Low-grade epilepsy-associated tumors: Epilepsy outcome and antiseizure medication discontinuation after lesionectomies as first-line surgical approach in pediatric population.

OBJECTIVE: This study aimed to evaluate epilepsy outcome and antiseizure medication (ASM) discontinuation after lesionectomies as first surgical approach in pediatric population diagnosed with low-grade epilepsy-associated neuroepithelial tumors (LEATs). METHODS: We conducted a retrospective study. Thirty-six consecutive patients with histological diagnoses of LEATs who underwent surgery between 2018 and 2021 at our institution were included. The clinical and surgical data were retrospectively analyzed. RESULTS: Thirty (83.3%) of 36 patients are free of disabling seizures (Engel class I) and 19 (63,4%) of them are classified as Engel Ia. In 17 (47.2%) patients, ASM could be discontinued. The mean age at surgery was 8.6 years (±4.04) and the mean age at onset of epilepsy was 7.2 years (±3.8), whereas the mean duration of epilepsy in months at the time of surgery was 21.3 months (±23.7). The epileptogenic tumor was in the temporal lobe in 20 (55.5%) patients. Because of seizure persistence, a second or a third surgery was necessary for six patients (16.7%) and four of them had residual lesions (three in temporal and one in extratemporal site). No perioperative complications were recorded, including acute seizures, with a median hospitalization time of 7 days. Shorter epilepsy duration at time of surgery as long as a single ASM was significantly correlated with an Engel class I outcome (p-value = .01 and p-value = .016, respectively). Focal seizure semeiology was associated with an increased probability of antiseizure medication discontinuation (p-value = .042). SIGNIFICANCE: Our findings confirm that shorter epilepsy disease duration, monotherapy before surgery, and seizure semeiology are determinant factors for a positive seizure outcome and medication discontinuation, also with less invasive surgical approaches such as lesionectomies. However, considering the intrinsic multifactorial epileptogenic nature of LEATs, a tailored surgical approach should be considered to optimize clinical and seizure outcome, especially for lesions located in the temporal lobe.

Gender gap in deep brain stimulation for Parkinson's disease: preliminary results of a retrospective study.

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment of PD for both women and men. However, discussions have been reported about the impact of STN-DBS surgery in PD. The aim of our study is to identify differences between men and women in terms of pre- and post-DBS symptoms and try to explain the possible causes. In the current study, we evaluated the gender impact on STN-DBS in PD at the Department of Neurosurgery of University of Naples "Federico II" from 2013 to 2021. Motor and non-motor symptoms were evaluated. To compare the data before and after surgery and between the genders, Wilcoxon-Mann-Whitney tests were performed. A total of 43 patients with PD were included; of them, 17 (39%) were female. Baseline evaluation revealed no gender differences in the age of onset (p = 0.87). Not significant differences were noted in the Unified Parkinson's Disease Rating Scale (UPDRS) pre-surgery score, but if we consider UPDRS subscores of motor examination, significant clinical improvement was reported in both male and female in terms of UPDRS pre- and post-surgery (p < 0.001). STN-DBS is a highly effective treatment for motor and non-motor symptoms of PD for both women and men but our study hints towards gender-specific outcomes in motor domains. Improving our knowledge in this field can allow us to implement strategies to identify new directions in the development of an adequate treatment of PD in terms of surgical intervention and in consideration of the gender.

Endoscopic Ultrasonic Aspiration of Brain Abscess.

Brain abscess is a focal infection occurring within the brain parenchyma consisting of a pus collection surrounded by a vascularized capsule and a fibrinous-caseous layer between the pus and capsule. Surgery is indicated for lesions with a diameter >25 mm. Different surgical approaches have been described, including puncturing of the abscess (under neuronavigation, stereotactic or echographic guidance) with aspiration of the purulent fluid through a catheter and craniotomy with microsurgical removal of the purulent material and surrounding capsule. In recent years, the endoscopic approach has become more frequently used to treat brain abscesses. The theoretical advantages are visual awareness of the completeness of pus removal and the possibility of also removing the more solid fibrinoid component, which could be the source of recurrence. Craniotomy is likewise avoided. We present the case of an 11-year-old boy affected by a parieto-occipital brain abscess and initial ventriculitis who underwent endoscopic surgery. An ultrasonic aspirator was used to wash and suck the purulent material and fragment and remove the more solid fibrinoid component. The occipital horn of the lateral ventricle was also entered, and pus was removed. At the end of the procedure, a ventricular drainage tube was left in the surgical cavity. It was removed 1 day later, because the cavity had completely collapsed. The key surgical steps are presented in Video 1.1-9 The procedure was uneventful, with very good clinical and radiological results. The endoscopic technique has been shown to be a safe and effective treatment option for intracranial abscess. In the case of large superficial lesions, the surgical risks appear similar to those of simple drainage through catheters, with a possible reduction of the 20% reported recurrence rate. The use of an ultrasonic aspirator could facilitate complete and faster pus removal, increasing the efficacy of the procedure. The patient and his parents consented to the procedure and the report of the patient's case details and imaging studies. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Review of the targeting accuracy of frameless and frame-based robot-assisted deep brain stimulation electrode implantation in pediatric patients using the Neurolocate module.

