Shenandoah Robinson, Jesse L. Winer, Justin Berkner, Lindsay A. S. Chan, Jesse L. Denson, Jessie R. Maxwell, Yirong Yang, Laurel O. Sillerud, Robert C. Tasker, William P. Meehan III, Rebekah Mannix, and Lauren L. Jantzie
Traumatic brain injury (TBI) is a leading cause of death and severe morbidity for otherwise healthy full-term infants around the world. Currently, the primary treatment for infant TBI is supportive, as no targeted therapies exist to actively promote recovery. The developing infant brain, in particular, has a unique response to injury and the potential for repair, both of which vary with maturation. Targeted interventions and objective measures of therapeutic efficacy are needed in this special population. The authors hypothesized that MRI and serum biomarkers can be used to quantify outcomes following infantile TBI in a preclinical rat model and that the potential efficacy of the neuro-reparative agent erythropoietin (EPO) in promoting recovery can be tested using these biomarkers as surrogates for functional outcomes.
With institutional approval, a controlled cortical impact (CCI) was delivered to postnatal Day (P)12 rats of both sexes (76 rats). On postinjury Day (PID)1, the 49 CCI rats designated for chronic studies were randomized to EPO (3000 U/kg/dose, CCI-EPO, 24 rats) or vehicle (CCI-veh, 25 rats) administered intraperitoneally on PID1–4, 6, and 8. Acute injury (PID3) was evaluated with an immunoassay of injured cortex and serum, and chronic injury (PID13–28) was evaluated with digitized gait analyses, MRI, and serum immunoassay. The CCI-veh and CCI-EPO rats were compared with shams (49 rats) primarily using 2-way ANOVA with Bonferroni post hoc correction.
Following CCI, there was 4.8% mortality and 55% of injured rats exhibited convulsions. Of the injured rats designated for chronic analyses, 8.1% developed leptomeningeal cyst–like lesions verified with MRI and were excluded from further study. On PID3, Western blot showed that EPO receptor expression was increased in the injured cortex (p = 0.008). These Western blots also showed elevated ipsilateral cortex calpain degradation products for αII-spectrin (αII-SDPs; p < 0.001), potassium chloride cotransporter 2 (KCC2-DPs; p = 0.037), and glial fibrillary acidic protein (GFAP-DPs; p = 0.002), as well as serum GFAP (serum GFAP-DPs; p = 0.001). In injured rats multiplex electrochemiluminescence analyses on PID3 revealed elevated serum tumor necrosis factor alpha (TNFα p = 0.01) and chemokine (CXC) ligand 1 (CXCL1). Chronically, that is, in PID13–16 CCI-veh rats, as compared with sham rats, gait deficits were demonstrated (p = 0.033) but then were reversed (p = 0.022) with EPO treatment. Diffusion tensor MRI of the ipsilateral and contralateral cortex and white matter in PID16–23 CCI-veh rats showed widespread injury and significant abnormalities of functional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD); MD, AD, and RD improved after EPO treatment. Chronically, P13–P28 CCI-veh rats also had elevated serum CXCL1 levels, which normalized in CCI-EPO rats.
Efficient translation of emerging neuro-reparative interventions dictates the use of age-appropriate preclinical models with human clinical trial–compatible biomarkers. In the present study, the authors showed that CCI produced chronic gait deficits in P12 rats that resolved with EPO treatment and that chronic imaging and serum biomarkers correlated with this improvement.
Farideh Nejat, Pari Zarrini, and Mostafa El Khashab
Timothy W. Vogel, Biji Bahuleyan, Shenandoah Robinson, and Alan R. Cohen
Hydrocephalus remains a major public health problem. Conventional treatment has relied on extracranial shunting of CSF to another systemic site, but this approach is associated with a high rate of complications. Endoscopic third ventriculostomy (ETV) is a novel treatment for select forms of hydrocephalus that can eliminate the need for implantation of a lifelong ventricular shunt system. However, the indications for ETV are contested and its long-term effectiveness is not well established.
