Anterior optic pathway pathology in CNS demyelinating diseases.

The anterior optic pathway is one of the preferential sites of involvement in CNS inflammatory demyelinating diseases, such as multiple sclerosis and neuromyelitis optica, with optic neuritis being a common presenting symptom. What is more, optic nerve involvement in these diseases is often subclinical, with optical coherence tomography demonstrating progressive neuroretinal thinning in the absence of optic neuritis. The pathological substrate for these findings is poorly understood and requires investigation. We had access to post-mortem tissue samples of optic nerves, chiasms and tracts from 29 multiple sclerosis (mean age 59.5, range 25-84 years; 73 samples), six neuromyelitis optica spectrum disorders (mean age 56, range 18-84 years; 22 samples), six acute disseminated encephalomyelitis (mean age 25, range 10-39 years; 12 samples) cases and five non-neurological controls (mean age 55.2, range 44-64 years; 16 samples). Formalin-fixed paraffin-embedded samples were immunolabelled for myelin, inflammation (microglial/macrophage, T- and B-cells, complement), acute axonal injury and astrocytes. We assessed the extent and distribution of these markers along the anterior optic pathway for each case in all compartments (i.e. parenchymal, perivascular and meningeal), where relevant. Demyelinated plaques were classified as active based on established criteria. In multiple sclerosis, demyelination was present in 82.8% of cases, of which 75% showed activity. Microglia/macrophage and lymphocyte inflammation were frequently found both in the parenchymal and meningeal compartments in non-demyelinated regions. Acute axonal injury affected 41.4% of cases and correlated with extent of inflammatory activity in each compartment, even in cases that died at advanced age with over 20 years of disease duration. An antero-posterior gradient of anterior optic pathway involvement was observed with optic nerves being most severely affected by inflammation and acute axonal injury compared with the optic tract, where a higher proportion of remyelinated plaques were seen. In neuromyelitis optica spectrum disorder, cases with a history of optic neuritis had extensive demyelination and lost aquaporin-4 reactivity. In contrast, those without prior optic neuritis did not have demyelination but rather diffuse microglial/macrophage, T- and B-lymphocyte inflammation in both parenchymal and meningeal compartments, and acute axonal injury was present in 75% of cases. Acute demyelinating encephalomyelitis featured intense inflammation, and perivenular demyelination in 33% of cases. Our findings suggest that chronic inflammation is frequent and leads to neurodegeneration in multiple sclerosis and neuromyelitis optica, regardless of disease stage. The chronic inflammation and subsequent neurodegeneration occurring along the optic pathway broadens the plaque-centred view of these diseases and partly explains the progressive neuroretinal changes observed in optic coherence tomography studies.

Vascular disease and multiple sclerosis: a post-mortem study exploring their relationships.

Vascular comorbidities have a deleterious impact on multiple sclerosis clinical outcomes but it is unclear whether this is mediated by an excess of extracranial vascular disease (i.e. atherosclerosis) and/or of cerebral small vessel disease or worse multiple sclerosis pathology. To address these questions, a study using a unique post-mortem cohort wherein whole body autopsy reports and brain tissue were available for interrogation was established. Whole body autopsy reports were used to develop a global score of systemic vascular disease that included aorta and coronary artery atheroma, cardiac hypertensive disease, myocardial infarction and ischaemic stroke. The score was applied to 85 multiple sclerosis cases (46 females, age range 39 to 84 years, median 62.0 years) and 68 control cases. Post-mortem brain material from a subset of the multiple sclerosis (n = 42; age range 39-84 years, median 61.5 years) and control (n = 39) cases was selected for detailed neuropathological study. For each case, formalin-fixed paraffin-embedded tissue from the frontal and occipital white matter, basal ganglia and pons was used to obtain a global cerebral small vessel disease score that captured the presence and/or severity of arteriolosclerosis, periarteriolar space dilatation, haemosiderin leakage, microinfarcts, and microbleeds. The extent of multiple sclerosis-related pathology (focal demyelination and inflammation) was characterized in the multiple sclerosis cases. Regression models were used to investigate the influence of disease status on systemic vascular disease and cerebral small vessel disease scores and, in the multiple sclerosis group, the relationship between multiple sclerosis-related pathology and both vascular scores. We show that: (i) systemic cardiovascular burden, and specifically atherosclerosis, is lower and cerebral small vessel disease is higher in multiple sclerosis cases that die at younger ages compared with control subjects; (ii) the association between systemic vascular disease and cerebral small vessel disease is stronger in patients with multiple sclerosis compared with control subjects; and (iii) periarteriolar changes, including periarteriolar space dilatation, haemosiderin deposition and inflammation, are key features of multiple sclerosis pathology outside the classic demyelinating lesion. Our data argue against a common primary trigger for atherosclerosis and multiple sclerosis but suggest that an excess burden of cerebral small vessel disease in multiple sclerosis may explain the link between vascular comorbidity and accelerated irreversibility disability.

