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Yang Wang, Ting Liu, Liangsong Song, Zhixin Zhang, Yanan Zhang, Jinsong Ni, and Laijin Lu

OBJECTIVE

Spontaneous paralysis from hourglass-like fascicular constriction of peripheral nerves is rare, its clinical manifestations are not well documented, and its pathogenesis remains unknown. The unclear origin of this disorder and difficulty in diagnosis result in its uncertain management. The authors sought to gain a more thorough understanding of this condition through describing the anatomy, clinical features, etiology, and treatment of hourglass-like constriction.

METHODS

The authors retrospectively reviewed 20 patients (22 nerves) with hourglass-like constriction. The patients’ clinical information was reviewed. Preoperative sonographic assessment and electrophysiological examination of involved nerves were performed. Surgical treatments included interfascicular neurolysis and neurorrhaphy. Samples of tissue subjected to resected constriction were sent for pathological analysis. The patients had regular face-to-face follow-up visits.

RESULTS

Acute pain was always the first symptom and was followed by paralysis. Paralysis progression was rapid and serious. Surgical exploration indicated an hourglass-like constricted segment completely unrelated to the compressive structures. Electrophysiological analysis showed severe denervation, and histopathological examination showed inflammatory cell infiltration, demyelination, and reduction of nerve fibers.

CONCLUSIONS

Hourglass-like fascicular constrictive neuropathy has an integrative effect from multiple different mechanisms. Surgical intervention is beneficial for selected patients who do not recover in a timely fashion and have hourglass-like lesions confirmed by preoperative ultrasound imaging. The authors recommend that early surgical intervention of the nerve be offered to patients who do not show any signs of recovery 3 months after onset. Both interfascicular neurolysis and neurorrhaphy are effective treatment methods. Mild to moderate constriction can usually be treated successfully by interfascicular neurolysis alone, whereas more advanced lesions with loss of fascicle continuity (severe constriction) may be best treated with resection and direct neurorrhaphy.

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Yahui Zhao, Jiaxi Li, Junlin Lu, Qian Zhang, Dong Zhang, Rong Wang, Yuanli Zhao, and Xiaolin Chen

OBJECTIVE

The effect of indirect revascularization to improve cerebral perfusion for moyamoya disease (MMD) is based on ingrowth of new vessels into the cortical brain. Preoperative indicators for neoangiogenesis would be helpful to the selection of appropriate procedures for MMD patients but have not yet been investigated. Our study aimed to identify potential predictors for neovascularization after indirect bypass surgery.

METHODS

The authors reviewed consecutive cases with complete clinical and radiological documentation of patients who had undergone surgery between December 2010 and January 2018. Patients who were treated with indirect bypass surgery were included. Cerebrovascular characteristics were evaluated by catheter angiography. Neoangiogenesis after indirect bypass was determined as “good” or “poor” based on the Matsushima standard. Univariate and multivariate analyses were performed to identify predictors for neoangiogenesis after indirect bypass. Subgroup analyses by onset type and surgical type were carried out to identify specific predictors for different populations.

RESULTS

In total, 231 hemispheres of 209 patients (mean ± SD age 23.06 ± 15.09 years, range 3–61 years) were retrospectively included. In 146 (63.2%) hemispheres, good neoangiogenesis was observed after indirect revascularization. Multivariate analysis showed that the status of ICA moyamoya vessels (p < 0.001, OR [95% CI] 3.242 [2.007–5.236]) is a predictor of favorable neoangiogenesis after indirect bypass surgery, whereas hemorrhagic onset (p < 0.001, OR [95% CI] 0.138 [0.054–0.353]) is a risk factor for poor neoangiogenesis. In addition, younger age was significantly associated with good neovascularization in patients with hemorrhagic onset (p = 0.027, OR [95% CI] 0.893 [0.808–0.987]), whereas age was not a significant predictor for neovascularization in non–hemorrhagic-onset patients (p = 0.955). Hemispheres with good revascularization had lower incidence of rebleeding, lower modified Rankin Scale scores, and more improvement of symptoms during long-term follow-up (p = 0.026, 0.006, and 0.013, respectively).

CONCLUSIONS

Hemorrhagic onset predicts poor neovascularization after indirect bypass surgery for MMD patients. Abundant ICA moyamoya vessels indicate good neoangiogenesis after indirect bypass and vice versa, whereas absent ICA moyamoya vessels predict poor revascularization. Good neovascularization was associated with better long-term outcome. Future studies are needed to further address this issue and clarify the underlying pathophysiological mechanisms.