The authors selected 100 consecutive patients who underwent ETV for hydrocephalus beginning in 1994. Patients were enrolled and treated at a single institution by a single surgeon. The primary outcome was success of ETV, with success defined as no need for subsequent surgery for hydrocephalus.
Ninety-five patients satisfied the inclusion criteria. The mean follow-up period was 5.1 years (median 4.7 years) with follow-up data available for as long as 17 years. Patients commonly presented with headache (85%), ataxia (34%), emesis (29%), and changes in vision (27%). The success rate for ETV was 75%. Twenty-one patients (22%) in the series had malfunctioning shunts preoperatively and 13 (62%) were successfully treated with ETV. Preoperative inferior bowing of the third ventricle floor on MRI was significantly associated with ETV success (p < 0.05).
Endoscopic third ventriculostomy is an effective and durable treatment for select patients with hydrocephalus. When successful, the procedure eliminates the lifelong complications associated with implanted ventricular shunts.
Nima Alan, Sunil Manjila, Nori Minich, Nancy Bass, Alan R. Cohen, Michele Walsh, and Shenandoah Robinson
Although survival for extremely low gestational age newborns (ELGANs) has improved in the past 3 decades, these infants remain prone to complications of prematurity, including intraventricular hemorrhage (IVH). The authors reviewed the outcomes for an entire cohort of ELGANs who suffered severe IVH at their institution during the past 12 years to gain a better understanding of the natural history of IVH and frequency of ventriculoperitoneal (VP) shunt placement in this population.
Data from the neonatal ICU (NICU) database, neurosurgery operative log, and medical records were used to identify and follow up all ELGANs who suffered a severe IVH between 1997 and 2008. Trends between Period 1 (1997–2001) and Period 2 (2004–2008) were analyzed using the Pearson chi-square test.
Between 1997 and 2008, 1335 ELGANs were admitted to the NICU at the authors' institution within 3 days of birth, and 111 (8.3%) of these infants suffered a severe IVH. Survival to 2 years, incidence of severe IVH, neonatal risk factors (gestational age, birth weight, and incidence of necrotizing enterocolitis), ventriculomegaly on cranial ultrasonography, and use of serial lumbar punctures for symptomatic hydrocephalus were all stable. Infants from Period 2 had a significantly lower incidence of bronchopulmonary dysplasia and sepsis than infants from Period 1 (both p < 0.001). All ELGANs with severe IVH and ventriculomegaly underwent long-term follow-up to identify shunt status at late follow-up. Twenty-two ELGANs (20%) with severe IVH required a temporary ventriculosubgaleal (VSG) shunt. Three infants with VSG shunts showed spontaneous hydrocephalus resolution, and 2 infants died of unrelated causes during the neonatal admission. The temporary VSG shunt complication rate was 20% (12% infection and 8% malfunction). Sixteen percent of all ELGANs (18 of 111) with severe IVH eventually required permanent ventricular shunt insertion. Six (35%) of 17 infants with a permanent VP shunt required at least 1 permanent shunt revision during the 1st year. The proportion of ELGANs with severe IVH who required a temporary VSG (35%) or permanent VP shunt (30%) during Period 1 decreased by more than 60% in Period 2 (10% [p = 0.005] and 8.3% [p = 0.009], respectively).
The authors report for the first time a marked reduction over the past 12 years in the proportion of ELGANs with severe IVH who required surgical intervention for hydrocephalus. Using the NICU database, the authors were able to identify and follow all ELGANs with severe IVH and ventriculomegaly. They speculate that the reduction in ventricular shunt rate results from improved neonatal medical care, including reduced infection, improved bronchopulmonary dysplasia, and postnatal steroid avoidance, which may aid innate repair mechanisms. Multicenter prospective trials and detailed analyses of NICU parameters of neonatal well-being are needed to understand how perinatal factors influence the propensity to require ventricular shunting.
