Diffuse White Matter Signal Abnormality Research Articles

Non-Iatrogenic Cerebral Air Embolism: A Case Report of an Extremely Rare Cause of Ischemic Stroke (P6-5.031)

<h3>Objective:</h3> NA <h3>Background:</h3> Air embolism is an uncommon but potentially catastrophic event due to air entry into the vasculature resulting in ischemic strokes. Cerebral air embolism (CAE) can be a complication of medical procedures, although non-iatrogenic sources have rarely been reported. Nonetheless, it is a life-threatening emergency with high mortality and disability. We present a patient with an acute infarct due to a CAE during air travel. <h3>Design/Methods:</h3> NA <h3>Results:</h3> <h3>Case Report:</h3> A 67-year-old woman presents with two episodes of impaired consciousness during flights while in Europe. Both happened shortly after ascent. Her symptoms quickly resolved after an emergent landing on her first trip. During the second trip, however, symptoms recurred, and she remained unconscious. She was evaluated at a local hospital where a head computed tomography (CT) showed multiple cortical air locules, predominantly in the right hemisphere, consistent with cerebral air embolism. CT chest revealed a large left bulla with surrounding neovascularization, likely the cause of the embolism. A magnetic resonance imaging (MRI) brain confirmed numerous subacute infarcts across multiple vascular territories and diffuse white matter signal abnormality, consistent with the sequela of cerebral air embolism. She was transported to the US by sea for further management at a tertiary hospital, where she had successful resection of left lung bulla. She was subsequently discharged home with very mild left ataxia. <h3>Conclusions:</h3> Non-iatrogenic CAE is an extremely rare cause of ischemic stroke. Previously described cases relate to barometric pressure changes: during diving and ascent. We describe a patient presenting with CAE secondary to pulmonary shunt from a large lung bulla under barometric pressure changes during aircraft ascent. While literature suggests CAE as a life-threatening emergency with poor prognosis, this patient had an excellent outcome after surgical resection of the lung bulla, indicating possibly different outcomes between non-iatrogenic vs. iatrogenic CAE. <b>Disclosure:</b> Dr. Su has nothing to disclose. Dr. Pandya has nothing to disclose. Dr. Reyes has nothing to disclose. Dr. Shastry has nothing to disclose. Dr. Varade has nothing to disclose.

Efficacy of cell-type specific rescue in a new mouse model of CLN3 disease

Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum.Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate.Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls.Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.

Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement

Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum.Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate.Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls.Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.

