There is insufficient evidence to support a strong, moderate strength or weak recommendation related to benefits and harms of early vs delayed cranioplasty.

Cranioplasty, irrespective of its timing, is indicated in order to optimize outcome following pTBI.

In the absence of direct scientific evidence, EXPERT CONSENSUS concluded that:

• Cranioplasty can be performed as soon as medically and surgically feasible. (88.5 % consensus)

No evidence or expert opinion supported distinct recommendations based on patient gender, age, wounding mechanism, or military vs. civilian context.

Penetrating traumatic brain injuries often result in skull defects due to surgical decompression or bone loss resulting from the injury itself. Cranioplasty is an important part of patient recovery and rehabilitation after pTBI. Cranioplasty, the surgical repair of cranial defects, is essential for restoring the brain's protective barrier and promoting neurological recovery.z Cranioplasty contributes to the restoration of intracranial pressure, cerebral blood flow, and cerebrospinal fluid dynamics, aiding in the normalization of brain function.2 Improved neurological outcomes and reduced complications, such as seizures and infection, have been observed post-cranioplasty.3 In general, Cranioplasty plays a pivotal role in enhancing patients' quality of life, addressing the psychosocial impact of skull defects.4-6 Size of defects for decompressive craniectomy have varied over the decades and in more recent times decompressive craniectomy sizes are larger than in the past (130-150 cm2).7 Timing of cranioplasty is typically called ultra-early (<30 days) , early (30-90 days), typical >30 days - <12 months, and delayed or late (>1 year).8

Timing of cranioplasty and choice of materials are controversial with some studies supporting the benefits of early cranioplasty and some demonstrating increased risks with early cranioplasty.9-20 The patient's overall medical condition and stabilization of pTBI-related complications influence the optimal timing for cranioplasty. Stability in intracranial pressure, resolution of infections, and control of seizures are crucial considerations.21 Timing may be influenced by the extent of neurological recovery, ensuring that the brain is adequately healed before cranioplasty to minimize complications. Material selection is influenced by factors such as biocompatibility, availability, and the surgeon's preference.22 There is a paucity of data specific to timing of cranioplasty after pTBI and pTBI timing of cranioplasty may differ from timing of cranioplasty in other patients who have acquired skull defects. Since the time of the prior guidelines twenty years ago there have been significant advances in care for critically injured patients with pTBI, antibiotic coverage, microsurgery, and patient specific synthetic cranioplasty implants.

In the 2001 guideline the existing literature at the time was not sufficient to support an evidence-based recommendation for timing of cranioplasty.23

Four articles met inclusion criteria and all of them were determined to have high bias (see table 1). Therefore no evidence based recommendations are presented at this time for timing of cranioplasty after penetrating brain injury. The Rish24 study is the only study that met inclusion criteria in both the previous guidelines twenty years ago and this review. The Rish24 and Stephens25 studies specifically address war related pTBI injuries and cranioplasty. Matthew26 and Javadi27 specifically study cranioplasty in the pediatric population with Mathew's paper describing outcomes for pediatric patients injured in a war zone. Javadi presents data on pediatric patients with pTBI in Iran. There are studies that present data on pTBI injuries in adult civilian populations, however they did not meet inclusion criteria as the population was mixed with non-pTBI cranioplasty patients. The recommendations presented regarding cranioplasty after pTBI are expert opinion.

Rish and Stephens report outcomes of cranioplasties received by U.S. soldiers who sustained penetrating brain injuries in overseas actions.1 The repairs were conducted in the United States and the studies had medium to large sample sizes. The potential utility of the evidence these studies provide is lessened because the authors provided no or very limited information on the characteristics of patients who received cranioplasties at different times and any differences in the patients are not incorporated into the analyses. This makes it difficult to attribute differences in outcomes to the timing of the cranioplasty.

Stephens25 provides a retrospective review of cranioplasties performed at two U.S. military hospitals between April 2002 and October 2008 collected data on soldiers injured and initially treated in Iraq or Afghanistan and included 117 cranioplasties on 108 patients.2 Ninety-three of these patients had penetrating brain injuries, mostly from blasts. The patients were young, with a mean age of 26 years and only one was female. The time from injury to cranioplasty ranged from 7 to 546 days with a mean of 190 days. There was one death (0.9%) and 12 patients of the 29 patients who experienced complications required reoperation to remove the prosthesis. The mean Glasgow Outcome Score was 4.0 at 1 to 2 years post injury, but details on the follow-up period and the distribution of scores were not provided. As improvement often continues over longer periods, this may not be the definitive finding. Time to cranioplasty was stratified by 90-day intervals and the authors report they found no difference in complications or the need for reoperation across the time intervals (data was not provided in the article). Injury type, pre-cranioplasty CSF leak, pre-cranioplasty CNS infection, cranioplasty material, time to cranioplasty had no statistically significance on need to revise or reverse cranioplasty. (raw data not provided)

