Ruptured pial-pial collateral aneurysm associated with left internal carotid artery occlusion: nuances of surgical management. Illustrative case.

BACKGROUND: Carotid occlusion often leads to the formation of a collateral network. On rare occasions, due to hemodynamic influence, aneurysms can occur. Here, the authors describe a 69-year-old male presenting with intracerebral hemorrhage secondary to a ruptured aneurysm within such a network. OBSERVATIONS: The patient presented to the emergency department with an altered level of consciousness. Imaging showed a left temporal lobe hemorrhage extending into the ventricle, subdural hematoma, and evidence of contrast extravasation. Digital subtraction angiography revealed an occluded left internal carotid artery with the left middle cerebral artery territory reconstituted by flow through an external carotid artery-internal carotid artery anastomosis. The latter was formed by the superficial temporal artery-superior orbital artery, as well as pial-pial collaterals from the posterior temporal artery. Notably, a 4-mm aneurysm arising from the pial-pial collateral network was identified. Surgical intervention involved a left temporal craniectomy and aneurysm excision, with special attention paid to preserving the anastomotic flow through the superficial temporal artery. LESSONS: This case underscores the importance of recognizing and preserving collateral vascular pathways in cases of carotid occlusion with an associated aneurysm. It emphasizes the necessary balance between managing aneurysm risk and maintaining cerebral perfusion, highlighting the need for careful preoperative planning and intraoperative caution.

Parietal bone agenesis and athelia in retinoic acid embryopathy: An expansion of the phenotype.

BACKGROUND: Retinoic acid signaling plays a critical role during embryogenesis and requires tight regulation. Exposure to exogenous retinoic acid during fetal development is known to have teratogenic effects, producing a recognizable embryopathy. CASE: We describe a case of retinoic acid embryopathy secondary to maternal isotretinoin use until the ninth week of gestation and expand the phenotype to include the rare features of parietal bone agenesis and athelia. Histology of the parietal region showed fibrous tissue with no intramembranous ossification. The fetus also had multiple craniofacial dysmorphisms, thymic agenesis, and transposition of the great arteries with double outlet right ventricle and subaortic perimembranous ventricular septal defect. Neuropathology revealed enlarged ventricles with agenesis of the cerebellar vermis, focal duplication of the central canal and scattered parenchymal ependymal rests, and possible cerebral heterotopias with associated abnormal neuronal lamination. A chromosomal microarray was normal. CONCLUSION: Parietal bone agenesis and athelia are both rare congenital anomalies not previously reported in retinoic acid embryopathy. However, retinoic acid or its degrading enzyme has been demonstrated to exert effects in both of these developmental pathways, offering biological plausibility. We propose that this case may represent an expansion of the phenotype of retinoic embryopathy.

Microvessel stenosis, enlarged perivascular spaces, and fibrinogen deposition are associated with ischemic periventricular white matter hyperintensities.

Periventricular white matter hyperintensities (pvWMH) are neuroimaging abnormalities surrounding the lateral ventricles that are apparent on magnetic resonance imaging (MRI). They are associated with age, neurodegenerative disease, and cerebrovascular risk factors. While pvWMH ultimately represent a loss of white matter structural integrity, the pathological causes are heterogeneous in nature, and currently, cannot be distinguished using neuroimaging alone. pvWMH could occur because of a combination of small vessel disease (SVD), ependymal loss, blood-brain barrier dysfunction, and microgliosis. In this study we aimed to characterize microvascular stenosis, fibrinogen extravasation, and microgliosis within pvWMH with and without imaging evidence of periventricular infarction. Using postmortem neuroimaging of human brains (n = 20), we identified pvWMH with and without periventricular infarcts (PVI). We performed histological analysis of microvessel stenosis, perivascular spaces, microgliosis, and immunohistochemistry against fibrinogen as a measure of serum protein extravasation. Herein, we report distinctions between pvWMH with and without periventricular infarcts based on associations with microvessel stenosis, enlarged perivascular spaces, and fibrinogen IHC. Microvessel stenosis was significantly associated with PVI and with cellular deposition of fibrinogen in the white matter. The presence of fibrinogen was associated with PVI and increased number of microglia. These findings suggest that neuroimaging-based detection of infarction within pvWMH may help distinguish more severe lesions, associated with underlying microvascular disease and BBB dysfunction, from milder pvWMH that are a highly frequent finding on MRI.

