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Paul D. Sawin, Vincent C. Traynelis, Gretchen Rich, Bruce A. Smith, Timothy J. Maves, Kenneth A. Follett and Steven A. Moore

✓ The mechanism of action underlying chymopapain (Chymodiactin) chemonucleolysis remains obscure. Radiographic studies suggest that chymopapain does not alter disc fragment size acutely; nonetheless, patients often report symptom resolution within a few days, even hours, of treatment. The authors postulate that, in addition to its chemonucleolytic action, chymopapain may possess antiinflammatory properties. To test this hypothesis, the authors assessed the ability of chymopapain to modulate the activity of the proinflammatory enzyme phospholipase A2 (PLA2) and to ameliorate behavioral changes associated with inflammatory neuropathy in an in vivo model of sciatica.

Thirty-nine male Fischer rats were randomly assigned to one of three treatment groups: 1) saline, 2) betamethasone, or 3) chymopapain. All of the rats underwent unilateral sciatic nerve ligation with loose chromic gut suture to induce inflammatory mononeuropathy. The animals were tested for thermal and mechanical hyperalgesia on Days 0 (preoperation), 7 (pretreatment), and 14 (prior to death). Three animals were killed on Day 0 to determine the baseline PLA2 activity within unmanipulated rat sciatic nerves. On Day 7, three animals from each group were killed to assess PLA2 activity prior to treatment. The remainder were given a single infusion of saline, betamethasone (0.3 mg/kg), or chymopapain (100 pKat U) around the inflamed nerve. On Day 14, the remaining animals were killed and their sciatic nerves were removed. The tissue was homogenized and the PLA2 activity was determined using [14C]arachidonate—labeled Escherichia coli phospholipid membrane as a substrate. Lipids were extracted and separated by thin-layer chromatography.

All animals developed behavioral changes consistent with inflammatory mononeuropathy 24 to 72 hours postoperatively; these included gait disturbance, flexion deformity, and hyperalgesia of the involved hindlimb. The degree of mechanical and thermal hyperalgesia was comparable between groups at Day 7. By Day 14, the thermal hyperalgesia had resolved; the mechanical hyperalgesia was less evident in the betamethasone- and chymopapain-treated groups than in the saline-treated controls (p = 0.003; saline- vs. chymopapain-treated groups p = 0.004; saline- vs. betamethasone-treated groups p = 0.008). The mean PLA2 activity at baseline (Day 0) was 11.6 ± 4.9 nmol phospholipid hydrolyzed per minute per milligram of protein. The PLA2 activity at Day 7 was 74.4 ± 18.2 (ligated side) and 21.2 ± 11.7 (nonligated side). At Day 14, PLA2 activity was reduced in the chymopapain- (47.8 ± 12.3) and betamethasone- (39.7 ± 9.5) treated groups compared with the saline control group (62.3 ± 11.2), (saline- vs. chymopapain-treated groups p < 0.05; saline- vs. betamethasone-treated groups p < 0.01). The PLA2 activity in nonligated specimens was 18.6 ± 10.1.

These data indicate that chymopapain exhibits antiinflammatory properties in vivo, reducing PLA2 activity and ameliorating mechanical hyperalgesia in this model of inflammatory sciatic neuropathy.

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Nickalus R. Khan, Brittany D. Fraser, Vincent Nguyen, Kenneth Moore, Scott Boop, Brandy N. Vaughn and Paul Klimo Jr.

OBJECTIVE

Despite established risk factors, abusive head trauma (AHT) continues to plague our communities. Cerebrovascular accident (CVA), depicted as areas of hypodensity on CT scans or diffusion restriction on MR images, is a well-known consequence of AHT, but its etiology remains elusive. The authors hypothesize that a CVA, in isolation or in conjunction with other intracranial injuries, compounds the severity of a child’s injury, which in turn leads to greater health care utilization, including surgical services, and an increased risk of death.

METHODS

The authors conducted a retrospective observational study to evaluate data obtained in all children with AHT who presented to Le Bonheur Children’s Hospital (LBCH) from January 2009 through August 2016. Demographic, hospital course, radiological, cost, and readmission information was collected. Children with one or more CVA were compared with those without a CVA.

RESULTS

The authors identified 282 children with AHT, of whom 79 (28%) had one or more CVA. Compared with individuals without a CVA, children with a stroke were of similar overall age (6 months), sex (61% male), and race (56% African-American) and had similar insurance status (81% public). Just under half of all children with a stroke (38/79, 48%) were between 1–6 months of age. Thirty-five stroke patients (44%) had a Grade II injury, and 44 (56%) had a Grade III injury. The majority of stroke cases were bilateral (78%), multifocal (85%), associated with an overlying subdural hematoma (86%), and were watershed/hypoperfusion in morphology (73%). Thirty-six children (46%) had a hemispheric stroke. There were a total of 48 neurosurgical procedures performed on 28 stroke patients. Overall median hospital length of stay (11 vs 3 days), total hospital charges ($13.8 vs $6.6 million), and mean charges per patient ($174,700 vs $32,500) were significantly higher in the stroke cohort as a whole, as well as by injury grade (II and III). Twenty children in the stroke cohort (25%) died as a direct result of their AHT, whereas only 2 children in the nonstroke cohort died (1%). There was a 30% readmission rate within the first 180-day postinjury period for patients in the stroke cohort, and of these, approximately 50% required additional neurosurgical intervention(s).

CONCLUSIONS

One or more strokes in a child with AHT indicate a particularly severe injury. These children have longer hospital stays, greater hospital charges, and a greater likelihood of needing a neurosurgical intervention (i.e., bedside procedure or surgery). Stroke is such an important predictor of health care utilization and outcome that it warrants a subcategory for both Grade II and Grade III injuries. It should be noted that the word “stroke” or “CVA” should not automatically imply arterial compromise in this population.

