The main finding of this study is the high incidence of SoT in patients with large craniectomies, suggesting that the condition is underreported. [16, 17, 30, 34, 39] Contrary to previous studies we have identified that 65% patients suffered from SoT. A detailed prospective neurologic and radiologic assessment within four days before and after cranioplasty, allowed to identify the spectrum of SoT condition. We then identified three independent risk factors contributing to SoT that may help stratify SoT risk in future studies. Third, we identified and quantified the impact of cranioplasty timing on neurological recovery. Our findings suggest an association between earlier cranioplasty and improved neurological recovery.
Detailed neurological assessment is instrumental in detecting SoT
A detailed neurological and cognitive assessment within four days before and after the cranioplasty allowed to detect the milder 'a posteriori' SoT cases. A posteriori SoT manifest by slow rehabilitation progress and presented an objective neurological improvement within four days after the cranioplasty. The improved diagnostic sensitivity explains a significantly higher incidence of SoT in our cohort. Our study adds to the growing body of literature demonstrating that a significant proportion of patients improve after cranioplasty even without evident neurological worsening beforehand. Our findings showing an improvement of neurological function in the 'a posteriori' SoT group corroborate the observations that a proportion of patients improve after cranioplasty even without an apparent worsening beforehand. Thus, our findings suggest that 'a priori' and 'a posteriori' SoT constitute a spectrum of clinical severity of SoT. Consequently, a significant proportion of patients after craniectomy is susceptible to develop SoT, and the lack of rehabilitation progress in craniectomized patients should alert clinicians to consider tailoring the cranioplasty timing to an individual patient.
The SoT diagnosis remains challenging due to the absence of robust diagnostic criteria. In the current study, the radiological assessment revealed that 81% of the SoT group presented at least one sign of shifting brain structures, e.g. sinking skin flap, paradoxical midline shift, compressed lateral or 3rd ventricle, but diagnostic yield individually remained low. SoT manifested without the classical radiological sign of sinking skin flap in 50% and without paradoxical herniation in more than 80% of the 'a posteriori' SoT patients, corroborating our previous study. As a result, the absence of a sinking skin flap or paradoxical herniation does not exclude SoT, and careful clinical evaluation should guide the diagnosis. Conversely, radiologic signs of the brain structure shifting should warrant a careful repeated neurological evaluation and to consider an expedited cranioplasty.
Brain injury, hemorrhage, and shifting of the brain are risk factors for SoT
Our results suggest that hemorrhagic lesions in the leptomeningeal compartment and shifting of brain structures are strongly associated with the development of SoT. Although TBI did not maintain a strong association in multivariable analysis, the association between TBI and SoT could be clinically significant, warranting confirmation in larger cohorts.
There was no significant confounding between the shift of brain structures and TBI or the hemorrhagic lesions and TBI. Consequently, we suggest a cumulative effect of these three risk factors on the development of SoT. Stiver et al. showed that brain contusions, together with abnormal cerebrospinal fluid (CSF) circulation, represent a risk factor for developing SoT. Similarly, in a study evaluating a large DC registry including 43 SoT cases Di Rienzo et al. found an association between TBI and SoT. On the other hand, although our results suggest that ischemic stroke presents a lower risk for SoT, stroke etiology should not exclude SoT, as it has been previously shown to occur in stroke cohorts.
The three-hit hypothesis for developing SoT
Based on the study results, we suggest a three-hit hypothesis for the pathophysiology of SoT:
- Initial brain injury by TBI causes a wide range of functional short- and long-term neurological deficits associated with contusions and diffuse axonal injury with underlying healthy brain tissue that has the potential to recover.
- Cranial window results in brain structure shift and disturbs physiologic intracranial fluid dynamics. The physical shift of brain structures and compression by a sinking skin flap causes blood flow disturbances, cerebral metabolism impairment[43, 47], and changes in the CSF flow[11, 41]. The loss of the brain's rigid enclosing causes reduced pulse wave amplitude, which impairs intracranial fluid movement, including capillary blood flow, CSF circulation, and perivascular drainage.
- Hemorrhagic lesions further impair CSF production and clearance. Increased atmospheric pressure and blood degradation products in the brain parenchyma and subarachnoid space impair CSF formation and clearance through blockade of arachnoid granulations by blood clots. Additionally, emerging evidence on the role of perivascular drainage of brain solutes and its impairment may additionally contribute to impaired brain fluids dynamics. [12, 23]
Interestingly, we did not find association between craniectomy size and SoT. Recent studies have shown an association between craniectomy size and SoT.[29, 39] In a study by Tarr et al. SoT incidence increased sharply when craniectomy area reached 50 cm2 and beyond. Although we did not find a difference in mean craniectomy area between SoT and non-SoT group, the inclusion of only large craniectomies in our study (mean craniectomy area 112.8 ± 35.4 cm2) limited the power to detect this association. Nevertheless, large craniectomies may have contributed to the higher incidence of SoT in our cohort.
Effect of cranioplasty on neurological symptoms and disability
All SoT patients improved in motor and cognitive function within four days after the cranioplasty confirming the SoT diagnosis. In contrast, Honeybul et al. reported a 16% improvement rate. However, their cohort did not include patients with worsening neurological status before the cranioplasty (i.e., 'a priori' SoT), arguably representing less severe SoT cases. According to the literature, the delay to improvement observed after cranioplasty varies from 1-4 days.[2, 17, 39] There is also evidence suggesting that cerebral perfusion abnormalities improve in a similar timeframe. As a result, evaluating neurological symptoms within four days in this study was considered optimal for increasing the SoT detection sensitivity.