33. A case of ocular ischaemic syndrome caused by severe giant cell arteritis

IntroductionThis case describes a very aggressive form of giant cell arteritis (GCA) complicated by ocular ischaemic syndrome (OIS), complete bilateral visual loss and bilateral scalp muscle necrosis, despite treatment with high dose intravenous steroids. OIS, defined as ischaemia of all intraorbital and intraocular structures, is rare, estimated at 7.5 cases per million. This case also highlights the use of PET CT in management of complex cases of GCA.Case descriptionA 79-year-old lady presented with sudden onset pain above her right eye. A month earlier she had undergone curative surgery for infiltrating adenocarcinoma of the colon. 6 months earlier she had complained of bilateral shoulder pain. A month earlier she had developed pain on chewing and was unable to fully open her mouth. The next day she was reviewed in the eye hospital due to 24hrs of intermittent blurred vision. CT head was normal. Fundoscopy was normal and she was diagnosed with ocular migraine. Later that evening she lost vision in the right eye. Bloods showed CRP 58 and ESR 43. She was given 5 days of IV methylprednisolone (5x1g). Despite this she developed a right 6th nerve palsy. 2 days later her left eye developed visual loss, complete ptosis and loss of eye movements in all directions. MRI head with gadolinium showed temporoparietal juxtacortical diffuse white matter signal abnormalities.She underwent extensive investigation. ANCA was negative, lumbar puncture normal and temporal artery biopsy showed extensive fibrinoid necrosis of the vessel wall, with possible granulomata but no eosinophilia. Oral cyclophosphamide (2mg/kg) was started. 5 days later she developed severe bi-temporal pain and a rash which progressed to severe scalp necrosis. There were no vesicles to suggest shingles. Ten days later she suffered an upper gastro-intestinal bleed requiring a 4 unit transfusion. Gastroscopy showed mild gastritis. After this, cyclophosphamide was withheld, following discharge on steroids alone. Bilateral scalp necrosis remained a problem, complicated by pseudomonas infections. When a decreased left radial pulse was noted a PET CT was arranged. This showed active extensive vasculitis of the aorta. At this point methotrexate 15mg per week was added. The scalp lesions rapidly healed and the radial pulse returned to normal. The CRP has remained consistently below 5. DiscussionAn antiplatelet agent, clopidogrel was started due to the ischaemic cerebral findings on MRI, but it probably contributed, along with steroids, to her upper GI bleed. Antiplatelet therapy is no longer recommended routinely in the management of GCA. However in this case the diagnosis was still uncertain. None of us had ever seen orbital infarction syndrome as a complication of GCA. Perhaps a PET CT earlier on in the course of this lady’s disease would have made us more secure in the diagnosis. It could be argued that given the severity of her disease, methotrexate or even tocilizumab should have been commenced earlier. In fact, cyclophosphamide was used initially as it wasn’t clear if this was a medium vessel vasculitis. This was withheld when she had a large upper GI bleed (Hb dropped to 76). Once recovering, her CRP was down to 10. By this time the temporal artery biopsy was available, the ANCA was negative and GCA was felt to be the most likely diagnosis. It was also felt that given the bilateral visual loss, the most feared complication of GCA had already occurred so what was there to gain by using such strong immunosuppression? Hence cyclophosphamide was discontinued, and she was discharged on steroids alone. The addition of methotrexate had an impressive effect in terms of healing her weeping, secondarily infected scalp necrosis. Methotrexate was added in light of the PET CT which showed active large vessel vasculitis. The scalp necrosis, on reflection was due to an ongoing vasculitis that was being undertreated.There were missed opportunities for starting steroids earlier in the course of the disease: polymyalgic symptoms 6 months earlier, jaw claudication a month earlier. However it remains uncertain whether or not earlier treatment would have altered the course of this aggressive, severe disease. Key learning pointsScalp necrosis, which very easily can be mistaken for shingles or infections complicating steroid treatment, can be a feature of GCA. Orbital infarction syndrome can be a feature of GCA. Early PET CT might have clarified the diagnosis. Methotrexate should probably have been started once the limited response to IV steroids was apparent. Antiplatelet agents are no longer recommended in the updated BSR guidelines for managing GCA.Conflicts of interestThe authors have declared no conflicts of interest.

Diffuse White Matter Signal Abnormalities on Magnetic Resonance Imaging Are Associated With Human Immunodeficiency Virus Type 1 Viral Escape in the Central Nervous System Among Patients With Neurological Symptoms.

Human immunodeficiency virus type 1 (HIV-1) can replicate independently in extravascular compartments such as the central nervous system, resulting in either cerebrospinal fluid (CSF) discordance (viral load [VL] in CSF 0.5 log10 copies HIV-1 RNA greater than plasma VL) or escape (detection of HIV VL >50 copies/mL in CSF in patients with suppressed plasma VL <50 copies/mL). Both discordance and escape may be associated with neurological symptoms. We explored risk factors for CSF discordance and escape in patients presenting with diverse neurological problems. HIV-infected adult patients undergoing diagnostic lumbar puncture (LP) at a single center between 2011 and 2015 were included in the analysis. Clinical and neuroimaging variables associated with CSF discordance/escape were identified using multivariate logistic regression. One hundred forty-six patients with a median age of 45.3 (interquartile range [IQR], 39.6-51.5) years underwent 163 LPs. Median CD4 count was 430 (IQR, 190-620) cells/µL. Twenty-four (14.7%) LPs in 22 patients showed CSF discordance, of which 10 (6.1%) LPs in 9 patients represented CSF escape. In multivariate analysis, both CSF discordance and escape were associated with diffuse white matter signal abnormalities (DWMSAs) on cranial magnetic resonance imaging (adjusted odds ratio, 10.3 [95% confidence interval {CI}, 2.3-45.0], P = .007 and 56.9 [95% CI, 4.0-882.8], P = .01, respectively). All 7 patients with CSF escape (10 LPs) had been diagnosed with HIV >7 years prior to LP, and 6 of 6 patients with resistance data had documented evidence of drug-resistant virus in plasma. Among patients presenting with diverse neurological problems, CSF discordance or escape was observed in 15%, with treatment-experienced patients dominating the escape group. DWMSAs in HIV-infected individuals presenting with neurological problems should raise suspicion of possible CSF discordance/escape.