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Nickalus R. Khan, Kenneth Moore, Jaafar Basma, David S. Hersh, Asim F. Choudhri, Brandy Vaughn and Paul Klimo Jr.

OBJECTIVE

An ischemic stroke following an elective craniotomy in a child is perceived to be a rare event. However, to date there are few papers on this topic. The purpose of this study was to investigate the occurrence of stroke following elective intracranial surgery at a children’s hospital.

METHODS

The authors performed a retrospective review of all patients who developed a perioperative stroke following an elective craniotomy from 2010 through 2017. Data were collected using an institutional database that contained demographic, medical, radiological, and outcome variables.

RESULTS

A total of 1591 elective craniotomies were performed at the authors’ institution during the study period. Of these, 28 (1.8%) were followed by a perioperative stroke. Radiographic diagnosis of the infarction occurred at a median of 1.7 days (range 0–9 days) from the time of surgery, and neurological deficits were apparent within 24 hours of surgery in 18 patients (62.5%). Infarcts tended to occur adjacent to tumor resection sites (86% of cases), and in a unilateral (89%), unifocal (93%), and supratentorial (93%) location. Overall, 11 (39.3%) strokes were due to a perforating artery, 10 (35.7%) were due to a large vessel, 4 (14.3%) were venous, and 3 (10.7%) were related to hypoperfusion or embolic causes. Intraoperative MRI (iMRI) was used in 11 of the 28 cases, and 6 (55%) infarcts were not detected, all of which were deep.

CONCLUSIONS

The incidence of stroke following an elective craniotomy is low, with nearly all cases (86%) occurring after tumor resection. Perforator infarcts were most common but may be missed on iMRI.

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David S. Hersh, Kenneth Moore, Vincent Nguyen, Lucas Elijovich, Asim F. Choudhri, Jorge A. Lee-Diaz, Raja B. Khan, Brandy Vaughn and Paul Klimo Jr.

OBJECTIVE

Stenoocclusive cerebral vasculopathy is an infrequent delayed complication of ionizing radiation. It has been well described with photon-based radiation therapy but less so following proton-beam radiotherapy. The authors report their recent institutional experience in evaluating and treating children with radiation-induced cerebral vasculopathy.

METHODS

Eligible patients were age 21 years or younger who had a history of cranial radiation and subsequently developed vascular narrowing detected by MR arteriography that was significant enough to warrant cerebral angiography, with or without ischemic symptoms. The study period was January 2011 to March 2019.

RESULTS

Thirty-one patients met the study inclusion criteria. Their median age was 12 years, and 18 (58%) were male. Proton-beam radiation therapy was used in 20 patients (64.5%) and photon-based radiation therapy was used in 11 patients (35.5%). Patients were most commonly referred for workup as a result of incidental findings on surveillance tumor imaging (n = 23; 74.2%). Proton-beam patients had a shorter median time from radiotherapy to catheter angiography (24.1 months [IQR 16.8–35.4 months]) than patients who underwent photon-based radiation therapy (48.2 months [IQR 26.6–61.1 months]; p = 0.04). Eighteen hemispheres were revascularized in 15 patients. One surgical patient suffered a contralateral hemispheric infarct 2 weeks after revascularization; no child treated medically (aspirin) has had a stroke to date. The median follow-up duration was 29.2 months (IQR 21.8–54.0 months) from the date of the first catheter angiogram to last clinic visit.

CONCLUSIONS

All children who receive cranial radiation therapy from any source, particularly if the parasellar region was involved and the child was young at the time of treatment, require close surveillance for the development of vasculopathy. A structured and detailed evaluation is necessary to determine optimal treatment.

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David S. Hersh, Kenneth Moore, Vincent Nguyen, Lucas Elijovich, Asim F. Choudhri, Jorge A. Lee-Diaz, Raja B. Khan, Brandy Vaughn and Paul Klimo Jr.

OBJECTIVE

Stenoocclusive cerebral vasculopathy is an infrequent delayed complication of ionizing radiation. It has been well described with photon-based radiation therapy but less so following proton-beam radiotherapy. The authors report their recent institutional experience in evaluating and treating children with radiation-induced cerebral vasculopathy.

METHODS

Eligible patients were age 21 years or younger who had a history of cranial radiation and subsequently developed vascular narrowing detected by MR arteriography that was significant enough to warrant cerebral angiography, with or without ischemic symptoms. The study period was January 2011 to March 2019.

RESULTS

Thirty-one patients met the study inclusion criteria. Their median age was 12 years, and 18 (58%) were male. Proton-beam radiation therapy was used in 20 patients (64.5%) and photon-based radiation therapy was used in 11 patients (35.5%). Patients were most commonly referred for workup as a result of incidental findings on surveillance tumor imaging (n = 23; 74.2%). Proton-beam patients had a shorter median time from radiotherapy to catheter angiography (24.1 months [IQR 16.8–35.4 months]) than patients who underwent photon-based radiation therapy (48.2 months [IQR 26.6–61.1 months]; p = 0.04). Eighteen hemispheres were revascularized in 15 patients. One surgical patient suffered a contralateral hemispheric infarct 2 weeks after revascularization; no child treated medically (aspirin) has had a stroke to date. The median follow-up duration was 29.2 months (IQR 21.8–54.0 months) from the date of the first catheter angiogram to last clinic visit.

CONCLUSIONS

All children who receive cranial radiation therapy from any source, particularly if the parasellar region was involved and the child was young at the time of treatment, require close surveillance for the development of vasculopathy. A structured and detailed evaluation is necessary to determine optimal treatment.