α-tropomyosin gene (TPM3) mutation in an infant with nemaline myopathy.

We report a case of neonatal nemaline myopathy with a de novo TPM3 mutation, which has been classified as a likely pathogenic mutation. With the expanding use of genetic testing in congenital myopathies, genotype-phenotype descriptions of novel variants are important to inform clinical care, diagnosis, genetic counseling, and management of disease.

Cranial nerve and intramedullary spinal malignant peripheral nerve sheath tumor associated with neurofibromatosis-1.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon but aggressive neoplasms associated with radiation exposure and neurofibromatosis Type I (NF1). Their incidence is low compared to other nervous system cancers, and intramedullary spinal lesions are exceedingly rare. Only a few case reports have described intramedullary spinal cord MPNST. Case Description: We describe the clinical findings, management, and outcome of a young patient with NF1 who developed aggressive cranial nerve and spinal MPNST tumors. This 35-year-old patient had familial NF1 and a history of optic glioma treated with radiation therapy (RT). She developed a trigeminal MPNST that was resected and treated with RT. Four years later, she developed bilateral lower extremity deficits related to an intramedullary cervical spine tumor, treated surgically, and found to be a second MPNST. Conclusion: To the best of our knowledge, this is the first report of cranial nerve and intramedullary spinal MPNSTs manifesting in a single patient, and only the third report of a confined intramedullary spinal MPNST. This unusual case is discussed in the context of a contemporary literature review.

Post-mortem 7 Tesla MRI detection of white matter hyperintensities: A multidisciplinary voxel-wise comparison of imaging and histological correlates.

White matter hyperintensities (WMH) occur in normal aging and across diagnostic categories of neurodegeneration. Ultra-high field imaging (UHF) MRI machines offer the potential to improve our understanding of WMH. Post-mortem imaging using UHF magnetic resonance imaging (MRI) is a useful way of assessing WMH, however, the responsiveness of UHF-MRI to pathological changes within the white matter has not been characterized. In this study we report post-mortem MRI sequences of white matter hyperintensities in normal aging, Alzheimer's disease, and cerebrovascular disease. Seven Tesla post-mortem MRI reliably detected periventricular WMH using both FLAIR and T2 sequences and reflects underlying pathology of myelin and axon density despite prolonged fixation time. Co-registration of histological images to MRI allowed for direct voxel- wise comparison of imaging findings and pathological changes. Myelin content and cerebrovascular pathology were the most significant predictors of MRI white matter intensity as revealed by linear mixed models. Future work investigating the utility of UHF- MRI in studying cell-specific changes within WMH is required to better understand radio-pathologic correlations.

Incisional Seeding of Metastatic Squamous Cell Carcinoma Following Carotid Endarterectomy: An Unusual Case of an Unknown Primary Cancer Presenting as a Presumed Neck Abscess.

BACKGROUND: Carotid endarterectomy (CEA) is a safe and effective procedure, with a low risk of complications when performed by experienced surgeons. Postoperative infections are particularly rare, reportedly affecting less than 1% of cases. Incisional metastases have not been described. OBJECTIVE: To describe a previously unreported complication, the incisional seeding of metastatic squamous cell carcinoma (SCC) during neck dissection, which presented and was treated as a presumed postoperative neck abscess. METHODS: Clinical records were reviewed regarding a 73-yr-old female who underwent routine CEA and presented 2 mo postoperatively with neck induration and erythema. Tissue submitted during the initial CEA was reexamined given the updated clinical history. RESULTS: Postoperatively, a complex, multi-cystic fluid collection beneath the incision was identified and percutaneously drained. Although cultures were negative, an infection was favored and antibiotic therapy initiated. The patient's symptoms worsened prompting surgical exploration, and tissue sent for pathological examination was consistent with metastatic SCC. Retrospective analysis of a lymph node excised during the initial dissection also revealed tumor deposits, indicating that the surgical site had been seeded during exposure. A primary origin was not identified. CONCLUSION: The time from initial presentation of postoperative complications to a final diagnosis of metastatic SCC was 2 mo, during which time the patient was treated as having a postoperative infection. Further investigations were consistent with diffuse and incurable metastatic disease. This report highlights the diagnostic challenges and potential avoidance strategies when dealing with rare complications following CEA.