Cross-sectional study of unexplained white matter lesions in HIV positive individuals undergoing brain magnetic resonance imaging.

White matter (WM) abnormalities are frequently seen on brain MRI of HIV positive (HIV+) patients. We aimed to determine the prevalence of unexplained WM abnormalities and their associations with HIV disease and cardiovascular risk factors. We conducted a retrospective, cross-sectional study of brain MRI of HIV+ patients conducted between 2004 and 2009 at our center. Clinical and laboratory data were compiled, and images were independently reviewed for WM lesions. Images were obtained from 254 patients: 70% male, 53% white, 40% black, mean age 42 years, median current CD4 count 240 cells/mm(3), and 41% not taking antiretroviral therapy (ART). Hyperintense WM lesions were present in 161 patients (63.4%): 89 scans (35.0%) showed diffuse WM signal abnormality (DWMSA), 61 (24.0%) were consistent with small vessel disease (SVD, graded by Fazekas' scale), and 37 (14.6%) showed large asymmetrical focal WM lesions. SVD changes were associated with age and cardiovascular risk factors, and while cerebral SVD may be related to HIV infection, the MRI findings were not associated with HIV-related factors. The only risk factor for DWMSA was black race, and no correlation with cardiovascular risk factors, CD4 count, or clinical presentation was identified. DWMSA are therefore of uncertain neurological significance in HIV+ patients and could represent more than one clinicopathological entity.

1055 Neuroimaging Prognostic Categorization in Newborns with Symptomatic Congenital Cytomegalovirus Infection (SCCI)

Background and AimsIn SCCI, Noyola’s neuroimaging prognostic categorization is restricted to destructive abnormalities.ObjectiveTo ascertain the predictive ability of a classification including destructive, developmental abnormalities and white matter signal changes on...

Good Outcome With Early Empiric Treatment of Neural Larva Migrans Due to Baylisascaris procyonis

We report a remarkably good outcome in a 14-month-old boy with early clinical diagnosis and aggressive empirical treatment of neural larva migrans caused by the raccoon roundworm Baylisascaris procyonis. He presented with fever, meningismus, lethargy, irritability and asymmetric spastic extremity weakness. Early findings of marked blood and cerebrospinal fluid eosinophilia and of diffuse white matter signal abnormality in the brain and spinal cord on MRI suggested a parasitic encephalomyelitis. Rapid presumptive treatment with albendazole and high-dose steroids halted progression of clinical signs. The diagnosis was confirmed by 2 sequential enzyme-linked immunosorbent assay studies positive for B procyonis serum immunoglobulin G and by Western blot. Field examination with soil sampling yielded infective Baylisascaris eggs. Repeat MRI 3 months later showed atrophy and diffuse, chronic white matter abnormalities, discordant with the marked clinical improvement in this interval. At 10 months, residual neurologic deficits included subtle paraparesis and moderate language delay. This case is the first in which spinal involvement in human Baylisascaris infection was clinically suspected and confirmed by neuroimaging. Importantly, early diagnosis and aggressive treatment of Baylisascaris meningo-encephalitis and myelitis with albendazole and high-dose steroids likely contributed to the good outcome in this patient, in contrast with previous reports.