John R. W. Kestle
Preterm infants are at risk for perinatal complications, including germinal matrix–intraventricular hemorrhage (IVH) and subsequent posthemorrhagic hydrocephalus (PHH). This review summarizes the current understanding of the epidemiology, pathophysiology, management, and outcomes of IVH and PHH in preterm infants.
The MEDLINE database was systematically searched using terms related to IVH, PHH, and relevant neurosurgical procedures to identify publications in the English medical literature. To complement information from the systematic search, pertinent articles were selected from the references of articles identified in the initial search.
This review summarizes the current knowledge regarding the epidemiology and pathophysiology of IVH and PHH, primarily using evidence-based studies. Advances in obstetrics and neonatology over the past few decades have contributed to a marked improvement in the survival of preterm infants, and neurological morbidity is also starting to decrease. The incidence of IVH is declining, and the incidence of PHH will likely follow. Currently, approximately 15% of preterm infants who suffer severe IVH will require permanent CSF diversion. The clinical presentation and surgical management of symptomatic PHH with temporary ventricular reservoirs (ventricular access devices) and ventriculosubgaleal shunts and permanent ventriculoperitoneal shunts are discussed. Preterm infants who develop PHH that requires surgical treatment remain at high risk for other related neurological problems, including cerebral palsy, epilepsy, and cognitive and behavioral delay. This review highlights numerous opportunities for further study to improve the care of these children.
A better grasp of the pathophysiology of IVH is beginning to impact the incidence of IVH and PHH. Neonatologists conduct rigorous Class I and II studies to advance the outcomes of preterm infants. The need for well-designed multicenter trials is essential because of the declining incidence of IVH and PHH, variations in referral patterns, and neonatal ICU and neurosurgical management. Well-designed multicenter trials will eventually produce evidence to enable neurosurgeons to provide their smallest, most vulnerable patients with the best practices to minimize perioperative complications and permanent shunt dependence, and most importantly, optimize long-term neurodevelopmental outcomes.
Mary I. Huang, Mary Ann O'Riordan, Ellen Fitzenrider, Lolita McDavid, Alan R. Cohen, and Shenandoah Robinson
Nonaccidental head trauma (NAHT) is a major cause of death in infants. During the current economic recession, the authors noticed an anecdotal increase in infants with NAHT without an increase in the overall number of infants admitted with traumatic injuries. An analysis was performed to determine whether there was an association between economic recession and NAHT.
With Institutional Review Board approval, the trauma database was searched for NAHT in infants 0–2 years old during nonrecession (December 2001 to November 2007) and recession (December 2007 to June 2010) periods. Incidence is reported as infants with NAHT per month summarized over time periods. Continuous variables were compared using Mann-Whitney U-tests, and proportions were compared using the Fisher exact test.
Six hundred thirty-nine infant traumas were observed during the study time period. From the nonrecession to the recession period, there was an 8.2% reduction in all traumas (458 in 72 months [6.4 /month] vs 181 in 31 months [5.8/month]) and a 3.5% reduction in accidental head traumas (142 in 72 months [2.0/month] vs 59 in 31 months [1.9/month]). Nonaccidental head trauma accounted for 14.6% of all traumas (93/639). The median patient age was 4.0 months and 52% were boys. There were no significant differences in the representative counties of referral or demographics between nonrecession and recession populations (all p > 0.05). The monthly incidence rates of NAHT doubled from nonrecession to recession periods (50 in 72 months [0.7/month] vs 43 in 31 months [1.4/month]; p = 0.01). During this recession, at least 1 NAHT was reported in 68% of the months compared with 44% of the months during the nonrecession period (p = 0.03). The severity of NAHTs also increased, with a greater proportion of deaths (11.6% vs 4%, respectively; p = 0.16) and severe brain injury (Glasgow Coma Scale score ≤ 8: 19.5% vs 4%, respectively; p = 0.06) during the recession.
In the context of an overall reduction in head trauma, the significant increase in the incidence of NAHT appears coincident with economic recession. Although the cause is likely multifactorial, a full analysis of the basis of this increase is beyond the scope of this study. This study highlights the need to protect vulnerable infants during challenging economic times.