Persistent behavioral impairments and neuroinflammation following global ischemia in the rat.

Cognitive deficits associated with cardiac arrest have been well documented; however, the corresponding deficits in animal models of global ischemia have not been comprehensively assessed, particularly after long-term, clinically relevant survival times. We exposed male Sprague-Dawley rats to 10 min of bilateral carotid artery occlusion + systemic hypotension (40-45 mmHg) or sham surgery, and used histopathological assessments for short-term survival animals (16 days) and both behavioral and histopathological assessments for long-term survival animals (270 days). Analyses revealed significant long-term deficits in ischemic animals' learning, memory (T-maze, radial arm maze), working memory (radial arm maze), and reference memory (Morris water maze, radial arm maze) abilities that were not associated with a general cognitive decline. Histological results showed significant increases in glial fibrillary acidic protein, neuron glia 2, OX-42 and ED-1 staining, as well as significant decreases in microtubule-associated protein 2 staining and cornu ammonis area 1 (CA1) cell counts 16 days post-ischemia. The pattern at 270 days was similar, but notably there was a persistent elevation of ED-1 staining, suggesting recent cell death as well as significant atrophy of CA1. Whereas previous work has primarily reported transient changes in behavior after global ischemia, this study describes disturbances in several different functional domains following CA1 cell loss at clinically relevant survival times. Moreover, the histopathological outcome is suggestive of a spontaneous repopulation of CA1, but this was not sufficient to offset the behavioral impairments arising from the ischemic insult.

Executive dysfunction and blockage of brain microvessels in a rat model of vascular cognitive impairment.

Most research focuses on overt stroke caused by blockage of major blood vessels. Less attention has been paid to small vessel disease which gives rise to covert stroke that often leads to vascular cognitive impairment (VCI). One reason for this may be the relative lack of relevant animal models. Herein, we describe, a model of VCI induced in middle-aged Sprague-Dawley rats exposed to a diet high in saturated fats, salt and refined sugar (HFSS). In Experiment 1, rats were fed HFSS and subjected to a small mediodorsal (MD) thalamic stroke with or without concomitant permanent bilateral carotid artery occlusion. MD lesions produce significant executive dysfunction in an attention set-shift task ( p = 0.012). In Experiment 2, rats were exposed to either HFSS or control diet and functional effects assessed. We found significant hypertension ( p = 0.013), blockage of brain microvessels ( p = 0.018) and white matter atrophy ( p = 0.039) in HFSS diet animals. As in Experiment 1, profound, specific set-shifting executive dysfunction was noted ( p = 0.003) following both small MD infarcts (0.332 mm3) and the HFSS diet. In summary, these data describe a middle-aged animal model of VCI that includes clinically relevant metabolic disturbances and small vessel disease and as such may be helpful in developing new cognitive therapies.

Early poststroke experience differentially alters periinfarct layer II and III cortex.

Early poststroke rehabilitation effectively improves recovery of function, likely by engaging multiple plasticity processes through use-dependent activation of neural circuits. The loci of such neuroplastic reorganization have not been examined during the initial phase of behavioral recovery. In the current study, we sought to evaluate sub-components of rehabilitation and to identify brain sites first engaged by early rehabilitation. Rats were subjected to endothelin-1 ischemia and placed in either enriched environment (EE), daily reach training (RT), combination of enriched environment and reach training (ER), or standard housing (ST) starting 7 days post ischemia. Functional and histopathological assessments were made after 2, 5, and 10 days of treatment. Animals exposed to 10 days of ER treatment exhibited significantly more use-dependent neuronal activity (FosB/ΔFosB expression) in perilesional cortex than those exposed to EE, RT, or ST treatments. Similar trends were observed in both perilesional striatum and contralesional forelimb motor cortex. This use-dependent plasticity was not explained by differences in neuronal death, inflammation, or lesion volume. The increased activity likely contributes to the neuroplastic changes and functional recovery observed after extended periods of rehabilitation. Importantly, EE or RT alone did not lead to enhanced activity suggesting that combination therapy is necessary to promote maximum recovery.