Asymptomatic Self-Limiting Diffuse White Matter Lesions in Subacute to Chronic Stage of Herpes Simplex Encephalitis

This study evaluated white matter changes in the subacute and chronic stages of herpes simplex encephalitis (HSE). Subjects comprised 15 patients with HSE. All patients were examined using MRI at onset, and then at seven to ten days, three to five weeks and two to three months after onset. In addition, the six patients who displayed white matter signal abnormalities were examined at six months and <one year after onset. Cell count, protein levels, polymerase chain reaction (PCR) of herpes simplex virus in cerebrospinal fluid (CSF), and exacerbation of neurological symptoms as well as dose of acyclovir were compared between patients with and without white matter abnormalities. Diffuse white matter signal changes were identified at the subacute stage (3-5 weeks after onset) of HSE in six patients (6/15, 40%). No significant relationship was observed between the presence of white matter signal abnormalities and laboratory data, acyclovir dose or clinical symptoms. These signal abnormalities disappeared or improved by two years without any clinical treatment. Diffuse white matter signal abnormalities occur frequently in the subacute stage of HSE. Although the mechanisms underlying these white matter lesions have not been elucidated, subclinical immune-mediated processes may be considered. Repeat MRI studies over a long period are necessary for evaluating the clinical process of patients with HSE.

Regional Specificity of Magnetic Resonance Imaging and Histopathology Following Cerebral Ischemia in Preterm Fetal Sheep

Early and accurate evaluation of the nature and extent of cerebral injury in the preterm infant brain is important for prognostication and decision making in the neonatal intensive care unit. The capability of magnetic resonance imaging (MRI) to define acute ischemic changes in white and gray matter in comparison to contemporaneous histopathology has not been adequately ascertained. The aim of this study is to assess whether postmortem MRI predicts the nature and extent of brain injury in a preterm fetal sheep model of cerebral hypoperfusion. MRI examinations were performed on fetal sheep brains (d99-100 gestation), perfusion fixed 72 hours after an ischemic insult (n = 7) with left-hemispheric placement of a microdialysis probe and compared with sham-occlusion (n = 3) and unoperated-control fetuses (n = 4). Cerebral ischemia was associated with MRI changes including global cerebral injury and diffuse white matter signal abnormality, which corresponded closely with histological damage. However, histological changes in deep structures, including the corona radiata, thalamus, and globus pallidus were not reliably detected on MRI. These findings confirm that in preterm fetal sheep, MRI can accurately assess cortical gray matter and subcortical and periventricular white matter abnormalities 3 days after hypoxic-ischemic injury but appears to have limited sensitivity to detect injury to deep structures.

Histopathology, electrodiagnostic testing, and magnetic resonance imaging show significant peripheral and central nervous system myelin abnormalities in the cat model of alpha-mannosidosis.

Alpha-mannosidosis is a disease caused by the deficient activity of alpha-mannosidase, a lysosomal hydrolase involved in the degradation of glycoproteins. The disease is characterized by the accumulation of mannose-rich oligosaccharides within lysosomes. The purpose of this study was to characterize the peripheral nervous system (PNS) and central nervous system (CNS) myelin abnormalities in cats from a breeding colony with a uniform mutation in the gene encoding alpha-mannosidase. Three affected cats and 3 normal cats from 2 litters were examined weekly from 4 to 18 wk of age. Progressively worsening neurological signs developed in affected cats that included tremors, loss of balance, and nystagmus. In the PNS, affected cats showed slow motor nerve conduction velocity and increased F-wave latency. Single nerve fiber teasing revealed significant demyelination/remyelination in affected cats. Mean G-ratios of nerves showed a significant increase in affected cats compared to normal cats. Magnetic resonance imaging of the CNS revealed diffuse white matter signal abnormalities throughout the brain of affected cats. Quantitative magnetization transfer imaging showed a 8%-16% decrease in the magnetization transfer ratio in brain white matter of affected cats compared to normal cats, consistent with myelin abnormalities. Histology confirmed myelin loss throughout the cerebrum and cerebellum. Thus, histology, electrodiagnostic testing, and magnetic resonance imaging identified significant myelination abnormalities in both the PNS and CNS that have not been described previously in alpha-mannosidosis.