Our results revealed that neurological improvement after cranioplasty in SoT patients led to a significant improvement in the quality of life (i.e., decreased disability) and a shift towards good neurological outcome within four days after the cranioplasty. This study reports a clear and measurable improvement in an individual's quality of life after the cranioplasty and adds to the growing body of literature on the impact of cranioplasty on neurological recovery.
Does timing of the cranioplasty improve neurological recovery?
We found an association between improved neurological recovery and shorter delays to cranioplasty. Although our results are in line with the emerging evidence that cranioplasty may improve neurological function, and earlier cranioplasty may enhance this effect [18, 25], the question of optimal timing for cranioplasty procedure remains a complex issue. Multiple factors are at play when determining the optimal timing. One of them, addressed in our study, is the resolution of brain swelling giving place to restore the skull integrity successfully.
Our study results suggest a potential window to perform cranioplasty as early as two weeks after the craniectomy as soon as the brain swelling resides. Potential benefits from cranioplasty, such as improved postural blood flow, cerebrovascular reserve capacity, cerebral metabolism[43, 47], and improvement in CSF flow, offer compelling arguments in favor of an earlier cranioplasty. In line with these previous studies, intracranial ICP measurements showed that physiological ICP dynamics during changes from supine to vertical position were restored after the cranioplasty. Thus, earlier cranioplasty could improve the aptitude to perform rehabilitation activities in a seated or standing position. However, to fully understand the equation for optimal cranioplasty timing, multiple variables must be considered, such as the cranioplasty-related complications, risk of infection, role of post-traumatic hydrocephalus, over-drainage related to ventriculoperitoneal shunting , pre-cranioplasty morbidity, bleeding diathesis, and conditions related to the initial etiology for a craniectomy.
The evidence for complication risk regarding the timing of cranioplasty is conflicting. In our clinical practice, cranioplasty is often performed three or more months after DC.[44, 45] Some authors have suggested that delaying the cranioplasty beyond two or even six months after DC might reduce the risk of complications and surgical site infections.[31, 40] Contrary to these findings, a meta-analysis of 18 studies and 2254 patients did not show any difference in infection rates when cranioplasty was performed earlier than three months after DC. Another meta-analysis of 1209 patients confirmed similar infectious and hemorrhagic complication rates regardless of timing. However, they also found an increased risk of hydrocephalus in the early cranioplasty group (relative risk 2.67, 95% CI 1.24 – 5.73), highlighting the complex relation of CSF circulation and the timing of cranioplasty.
In addition, the time of onset of 'a posteriori' SoT cannot be fully appreciated as this insidious form of SoT rarely presents the 'red flags', such as sinking skin flap, paradoxical herniation, orthostatic phenomena, headaches, vertigo, etc. Our findings suggest that some of the SoT symptoms might not be fully reversible, further adding to the argument in favor of an earlier cranioplasty. In line, with our findings in previous studies the proportion of complete recovery ranged from 34.6% to 78% [2, 29, 39] and the improvement continued up to 7 weeks . It is possible that earlier cranioplasty could prevent SoT but it remains unclear if earlier cranial may be beneficial in all craniectomized patients or a subgroup with higher SoT risk. Performing cranioplasty as soon as brain tissue edema resolves may be preferable as it could improve participation in rehabilitation and neurological outcome.[18, 25] Because of the varying delay to brain swelling resolution and growing observational evidence of neurological improvement after cranioplasty, future studies should seek to risk stratify patients and tailor the timing of the cranioplasty to an individual patient rather than perform it at a fixed delay.
The reasons for the increased delay between brain edema resolution and cranioplasty in our study are not clear. However, some of the contributing factors might be administrative and logistical considerations. It is crucial to foresee a timely transfer to a neurosurgical center when one is not available in the rehabilitation center's vicinity. Secondly, some delays may occur due to the logistical delays required to produce and deliver a personalized cranial flap, such as using the custom-made polyetheretherketone flaps. Thus, efforts should be made to establish an early collaboration between the rehabilitation and neurosurgical teams to streamline the logistical aspects of the cranioplasty procedure.
The relatively small sample size resulted in wide confidence intervals, signifying a low level of precision, and should be interpreted with caution. Due to the increased number of univariate analyses, we ran into the risk of type I error due to multiple comparisons that we adjusted for using FDR corrections. Hence, our results should be regarded as hypothesis-generating, highlighting potential mechanisms and associations to be confirmed in future studies on SoT. Nevertheless, it is reasonable to provide an informed discussion based on these pathophysiological hypotheses and assumptions in an effort to build a model or apply advanced neuroimaging techniques such as perfusion-weighted imaging or glymphatic MRI, which could further explain clinical and research findings and help develop hypothesis-driven studies in the field. More imaging and histopathological studies are needed to unravel the mechanisms of SoT that could lead to improved neurological recovery in this fragile patient population.
Due to the relatively small sample size and observational design, we could not control for multiple variables influencing the delay to cranioplasty. Our findings, although preliminary, suggest an association between earlier cranioplasty and improved neurological recovery. Randomized trials with larger sample sizes are warranted to explore this association, further controlling for multiple confounding factors and effect modifiers. Furthermore, cranioplasty is known to carry a high risk of postoperative complications, and therefore, post-operative hemorrhagic complications might mask the effect of cranioplasty on neurological improvement. Lastly, ten patients failed to consent, potentially contributing to consent bias, which is relatively low due to the random distribution of non-consenting patients.