A cognitive rehabilitation paradigm effective in male rats lacks efficacy in female rats.

Cognitive dysfunction, as a consequence of dementia, is a significant cause of morbidity lacking efficacious treatment. Females comprise at least half of this demographic but have been vastly underrepresented in preclinical studies. The current study addressed this gap by assessing the protective efficacy of physical exercise and cognitive activity on learning and memory outcomes in a rat model of vascular dementia. Forty ovariectomized Sprague-Dawley rats (∼6 months old) were exposed to either a diet high in saturated fats and refined sugars or standard laboratory chow and underwent either chronic bilateral carotid occlusion or Sham surgery. Learning and memory abilities were evaluated using standard cognitive outcomes over the ensuing 6 months, followed by histologic analyses of hippocampal CA1 neurons. In Experiment 1, we confirmed hypoperfusion-induced cognitive dysfunction using a 2 × 2 (Surgery × Diet) experimental design, without alterations in hippocampal architecture. In Experiment 2, hypoperfused animals were either exposed to alternating days of physical (wheel running) and cognitive activity (modified Hebb-Williams maze) or sedentary housing. In contrast to males, this combination rehabilitation paradigm did not improve cognition or histopathologic outcomes in hypoperfused animals. These findings, highlighting differences between female and male animals, show the necessity of including both sexes in preclinical experimentation.

Impaired executive function following ischemic stroke in the rat medial prefrontal cortex.

Small (lacunar) infarcts frequently arise in frontal and midline thalamic regions in the absence of major stroke. Damage to these areas often leads to impairment of executive function likely as a result of interrupting connections of the prefrontal cortex. Thus, patients experience frontal-like symptoms such as impaired ability to shift ongoing behavior and attention. In contrast, executive dysfunction has not been demonstrated in rodent models of stroke, thereby limiting the development of potential therapies for human executive dysfunction. Male Sprague-Dawley rats (n=40) underwent either sham surgery or bilateral endothelin-1 injections in the mediodorsal nucleus of the thalamus or in the medial prefrontal cortex. Executive function was assessed using a rodent attention set shifting test that requires animals to shift attention to stimuli in different stimulus dimensions. Medial prefrontal cortex ischemia impaired attention shift performance between different stimulus dimensions while sparing stimulus discrimination and attention shifts within a stimulus dimension, indicating a selective attention set-shift deficit. Rats with mediodorsal thalamic lacunar damage did not exhibit a cognitive impairment relative to sham controls. The selective attention set shift impairment observed in this study is consistent with clinical data demonstrating selective executive disorders following stroke within specific sub-regions of frontal cortex. These data contribute to the development and validation of a preclinical animal model of executive dysfunction, that can be employed to identify potential therapies for ameliorating cognitive deficits following stroke.

A model of persistent learned nonuse following focal ischemia in rats.