The Rish24 study is based on a registry created by military surgeons in Vietnam of 1,030 cases of penetrating brain injury among soldiers treated from 1967 to 1970 and their records were reviewed by the National Research Council from 1976 to 1979 to obtain follow-up information.1 They identified 491 cranioplasties conducted at military, Veterans Administration, and private civilian hospitals to repair these injuries. When cranioplasties were sorted by the time from initial operation, the rate of complications decreased as the time from injury increased and leveled out at under 5% after 12 months. When only cases with complications after the initial surgery are examined, the complication rate for cranioplasties done in the 2^nd year after the original surgery was lower (4%) than the rate for patients with cranioplasties in the 1st year (20%). The Rish24 study was discussed in the previous guidelines and although there were no recommendations on timing many surgeons of the time considered delayed cranioplasty after one year, especially in the face of contamination. Although not voted on through the Delphi process the experts identified that the management of pTBI has changed significantly since the Vietnam era so the applicability of the Rish24 study to modern pTBI care was in question. The management of penetrating brain injury, size of cranioplasty, medical management of traumatic brain injury and antibiotic options have changed significantly since the Vietnam War decreasing the validity of these results for today's pTBI patient population.

Mathew26 and Javadi27 provide information about the timing of cranioplasty in pediatric patients, limited by design and low numbers of patients. We included these since studies of pediatric patients with penetrating brain injury are limited. Both involve children injured in war zones. One study reported on all cases of children treated at the Multinational Medical Unit at Kandahar Airfield in Afghanistan by the only neurosurgeon in the region.3 During three periods totaling 237 days between September 2008 and April 2010 in which the unit could take local cases, 16 children under 15 years old treated for penetrating brain injuries were included and followed. In six cases the bone flap was left out and the patient discharged, with instructions about when to return for cranioplasty, based on both expectations of healing and operational availability. Four returned as scheduled 5, 8, and 10 weeks later, one patient returned early at 4 weeks and one patient did not return. All five of the cranioplasties were completed without difficulties and the patients were discharged with no focal neurological deficits.

Javadi27 presents a prospective series of patients who underwent decompressive craniectomies to treat penetrating blast injuries in children treated in a 2-year period in Iran near the border with Iraq (dates and hospital location not reported).4 All three of the children who survived had cranioplasties 3 months later and all had good outcomes at 1 year with no major motor deficits and reports of excellent school performance.

These four studies that meet inclusion criteria provide very low strength evidence that the timing of cranioplasty is associated with outcomes. This is based on the inconsistent findings and study risk of bias due to a lack of reporting and adjustment for patient characteristics by early and late cranioplasty that may have influenced findings. Specific difference in management based on age, gender or military status were not supported by the evidence.

Penetrating brain injury is a lethal mechanism of injury that is very difficult to study patient outcomes with prospective, randomized trials. The literature remains largely retrospective or observational in nature with many mere case reports (Class III or IV). The literature therefore does not support Level I or II recommendations. Timing of cranioplasty remains controversial. Conclusions in the literature are varied.9-21 While some studies reported a reduced rate of complications when cranioplasty is performed at late post-injury time points, other studies found good outcomes when cranioplasty was performed early. In the absence of guiding evidence, it is important that clinicians exercise good judgement with respect to the timing of cranioplasty. Cranioplasty is a crucial surgical intervention in the comprehensive rehabilitation of patients with traumatic brain injuries. The timing and type of reconstruction are influenced by a myriad of factors, necessitating a multidisciplinary approach to optimize patient outcomes.27 The literature reviewed did not provide robust evidence-based variables that could help us to determine optimal timing of cranioplasty. Also of note, we considered whether patients with complications following the index surgery should undergo a delayed cranioplasty with the goal of reducing the risk of infection. In Delphi voting 52% of our panelists supported delayed surgery in this context but this did not meet our 80% threshold reflecting some but not strong support for the idea.

