence of neovascular age-related macular degeneration after cessation of treat and extend regimen.

The appropriate timing of treatment cessation after treat and extend (TAE) regimen for age-related macular degeneration has not been established. This study aimed to investigate the incidence and risk factors of recurrence after cessation of the TAE regimen. We included patients who received and discontinued the TAE regimen, after extension of the treatment interval to ≥ 12 weeks. Forty-nine patients were included in the study. The estimated recurrence rates were 33% at 1 year and 48% at 2 years after treatment cessation, respectively. Good visual acuity at cessation and a large number of injections in the 6 months before cessation were significant risk factors. Higher chances of recurrence were associated with < 0.1 logarithm of the minimum angle of resolution (logMAR) at cessation (P < 0.002). Meanwhile, five patients with visual acuity ≥ 1.0 logMAR at cessation did not show recurrence. Among the 25 recurrences, two lines of vision loss were noted in only two cases after resumed treatment. This study confirmed the importance of the number of injections in reducing recurrence and the association between visual acuity and recurrence. Recurrence is generally well-controlled with resumed treatment.

Pulse-gated noncontrast thoracic magnetic resonance angiography for acute aortic dissection with transient ischemic attack: A case report.

Aortic dissection is a rare cause of an acute ischemic stroke or transient ischemic attack (TIA). Aortic dissection is particularly challenging in stroke patients who are eligible for thrombolysis secondary to the diagnostic difficulty within a narrow time window (4.5 h) and have a risk of developing life-threatening hemorrhagic complications following thrombolysis. Computed tomographic angiography (CTA) has been the mainstay of imaging when evaluating acute aortic syndrome. However, it cannot be routinely performed for pregnant patients and those with renal failure or iodine-contrast media allergy. We report a case of a 72-year-old woman who developed transient right-hand paralysis without any chest symptoms. Brain magnetic resonance imaging (MRI) showed no recent infarction; however, the brachiocephalic trunk was not well visualized on carotid magnetic resonance angiography (MRA). Subsequent thoracic pulse-gated noncontrast three-dimensional balanced steady-state free precession MRA (bSSFP-MRA) detected a Stanford type A acute aortic dissection (TAAAD). This was confirmed by CTA, leading to the diagnosis of TIA due to Stanford TAAAD. Pulse-gated noncontrast thoracic bSSFP-MRA was acquired a few minutes after a series of brain MRI scans. This imaging modality is expected to be used as a screening platform to rule out Stanford TAAAD during the hyperacute phase of stroke.

Activation of a Cryptic Splice Site of GFAP in a Patient With Adult-Onset Alexander Disease.

BACKGROUND AND OBJECTIVE: Alexander disease (ALXDRD) is an autosomal dominant neurologic disorder caused by mutations in the glial fibrillary acidic protein (GFAP) gene and is pathologically defined by Rosenthal fiber accumulation. Most mutations are exonic missense mutations, and splice site mutations are rare. We report a very-late-onset autopsied case of adult-onset ALXDRD with a novel splice site mutation. METHODS: Genetic testing of GFAP was performed by Sanger sequencing. Using autopsied brain tissues, GFAP transcript analysis was performed. RESULTS: The patient presented mild upper motor neuron symptoms in contrast to the severe atrophy of spinal cord and medulla oblongata. The patient had c.619-1G>A mutation, which is located in the canonical splice acceptor site of intron 3. The brain RNA analysis identified the r.619_621del (p.Glu207del) mutation, which is explained by the activation of the cryptic splice acceptor site in the second and third nucleotides from the 5' end of the exon 4. DISCUSSION: GFAP gene expression analysis is necessary to clarify the effects of intronic mutations on splicing, even if they are in canonical splice sites. This case showed a much milder phenotype than those in previous cases with missense mutations at Glu207, thereby expanding the clinical spectrum of ALXDRD with Glu207 mutation.

Unique HLA haplotype associations in IgG4 anti-neurofascin 155 antibody-positive chronic inflammatory demyelinating polyneuropathy.

To clarify the immunogenetic background of patients with immunoglobulin G (IgG)4 anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP), we genotyped the extended human leukocyte antigen (HLA) haplotypes in 22 Japanese patients with this disorder and compared them with those of healthy Japanese controls. All IgG4 anti-NF155 antibody-positive CIDP patients exclusively carried either HLA-DRB1*15:01-DRB5*01:01-DQA1*01:02-DQB1*06:02 or -(A*24:02)-B*52:01-C*12:02-DRB1*15:02-DRB5*01:02-DQA1*01:03-DQB1*06:01, resulting in significantly increased HLA-DRB1*15, -DRB1*15:01, -DQB1*06:01/06:02, -DQB1*06:02, and -DRB1*15:01-DQB1*06:02 frequencies compared with healthy Japanese controls. These findings indicate the involvement of specific HLA class II molecules in the pathomechanisms of IgG4 anti-NF155 antibody-positive CIDP.

Metastatic CNS lymphoma presenting with periventricular dissemination - MRI and neuropathological findings in an autopsy case.

Metastatic CNS lymphoma usually manifests as pachymeningeal or leptomeningeal infiltrates, and periventricular dissemination is rare. A 70-year old man first noticed a mass in the left supraclavicular fossa, and then presented with bilateral parkinsonism, followed by consciousness disturbance. Fluid attenuated inversion recovery (FLAIR) image of brain MRI demonstrated hyperintensities at the parenchyma around the lateral ventricle, third ventricle, and fourth ventricle. Gadolinium-enhanced T1-weighted image demonstrated enhancement along the whole wall of the ventricle. Biopsy of the left supraclavicular lymph nodes established a diagnosis of diffuse large B-cell lymphoma. The patient died of multiple organ failure about 5 months after the onset. Autopsy disclosed periventricular dissemination of lymphoma cells that was most severe around the lateral ventricle. We considered that the lymphoma cells entered the ventricular system through the choroid plexus of the lateral ventricle, followed by dissemination of the periventricular parenchyma.

Intrathecal IgG Synthesis and Persistent Inflammation Are Associated with White Matter Lesions in HIV-negative Patients with Cryptococcal Meningoencephalitis.

Objective Cryptococcal meningoencephalitis (CM) causes significant morbidity and mortality in human immunodeficiency virus (HIV)-negative and HIV-positive populations. White matter lesions (WMLs) have been reported in both populations of CM patients; however, the mechanisms underlying WML formation remain unknown. We herein report the relationship between the intrathecal immune response and the development of WMLs in HIV-negative patients with CM. Methods Eleven consecutive HIV-negative patients with CM who presented at one of three emergency hospitals in Japan from April 2001 to March 2018 were enrolled. For all patients, we retrospectively assessed the relationships between clinical and laboratory information and the presence of WMLs. Results At presentation, 6 patients had WMLs on magnetic resonance imaging (MRI). The cerebrospinal fluid immunoglobulin G (CSF IgG) index was significantly higher in the patients with WMLs than in those without WMLs (mean, 1.34 vs. 0.70, p=0.017). The time from the symptom onset to initial neuroimaging was also significantly longer in the patients with WMLs than in those without WMLs (median, 31.5 vs. 7.0 days; p=0.008). The clinical outcome was comparable among the patients with and without WMLs. Conclusion In HIV-negative patients with CM, a persistent, aberrant immune response to Cryptococcus, such as intrathecal IgG synthesis, may induce WML formation.