BACKGROUND: After hemiplegic stroke, people often rely on their unaffected limb to complete activities of daily living. A component of residual motor dysfunction involves learned suppression of movement, termed learned nonuse. OBJECTIVE: To date, no rodent stroke model of persistent learned nonuse has been described that can facilitate understanding of this phenomenon and test interventions to overcome it. METHODS: Rats were trained in the staircase skilled-reaching and limb use asymmetry (cylinder) tasks. Endothelin-1 was injected into the cortex and striatum to create focal ischemia. Starting 7 days poststroke, half of the rats (ipsilateral training; n = 15) were trained to reach for food reward pellets in the tray-reaching task with the ipsilateral forelimb. Training lasted 20 days. Rats in the control group (control; n = 15) did not receive training. All rats then remained in their home cages for an additional 30 days. Performance on the cylinder and staircase tasks was assessed ~2 months poststroke. RESULTS: Ischemia caused significant functional impairments in all rats. Significant contralateral forelimb skilled-reaching recovery was evident in the control group at 2 months but not the ipsilateral training group. There was no difference in performance in the cylinder task. Similarly, the volume of brain injury (~66 mm(3)) was similar between groups. Ipsilateral forelimb training reduced poststroke motor recovery. CONCLUSION: This rodent model of persistent nonuse after stroke may be used to further understand mechanisms of learned nonuse as well as to evaluate pharmacological and rehabilitation treatments to overcome it.

Cognitive rehabilitation reduces cognitive impairment and normalizes hippocampal CA1 architecture in a rat model of vascular dementia.

Dementia is a major cause of morbidity in the western society. Pharmacological therapies to delay the progression of cognitive impairments are modestly successful. Consequently, new therapies are urgently required to improve cognitive deficits associated with dementia. We evaluated the effects of physical and cognitive activity on learning and memory in a rat model of vascular dementia (VasD). Male Sprague-Dawley rats (6 months old) were exposed to either regular chow or a diet rich in saturated fats and sucrose and chronic bilateral common carotid artery occlusion or sham surgery. First, this model of VasD was validated using a 2 × 2 experimental design (surgery × diet) and standard cognitive outcomes. Next, using identical surgical procedures, we exposed animals to a paradigm of cognitive rehabilitation or a sedentary condition. At 16 weeks post surgery, VasD animals demonstrated significant learning and memory deficits in the Morris water maze, independent of diet. Rehabilitation significantly attenuated these cognitive deficits at this time point as well as at 24 weeks. Further, rehabilitation normalized hippocampal CA1 soma size (area and volume) to that of control animals, independent of cell number. Importantly, these findings demonstrate beneficial neuroplasticity in early middle-aged rats that promoted cognitive recovery, an area rarely explored in preclinical studies.

Improved working memory following novel combinations of physical and cognitive activity.

BACKGROUND: In humans, retrospective studies suggest that habitual physical activity (PA) or cognitive activity (CA) can help maintain or improve cognitive function. Similar findings have been reported using physical exercise in animal studies; however, the exercise paradigms differ markedly in duration and frequency, making extrapolation difficult. Here, the authors present a novel PA and CA paradigm that combines voluntary wheel running with Hebb-Williams and radial arm maze (RAM) training. METHODS: A total of 57 male Sprague-Dawley rats were divided into 4 treatment groups: the PA, CA, and combined PA and CA groups and sedentary controls. PA (voluntary wheel running) and CA (Hebb-Williams mazes) consisted of a moderate 2 h/d, 5 d/wk treatment paradigm. RESULTS: Animals exposed to a combination of PA and CA made significantly fewer working memory errors and exhibited superior choice accuracy when compared with animals exposed to either PA or CA alone in the 8-arm baited configuration of the RAM. Additional analyses revealed that the cognitive improvements were independent of exercise intensity/duration. Assessment of brain-derived neurotrophic factor (BDNF) levels revealed a significant increase in hippocampal BDNF only in the PA-alone group. CONCLUSION: A novel combination of PA and CA improves learning and memory abilities independent of activity intensity, BDNF, or phosphorylated cyclic AMP response element binding protein levels. This is the first report of significant changes in cognitive ability using a paradigm involving moderate levels of PA plus cognitive stimulation. An adaptation of this paradigm may be particularly beneficial in slowing the development of mild cognitive impairment and subsequent dementia in elderly people.

Prolonged, 24-h delayed peripheral inflammation increases short- and long-term functional impairment and histopathological damage after focal ischemia in the rat.