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Hao Wang, Wenhua Yu, Zuyong Zhang, Yongmin Lu, and Xiao Li

Almost all cases of cervical spinal dysraphism published to date have involved cystic lesions and were treated in very early childhood. The authors describe a unique case of a 21-year-old woman who harbored a solid cervical rudimentary meningocele. On preoperative CT and MR images, a cutaneous solid mass was shown to be connected to intraspinal contents by a stalk traversing the C-3 lamina defect. The authors resected the cutaneous mass and released the tethering neural band from the vertical axis of the spinal cord without causing injury. Pathological examination demonstrated a dense collagenous tissue containing clusters of meningocytes and psammoma bodies in the cutaneous mass. This rare entity, a spinal dysraphism with a benign natural history, may contribute to the current classification of cervical spinal dysraphism.

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Yanlu Zhang, Michael Chopp, Yi Zhang, Zheng Gang Zhang, Mei Lu, Talan Zhang, Kuan-Han H. Wu, Li Zhang, Asim Mahmood, and Ye Xiong

OBJECTIVE

The authors previously demonstrated that Cerebrolysin is effective for treatment of mild closed head injury (CHI) when administered 4 hours after injury. The aim of this study was to determine Cerebrolysin’s effects on functional and histological outcomes in rats subjected to moderate CHI.

METHODS

In this randomized, blinded, and vehicle-controlled preclinical trial, male adult Wistar rats subjected to moderate CHI received either Cerebrolysin treatment at a dose of 2.5 ml/kg (n = 13) or vehicle (saline, n = 13) intraperitoneally administered daily for 10 days, starting at 4 hours after injury. Animals were subjected to cognitive and sensorimotor functional tests at multiple time points, and they were killed 3 months after injury. The brains were processed for analyses of neuronal cell loss, amyloid precursor protein, axonal damage, and neurogenesis.

RESULTS

Compared with rats treated with vehicle (saline), rats treated with Cerebrolysin had significantly increased numbers of neuroblasts and newborn mature neurons in the dentate gyrus (DG) and attenuated amyloid precursor protein accumulation and axonal damage in various brain regions, as well as decreased neuronal loss in the DG and cornu ammonis 3 (CA3) region of the hippocampus (p < 0.05). Global testing using generalized estimating equations showed a significant beneficial effect of Cerebrolysin treatment on sensorimotor functional outcomes from 1 day to 3 months after injury compared to that of saline treatment (p < 0.05). Compared with vehicle-treated rats, Cerebrolysin-treated rats showed significantly and robustly improved long-term (up to 3 months) cognitive functional recovery, as measured by social interaction, Morris water maze, novel object recognition, and odor recognition tests. In the Cerebrolysin-treated rats there were significant correlations between multiple histological outcomes and functional recovery evident 3 months after moderate CHI, as indicated by Pearson partial correlation analyses.

CONCLUSIONS

The authors’ findings demonstrate that Cerebrolysin treatment significantly improves long-term functional and histological outcomes in rats with moderate CHI, with functional outcomes significantly correlated with histological indices of neuroplasticity and neuroprotection. These data indicate that Cerebrolysin may be useful for the treatment of moderate CHI.

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Yanlu Zhang, Michael Chopp, Zheng Gang Zhang, Yi Zhang, Li Zhang, Mei Lu, Talan Zhang, Stefan Winter, Hemma Brandstätter, Asim Mahmood, and Ye Xiong

OBJECTIVE

Cerebrolysin is a neuropeptide preparation that mimics the properties of neurotrophic factors and has had beneficial effects in the treatment of neurodegenerative diseases, stroke, and traumatic brain injury (TBI). To further evaluate treatment schemes, the authors assessed the dose-response of Cerebrolysin on functional improvement in a rat model of mild TBI (mTBI).

METHODS

This dose-response study was a prospective, randomized, blinded, and placebo-controlled preclinical experiment. Male Wistar adult rats, subjected to mTBI induced by a closed head impact, were treated randomly with 0 (saline as placebo), 0.8, 2.5, or 7.5 ml/kg of Cerebrolysin 4 hours after mTBI and daily for a total of 10 consecutive days. A battery of cognitive and sensorimotor functional tests was performed over 90 days.

