Our study demonstrated that varying extent of clinical improvement occurred in 69.2% of AH patients. IL-6 level are significantly elevated in the CSF of AH patients compared to controls and are correlated with functional outcome. ROC analyses revealed that elevated IL-6 CSF level could serve as a objective prognostic marker for predicting functional outcome of AH following shunt operation. A difference ≥ 6.98-pg/ml for IL-6 CSF level was highly correlated with the improvement of outcome after the treatment of AH. Therefore, the assessment of IL-6 levels in CSF seems to be a promising strategy for treatment stratification and a step toward personalized medicine in AH patients. Additionally, the present study also validated the correlation between the GCS score at admission and the post-shunt outcome of AH.
AH may occur in the short-term or long-term after initial brain injury, and is divided into an acute (hours), sub-acute (days), or a late-onset (weeks-months) type.[18] The incidence of late-onset hydrocephalus seems relatively high in the literature, especially in patients with TBI and SAH.[2] Similarly, AH in the present study occurred within 3 months after the initial injury in most patients, and within 6 month in nearly all patients. The interval from injury onset to shunt surgery may be an important issue in shunt surgery. However, we failed to find a significant correlation between time to shunt placement and functional outcome in AH.
IL-6 is a pleiotropic cytokine with hormone like activity. In pathological conditions, elevated IL-6 CSF level stimulates the neuroinflammatory response that may contribute to the disease progression.[13, 14] Some preliminary data supported feasibility of measurement and potential association between IL-6 and poor neurological outcome of SAH patient.[16] Moreover, the assessment of CSF IL-6 levels may be regarded as a valuable diagnostic indicator for shunt dependency in patients with PHH.[17] However, few studies have focused on the association between levels of IL-6 in CSF and other relevant endpoints, such as functional outcome in patients with AH after brain injury. We therefore aimed to assess the contribution of IL-6 level in CSF to functional outcome in AH patients at 3 months postoperatively and evaluate its prognostic capacity.
During a 3-month follow-up, 69.2% of the patients with AH were found to have signs of clinical improvement in their neurological status after a shunting procedure, suggesting that CSF shunting surgery seems to be an important step in surgical rehabilitation of AH patients. Most notably, the positive effect of shunting surgery in cases with gross impairment of consciousness is associated with transition to higher levels of consciousness (Fig. 1).This is consistent with previous study.[19] Although the mRS score of all AH patients improved merely by an average of 1.1 points in the study, a small gain of functional capacity can contribute to major differences in daily care and might support the deployment of rehabilitation interventions.[7] Further, we investigated the possible factors affecting short-term functional outcome after shunting in AH patients. Knowledge of such factors could possibly aid in the preoperative decision-making process by enhancing both operative indications and patient informed consent. We confirmed that IL-6 was elevated in the CSF of the AH group compared to the iNPH group, suggesting that inflammatory responses mediated by IL-6 may play an important role in hydrocephalus development and progression after brain injury. Consistent with this, previous studies reported that increased IL-6 levels in CSF could be a direct cytokine reaction facilitating microgliosis and scar formation within the CSF system, thereby resulting in chronic CSF obstruction.[13, 17] In subgroup analysis, our results showed that CSF levels of IL-6 were higher in good outcome group compared to poor outcome group and had a positive correlate with improvement of mRS score. Collectively, these results suggested that elevated IL-6 CSF level may reflect the effectiveness of shunt operation in AH patients and may hold significant promise as a clinical biomarker to predict functional outcome of AH.
To visualize the prognostic capacity of changes in CSF level of IL-6, a ROC analysis based on functional outcome yielded a IL-6 cut-off value with high sensitivity and specificity which resulted in sub-populations with significantly different therapy response and post-shunt functional outcomes of AH. Concluding from our data, the optimal threshold of 6.98-pg/ml for the exclusion of non-response and poor outcome patients might help to further characterize AH patients above the 6.98-pg/ml threshold as good outcome, which is of clinical relevance, especially in cases of unclear indications prior to therapy. We therefore consider that IL-6 might serve as a complementary surrogate parameter which might be of interest to differentiate between the atrophic process and normotensive AH, reducing unnecessary operations, especially in cases with ventriculomegaly and impaired consciousness.
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ncidentally, a study in animal models reported similar results. The authors observed that distension of the ventricles is accompanied by an increase of CSF IL-6, and IL-6 concentrations decreased significantly after reduction of lateral ventricular volume using an indwelling VPS system.[20] This suggests that IL-6 in CSF can be indicators of ventriculomegaly and of improvement after the treatment of hydrocephalus. However, in addition to involving in the development of hydrocephalus, IL-6 still mediates a variety of pathological brain injuries. For example, increased IL-6 levels in CSF could significantly elevated the number of glial fibrillary acidic protein-immunoreactive astrocytes and ionized calcium-binding adaptor molecule-1-reactive microglia, causing a massive reactive gliosis, which results in ubiquitous cerebral hypertrophy.[13, 17] Moreover, changes in IL-6 concentrations in the CSF can contribute to damage of periventricular white matter injury. Damage to the white matter may influence brain integrity in hydrocephalus cases.[20] Therefore, it is conceivable that CSF shunt surgery could help to mitigate the deleterious effect of IL-6 in AH cases.
Taken together, our study expands upon these findings by showing that not only is IL-6 correlated to development of chronic hydrocephalus after brain injury, but it has an ability to predict shunt response and functional outcome of AH patients, especially in cases with the vegetative and minimally conscious state. Even if IL-6 only has a correlative — as opposed to causative — relationship with functional outcome, the identification of the measurable biomarker of outcome may allow objective prognostication of patients and facilitate addressing goals of care early for AH patients following brain injury.
Additionally, we observed a statistically significant difference between the two subgroups depending on GCS score at the time of admission, and logistic regression analysis revealed that GCS was associated with the post-shunt outcome of AH, indicating GCS at presentation could serve as a risk factor for predicting the unfavorable functional outcome of AH patients. In fact, patients with a worse baseline clinical status was more likely to undergo shunt failure due to the deleterious effects of primary brain injury on neurological presentation.[3, 21] Contrary to expectations, recent studies have reported GCS on admission and outcome in patients with AH, but the results are contradictory.[6, 8] Therefore, GCS obtained upon admission may have variable predictive value and is not entirely objective. Comparatively speaking, levels of IL-6 in CSF may be more stable and objective than admission GCS, and has therefore been emphasized as a more reliable test before surgery. Yet even that, when clinician have difficulties in the preoperative decision-making process, it is recommend admission GCS of 10.5 as a reference threshold for assessing the postoperative outcome of AH.
In summary, this study included an investigation of preoperative factors associated with short-term outcomes following shunt surgery in AH patients. Our results indicated that the CSF level of IL-6 and admission GCS were the most useful measures for predicting short-term outcome after shunt surgery. The identification of both factors may translate into better surgical patient selection, which may result in improvement of postoperative outcomes and a reduction in unnecessary operations.