Classification and Management of Metopic Craniosynostosis.

BACKGROUND: In the craniofacial surgery literature, there is a wide disparity of opinions regarding the management of nonsyndromic metopic synostosis. With the lack of level I evidence to support a particular regimen, we aimed to elucidate the current state of practice among craniofacial surgeons with the hope of establishing a standard of care. METHODS: A survey was sent to 102 craniofacial surgeons. The survey featured 2 parts: clinical scenarios and questions regarding the following: primary indication for surgery, preference of timing, and choice of operative intervention for patients presenting with nonsyndromic isolated metopic synostosis. Surgeons were also queried regarding preoperative, intraoperative, and postoperative protocols. RESULTS: The total response rate was 72% (73/102) for the clinical scenarios and 63% (64/102) for the complete survey. There was a large discrepancy when classifying and managing mild metopic synostosis, with between 16% and 35% of surgeons electing to operate on a mild case. All surgeons agreed to operate on moderate and severe cases. For 95% of respondents, skull deformity was the primary indication for treatment of craniosynostosis. Open surgical management was most commonly performed at 6 months (29%) of age. Open frontal orbital advancement was the most commonly performed procedure in mild (27%), moderate (77%), and severe (89%) cases. Endoscopic approaches were more likely to be used in milder cases by 19% of surgeons. CONCLUSION: Our survey demonstrates that there is a wide disparity of opinion among craniofacial surgeons regarding the diagnosis and management of mild nonsyndromic metopic synostosis. LEVEL OF EVIDENCE: Diagnostic, level 5.

A role for vessel-associated extracellular matrix proteins in multiple sclerosis pathology.

Multiple sclerosis (MS) is unsurpassed for its clinical and pathological hetherogeneity, but the biological determinants of this variability are unknown. HLA-DRB1*15, the main genetic risk factor for MS, influences the severity and distribution of MS pathology. This study set out to unravel the molecular determinants of the heterogeneity of MS pathology in relation to HLA-DRB1*15 status. Shotgun proteomics from a discovery cohort of MS spinal cord samples segregated by HLA-DRB*15 status revealed overexpression of the extracellular matrix (ECM) proteins, biglycan, decorin, and prolargin in HLA-DRB*15-positive cases, adding to established literature on a role of ECM proteins in MS pathology that has heretofore lacked systematic pathological validation. These findings informed a neuropathological characterisation of these proteins in a large autopsy cohort of 41 MS cases (18 HLA-DRB1*15-positive and 23 HLA-DRB1*15-negative), and seven non-neurological controls on motor cortical, cervical and lumbar spinal cord tissue. Biglycan and decorin demonstrate a striking perivascular expression pattern in controls that is reduced in MS (-36.5%, p = 0.036 and - 24.7%, p = 0.039; respectively) in lesional and non-lesional areas. A concomitant increase in diffuse parenchymal accumulation of biglycan and decorin is seen in MS (p = 0.015 and p = 0.001, respectively), particularly in HLA-DRB1*15-positive cases (p = 0.007 and p = 0.046, respectively). Prolargin shows a faint parenchymal pattern in controls that is markedly increased in MS cases where a perivascular deposition pattern is observed (motor cortex +97.5%, p = 0.001; cervical cord +49.1%, p = 0.016). Our findings point to ECM proteins and the vascular interface playing a central role in MS pathology within and outside the plaque area. As ECM proteins are known potent pro-inflammatory molecules, their parenchymal accumulation may contribute to disease severity. This study brings to light novel factors that may contribute to the heterogeneity of the topographical variation of MS pathology.

The influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter.

Cortical tissue injury is common in multiple sclerosis (MS) and associates with disability progression. We have previously shown that HLA-DRB1*15 genotype status associates with the extent of cortical inflammatory pathology. In the current study, we sought to examine the influence of HLA-DRB1*15 on relationships between inflammation and neurodegeneration in MS. Human post-mortem MS cases (n = 47) and controls (n = 10) were used. Adjacent sections of motor cortex were stained for microglia (Iba1+, CD68+, TMEM119+), lymphocytes (CD3+, CD8+), GFAP+ astrocytes, and neurons (NeuN+). A subset of MS cases (n = 20) and controls (n = 7) were double-labeled for neurofilament and glutamic acid decarboxylase 65/67 (GAD+) to assess the extent of the inhibitory synaptic loss. In MS cases, microglial protein expression positively correlated with neuron density (Iba1+: r = 0.548, p < 0.001, CD68+: r = 0.498, p = 0.001, TMEM119+ r = 0.437, p = 0.003). This finding was restricted to MS cases not carrying HLA-DRB1*15. Evidence of a 14% reduction in inhibitory synapses in MS was detected (MS: 0.299 ± 0.006 synapses/µm2 neuronal membrane versus control: 0.348 ± 0.009 synapses/µm2 neuronal membrane, p = 0.005). Neurons expressing inhibitory synapses were 24% smaller in MS cases compared to the control (MS: 403 ± 15 µm2 versus control: 531 ± 29 µm2 , p = 0.001), a finding driven by HLA-DRB1*15+ cases (15+: 376 ± 21 µm2 vs. 15-: 432 ± 22 µm2 , p = 0.018). Taken together, our results demonstrate that HLA-DRB1*15 modulates the relationship between microglial inflammation, inhibitory synapses, and neuronal density in the MS cortex.

Posterior component separation and transversus abdominis muscle release for complex incisional hernia repair in patients with a history of an open abdomen.

BACKGROUND: The best reconstructive approach for large fascial defects precipitated from a previous open abdomen has not been elucidated to date. We use a posterior component separation with transversus abdominis muscle release (TAR) in this scenario. METHODS: Patients with a history of an open abdomen who ultimately underwent complex hernia repair with TAR from 2010 to 2013 at Case Medical Center were identified in our prospective database and analyzed. RESULTS: Of 34 patients (mean [SD] age, 54 [11.3] years; mean [SD] body mass index, 32.5 [7.2]) with a history of an open abdomen, the fascia was closed primarily in 11 and skin alone closed primarily in 4 patients after a mean (SD) of 5.9 (6.7) days. Those unable to achieve primary closure either received a skin graft (n = 16) or healed by secondary intention (n = 3). Patients presented to our institution a mean (SD) of 25.1 (26.5) months after their initial operation, eight having already undergone at least one hernia repair, including four anterior component separations. Operations consisted of 21 (61.8%) contaminated cases, including 7 enterocutaneous fistula takedowns, 2 stoma revisions, 2 stoma reversals, and 3 excisions of infected mesh. Wound morbidity consisted of 12 (35%) surgical site occurrences: 1 wound dehiscence, 2 hematomas, 1 seroma, 8 surgical site infections (23.5%; 3 superficial, 3 deep, and 2 organ space), and no enterocutaneous fistulas or chronic mesh infections. One reoperation was necessary for debridement of a hematoma and deep surgical site infection. With a mean follow-up of 18 months (range, 3-42 months), two (5.9%) new parastomal hernias and three (8.8%) midline recurrences have been documented. CONCLUSION: To our knowledge, this is the first report describing the use of TAR in patients with a history of an open abdomen for definitive abdominal wall reconstruction. We have demonstrated that this approach is associated with low significant perioperative morbidity and recurrence. LEVEL OF EVIDENCE: Therapeutic study, level V.