RESULTS

The primary outcome was functional improvement over the 90 days; animal weight and death were the secondary and safety outcomes, respectively. A significant (p < 0.001) dose effect of Cerebrolysin on cognitive recovery 3 months after injury was found. Cerebrolysin at a dose of ≥ 0.8 ml/kg significantly (p < 0.001) improved cognitive outcome. The higher dose (7.5 ml/kg) resulted in significantly better cognitive recovery than the lowest doses (0.8 ml/kg) but not relative to the 2.5-ml/kg dose. Cerebrolysin at a dose of 2.5 or 7.5 ml/kg also caused different onset times of significant improvement in sensorimotor function. No differences in body weight or mortality rate among the groups were found.

CONCLUSIONS

This preclinical randomized, placebo-controlled, and blinded study with a clinically relevant treatment scheme revealed that Cerebrolysin at doses of 0.8–7.5 ml/kg, administered 4 hours after mTBI and then once daily for a total of 10 consecutive days, improved functional outcomes 3 months after injury. A dose of 2.5 ml/kg is likely an optimal dose for the treatment of experimental mTBI.

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Asim Mahmood, Dunyue Lu, Changsheng Qu, Anton Goussev, Zheng Gang Zhang, Chang Lu, and Michael Chopp

Object

This study was designed to investigate the neuroprotective properties of recombinant erythropoietin (EPO) and carbamylated erythropoietin (CEPO) administered following traumatic brain injury (TBI) in rats.

Methods

Sixty adult male Wistar rats were injured with controlled cortical impact, and then EPO, CEPO, or a placebo (phosphate-buffered saline) was injected intraperitoneally. These injections were performed either 6 or 24 hours after TBI. To label newly regenerating cells, bromodeoxyuridine was injected intraperitoneally for 14 days after TBI. Blood samples were obtained on Days 1, 2, 3, 7, 14, and 35 to measure hematocrit. Spatial learning was tested using the Morris water maze. All rats were killed 35 days after TBI. Brain sections were immunostained as well as processed for the enzyme-linked immunosorbent assay to measure brain-derived neurotrophic factor (BDNF).

Results

A statistically significant improvement in spatial learning was seen in rats treated with either EPO or CEPO 6 or 24 hours after TBI (p < 0.05); there was no difference in the effects of EPO and CEPO. Also, these drugs were equally effective in increasing the number of newly proliferating cells within the dentate gyrus at both time points. A statistically significant increase in BDNF expression was seen in animals treated with both EPO derivatives at 6 or 24 hours after TBI. Systemic hematocrit was significantly increased at 48 hours and 1 and 2 weeks after treatment with EPO but not with CEPO.

Conclusions

These data demonstrate that at the doses used, EPO and CEPO are equally effective in enhancing spatial learning and promoting neural plasticity after TBI.

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Victor M. Lu, Erica A. Power, Liang Zhang, and David J. Daniels

Diffuse intrinsic pontine glioma (DIPG), otherwise known as diffuse midline glioma with H3K27M mutation, is a devastating brainstem glioma without a cure. Efforts are currently underway to better optimize molecular diagnoses through biological sampling, which today remains largely limited to surgical biopsy sampling. Surgical intervention is not without its risks, and therefore a preference remains for a less invasive modality that can provide biological information about the tumor. There is emerging evidence to suggest that a liquid biopsy, targeting biofluids such as CSF and blood plasma, presents an attractive alternative for brain tumors in general. In this update, the authors provide a summary of the progress made to date regarding the use of liquid biopsy to diagnose and monitor DIPG, and they also propose future development and applications of this technique moving forward, given its unique histone biology.

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Zhe-Feng Zhao, Li-Zhuang Yang, Chuan-Lu Jiang, Yong-Ri Zheng, and Jin-Wei Zhang

Object

The authors' goal was to observe histopathological changes in the trigeminal nerve after Gamma Knife surgery (GKS) in rhesus monkeys, and to investigate the radiobiological mechanism of GKS for primary trigeminal neuralgia. The nerve length–dosage effect of irradiation is also discussed.

Methods

One of 5 rhesus monkeys randomly served as a control, and the other 4 monkeys were randomly administered a target radiation dose of 60, 70, 80, or 100 Gy (a different dose in each animal). The size of the collimator was 4 mm, and the target point was the trigeminal nerve root. In each experimental monkey, one side was exposed to single-target-point irradiation, and the contralateral side was exposed to double-target-point irradiation. After 6 months, the trigeminal nerve root was examined using light microscopy, transmission electron microscopy, and immunohistochemistry.