In the discussion leading up to the vote the expert panel acknowledged the complexity involved in determining the appropriate timing of cranioplasty. The experts discussed factors that may influence timing include complete wound healing, resolution of brain swelling, presence or absence of hydrocephalus, history of CSF leak, history of infection or active sources of infection, infection risk, and findings of syndrome of the trephined. The consensus is that cranioplasty should be done as early as feasible per our Delphi vote. A definition for feasibility or further defining criteria to proceed with cranioplasty were not further clarified by our group despite extensive debate and discussion. (see Table 2)

Timing of cranioplasty may be influenced by the management and rehabilitation for other injuries and surgical planning is often best performed with a team approach in a holistic manner considering various medical and surgical needs of the patient. Patients may benefit from additional procedures to prepare for cranioplasty especially in the case of soft tissue deficiencies, CSF leak or persistent communications with air sinuses. Indeed, efforts to reduce the risk of infection and removal of the cranioplasty after placement is key and central to the decision of when it is best to perform a cranioplasty. Each patient may have unique mechanisms of injury, complications, rehabilitation needs and family support requirements that also can influence timing. Here decision-making must thus be tailored to the individual patient. Given the complexity of presentations of pTBI and the lack of evidence to base recommendations on, timing of cranioplasty recommendations are limited to consensus that cranioplasty should be performed as soon as medically and surgically feasible.

There was some evidence that pediatric patients may benefit from early cranioplasty27,28 however, the consensus opinion of our group was that this finding was not robust enough to generate an evidence-based or consensus recommendation. Pediatric patients may benefit from use of autologous bone in early or ultra-early cranioplasty when possible, although the evidence was not robust enough to generate an evidence based recommendation. The two studies that met inclusion criteria described autologous cranioplasty.

The timing of cranioplasty is generally a more complex issue following pTBI than blunt TBI. Issues of soft tissue injury and wound contamination make decision making in pTBI more challenging. Multidisciplinary care is an important care strategy in care of all trauma patients and remains the case for patients who have sustained pTBI. Members of the team focused on associated soft tissue and facial injuries may be essential team members to help in optimizing the soft tissue healing and determining the timing of cranioplasty. The timing of cranioplasty is best individualized based on our current understanding. The brain must be sunken and the wound should be well-healed without erythema or scabbing. Every effort should be made to ensure that risk of the implant becoming infected is minimized. In the setting of polytrauma coordination with the trauma team to ensure the patient is free from infection at other sources is also important to consider when planning cranioplasty. While there has been a view that delaying cranioplasty may allow the body additional time to clear microbes from the surgical site, the literature has not provided consistent support for this notion. Importantly, our recommendation to perform cranioplasty "as soon as feasible" (Table 2) does not reflect a desire to rush the procedure. Instead, it reflects that benefits of cranioplasty are desirable as soon as they can be achieved safely with low surgical risk. There is some evidence that performing a cranioplasty can lead to neurological improvement perhaps as a result of the brain returning to its more normal shape. This combined with the restoration of protection of the brain as well as a desire to advance the patient's care with reasonable expediency have us favoring cranioplasty as early as possible. Surgeons should not hesitate to delay a cranioplasty if they feel it could improve the odds the procedure will be durably successful (Table 3).

It is generally considered that hydrocephalus cannot be diagnosed before a cranioplasty is performed. If possible, consideration of a shunt is delayed until after the cranioplasty. Lumbar puncture can often be performed safely to enable cranioplasty if ventricles are enlarged preventing a cranioplasty. An external ventricular drain is another option. In some cases with progressive ventricular enlargement shunting prior to a cranioplasty can be required.

A multidisciplinary approach is often helpful with cranial reconstruction. Plastic surgery techniques like additional scalp dissection or subcutaneous slits can help to achieve soft tissue closure that would not be otherwise possible. The scalp flap contracts with each surgery at the site so many patients troubled by recurrent surgical site infections may require scalp expanders or microsurgical flaps prior to another attempt at cranioplasty.21 Plastic surgery involvement with complex skull defects and especially those involving the orbit or face can also be helpful and important.21

Unlike other aspects of pTBI are, cranioplasty is highly amenable to rigorous academic study. A High quality prospective studies which assess cranioplasty outcomes, timing and materials based on different patient characteristics and treatments would be highly valuable contributions to the literature. Study comparing the incidence of postoperative complications including infection, based on the timing of cranioplasty and materials selected would be very helpful in patients with pTBI. Demographics and patient characteristics (such as previous infection, CSF leak, scalp healing problems, neurologic status) would be helpful to discern if there are outcome differences based on patient specific variables. The medical factors and surgical variables required to move forward with cranioplasty are not agreed upon and should also be an area for future research. If enough data could be assembled, it is possible that a prediction model could be developed to assist neurosurgeons with decision-making. Our understanding of the ideal timing to perform a cranioplasty in the setting of pTBI remains to be determined. Future research should focus on refining guidelines for cranioplasty and exploring emerging technologies to further improve the efficacy of this essential procedure. Additionally, future studies should look beyond infection and other complication rates and include benefits and comprehensive neurorehabilitation outcome data, including speed of recovery and neurological status after cranioplasty.