The incidence of infection among stroke patients is alarmingly high and both acute and delayed infections increase morbidity and mortality. Experimental studies support the acute clinical data, but little attention has focused on delayed systemic infections. Here, we investigated the effects of prolonged systemic inflammation either before or 24-h after ischemia. Systemic inflammation was induced by injecting rats with three separate doses of lipopolysaccharide (LPS; 50 mug/kg, i.p.) with core temperature monitoring for 48-h after middle cerebral artery occlusion (MCAo). Lipopolysaccharide injected before MCAo increased injury by approximately 30%, whereas delayed injection increased injury by approximately 85% (30-day survival). Proinflammatory cytokines assessed repeatedly for 72 h were significantly and persistently elevated with inflammation. This was accompanied by increases in microglia/macrophage and infiltrating leukocyte numbers in delayed LPS-treated animals. Behavioral assessments at 7 and 30 days revealed approximately 15% deficit in hindlimb function in animals treated with LPS 24-h after ischemia. Clearly, delayed and prolonged postischemic systemic inflammation has devastating effects on stroke outcome, in the absence of a prolonged febrile response. These findings, together with corroborative clinical data, emphasize the importance of early intervention to counteract the deleterious consequences of stroke-associated inflammation and infection.

Contribution of physical fitness, cerebrovascular reserve and cognitive stimulation to cognitive function in post-menopausal women.

UNLABELLED: Studies of the effects of physical fitness on cognition suggest that exercise can improve cognitive abilities in healthy older adults, as well as delay the onset of age-related cognitive decline. The mechanisms for the positive benefit of exercise and how these effects interact with other variables known to influence cognitive function (e.g., involvement in cognitive activities) are less well understood. The current study examined the associations between the physical fitness, cerebrovascular blood flow regulation and involvement in cognitive activities with neuropsychological function in healthy post-menopausal women. METHODS: Forty-two healthy women between the ages of 55 and 90 were recruited. Physical fitness (V˙O2 max), cerebrovascular reserve (cerebral blood flow during rest and response to an increase in end-tidal (i.e., arterial) PCO2), and cognitive activity (self-reported number and hours of involvement in cognitive activities) were assessed. The association of these variables with neuropsychological performance was examined through linear regression. RESULTS: Physical fitness, cerebrovascular reserve and total number of cognitive activities (but not total hours) were independent predictors of cognitive function, particularly measures of overall cognitive performance, attention and executive function. In addition, prediction of neuropsychological performance was better with multiple variables than each alone. CONCLUSIONS: Cognitive function in older adults is associated with multiple factors, including physical fitness, cerebrovascular health and cognitive stimulation. Interestingly, cognitive stimulation effects appear related more to the diversity of activities, rather than the duration of activity. Further examination of these relationships is ongoing in a prospective cohort study.

Assessing cognitive function after intracerebral hemorrhage in rats.

Preclinical studies must rigorously assess whether putative therapies improve motor and cognitive function following brain injury. Intracerebral hemorrhage (ICH) causes significant sensory-motor and cognitive deficits in humans. However, no study has evaluated cognition in rodent ICH models. Thus, we used a battery of tests to comprehensively examine whether a striatal ICH causes cognitive impairments in rats. Bacterial collagenase (or sterile saline for SHAM surgery) was injected into the striatum to create an ICH. Two days later, functional deficits were assessed using a neurological deficit scale (NDS), which is most sensitive to ICH injury. Sensory and/or motor deficits may confound cognitive testing; thus, we waited until these had resolved before testing learning and memory. Testing was conducted 1-7 months after ICH and included spontaneous alternation, elevated plus maze, open-field, Morris water maze, T-maze (win-shift and win-stay paradigms), and the radial arm maze (eight and four arms baited protocols). Significant motor deficits at 2 days completely resolved by 1 month, at which time cognitive testing began. In contrast to persistent cognitive deficits that occur after ICH in humans, we did not detect significant learning or memory deficits after ICH in rats. Our results suggest that these tests will not likely be useful for assessing outcome in experimental ICH studies. In conclusion, animal models that better mimic clinical ICH (both motor and cognitive deficits) must be developed. This may include increasing ICH severity or injuring other functional subdivisions within the striatum that may lead to more profound cognitive deficits.