Results

At each radiation dose, the damage to the nerve tissue by single-target-point irradiation was identical to that caused by double-target-point irradiation. In the trigeminal nerve tissues of the monkeys irradiated with 60 and 70 Gy, there was limited nerve demyelination and degeneration, fragmentation, or loss of axons. In the trigeminal nerve tissue of the monkey irradiated with 80 Gy, the nerve tissue showed a disordered structure. In the trigeminal nerve tissue of the monkey irradiated with 100 Gy, there was severe derangement in the structure of the nerve tissue, and extensive demyelination, fragmentation, and loss of axons.

Conclusions

The target doses of 60 and 70 Gy have very little impact on the structure of the trigeminal nerve. Irradiation at 80 Gy can cause partial degeneration and loss of axons and demyelination. A 100-Gy dose can cause some necrosis of neurons. Comparing the single-target-point with the double-target-point irradiation, the extent of damage to the nerve tissue is identical, and no difference in the nerve length–dosage effect was found.

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Dunyue Lu, Asim Mahmood, Ruilan Zhang, Yi Li, and Michael Chopp

Object. Neurogenesis, which is upregulated by neural injury in the adult mammalian brain, may be involved in the repair of the injured brain and functional recovery. Therefore, the authors sought to identify agents that can enhance neurogenesis after brain injury, and they report that (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NONOate), a nitric oxide donor, upregulates neurogenesis and reduces functional deficits after traumatic brain injury (TBI) in rats.

Methods. The agent DETA/NONOate (0.4 mg/kg) was injected intraperitoneally into 16 rats daily for 7 days, starting 1 day after TBI induced by controlled cortical impact. Bromodeoxyuridine (100 mg/kg) was also injected intraperitoneally daily for 14 days after TBI to label the newly generated cells in the brain. A neurological functional evaluation was performed in all rats and the animals were killed at 14 or 42 days postinjury. Immunohistochemical staining was used to identify proliferating cells.

Conclusions. Compared with control rats, the proliferation, survival, migration and differentiation of neural progenitor cells were all significantly enhanced in the hippocampus, subventricular zone, striatum, corpus callosum, and the boundary zone of the injured cortex, as well as in the contralateral hemisphere in rats with TBI that received DETA/NONOate treatment. Neurological functional outcomes in the DETA/NONOate-treated group were also significantly improved compared with the untreated group. These data indicate that DETA/NONOate may be useful in the treatment of TBI.

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Qian Zhang, Yaping Liu, Dong Zhang, Rong Wang, Yan Zhang, Shuo Wang, Lanbing Yu, Chaoxia Lu, Fang Liu, Jian Zhou, Xue Zhang, and Jizong Zhao

OBJECTIVE

Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease. The authors conducted a genetic study of really interesting new gene (RING) finger protein 213 (RNF213); actin alpha 2 (ACTA2); BRCA1/BRCA2-containing complex subunit 3 (BRCC3); and guanylate cyclase 1, soluble, alpha 3 (GUCY1A3) as well as a clinical phenotype analysis in Chinese MMD patients to determine whether genetic differences are responsible for the different clinical features that appear in MMD in different ethnicities.

METHODS

A panel was designed to identify disease-causing mutations in MMD genes and those involved in related disorders (RNF213, ACTA2, BRCC3, and GUCY1A3). The panel was used to detect disease-causing mutations in 255 Chinese MMD patients. Genotype and allele frequencies were compared between patients and 300 controls. A mutation segregation analysis was performed in 34 families, and genotype-phenotype correlations were made.

RESULTS

Twenty-seven rare missense variants of RNF213 were identified and were not found in controls. Among them, p.R4810K was identified in 31.4% of patients (80 of 255) with MMD. Significantly higher frequencies of the A allele and G/A genotype of p.R4810K were observed in MMD patients compared with controls (χ2 = 104.166, p < 0.000). Twenty-five rare variants were identified in 10.6% of patients (27 of 255) without p.R4810K variants. Segregation analysis supported an association between MMD and 3 variants. No possible disease-causing mutations were identified in ACTA2, BRCC3, or GUCY1A3. Compared with patients without the rare variants in RNF213, the p.R4810K heterozygous patients were younger at diagnosis (25 vs 29 years old, p = 0.049) and had more familial cases (24% vs 4.4%, p = 0.000), ischemic cases (81.3% vs 67.5%, p = 0.037), and involvement of the posterior cerebral artery (52% vs 32.5%, p = 0.007).

CONCLUSIONS

RNF213 is the major susceptibility gene in Chinese MMD patients. The spectrum of rare variants identified in Chinese MMD patients was diverse. Compared to patients without the rare variants in RNF213, the p.R4810K heterozygous patients exhibited different clinical features.