OBJECTIVE: The Neurolocate module is a 3D frameless patient registration module that is designed for use with the Neuromate stereotactic robot. Long-term electrical stimulation of the globus pallidus internus (GPi) and subthalamic nucleus (STN) via deep brain electrode implantation is particularly successful in a select group of movement disorders in pediatric patients. This study aimed to review the targeting accuracy of deep brain stimulation (DBS) electrode implantation in a single center, comparing standard frame-based techniques to the frameless Neurolocate module. METHODS: Twenty-four pediatric patients underwent implantation of bilateral DBS electrodes under general anesthesia during the period of August 2018-August 2022. All patients underwent robot-assisted stereotactic implantation of DBS electrodes using an intraoperative O-arm 3D scanner to confirm the final electrode position. These coordinates were compared with the planned entry and target, with attention to depth, radial, directional, and absolute errors, in addition to Euclidean distance (ED). The primary outcome evaluated the accuracy and safety of the Neurolocate frameless technology compared with standard frame-based techniques. RESULTS: Of the 24 bilateral DBS electrode implantations performed, 62.5% used Neurolocate technology: 87.5% were delivered to the GPi and the remaining 12.5% to the STN. The mean patient age was 11.0 (range 4-18) years and 70.8% were male. The median absolute errors in x-, y-, and z-axes were 0.35, 0.75, and 0.9 mm, respectively, using the Neurolocate module compared with 0.30, 0.95, and 1.1 mm using the standard frame-based technique. The median ED from the planned target to the actual electrode position with the Neurolocate module was 1.28 mm versus 1.69 mm using standard frame-based techniques. No major perioperative complications occurred. CONCLUSIONS: Stereotactic robot-assisted DBS implantation with the frameless Neurolocate module is safe for use in the pediatric population, showing good surgical accuracy and no inferiority to standard frame-based techniques. The Neurolocate module for robotic DBS surgery has the potential to improve surgical targeting accuracy, surgical time, patient comfort, and safety.

Dry Field Technique and Ultrasonic Aspirator in Endoscopic Removal of a Hemorrhagic Intraventricular Tumor in a 2-Year-Old Girl.

Neuroendoscopic procedures inside the ventricular system always bear the risk for an unexpected intraoperative hemorrhage. Most hemorrhages can be managed by constant irrigation with low- and high-pressure washes. In the other rare cases, the dry field technique may be necessary.1-5 It requires the aspiration of the entire intraventricular cerebrospinal fluid with the aim of establishing a proper environment for hemostasis. Video 1 illustrates a step-by-step removal of an intraventricular tumor in a 2-year-old girl through an endoscopic technique where the dry field technique was undertaken because of its hemorrhagic nature. Postoperative magnetic resonance imaging showed complete removal of the left frontal tumor infiltration at the level of the left frontal ependyma. The small residual tumor on the left frontal horn was removed using microsurgical technique with another procedure and after achieving complete removal of all visible tumor, the patient was referred to radiotherapy.

Endoscopic ultrasonic aspiration of posterior fossa abscess in Dandy-Walker malformation: case report.

BACKGROUND: Dandy-Walker malformation (DWM) is a posterior fossa malformation characterized by a huge posterior fossa cyst in communication with the fourth ventricle. Hydrocephalus is associated with more than 80% of cases and is usually treated by shunting. Despite infection being a common complication of the shunt, abscess formation within the cyst was reported only once. CASE REPORT: A neonate affected by DWM developed a posterior fossa abscess following a shunt infection. The purulent collection was refractory to standard treatment (antibiotics and burr hole drainage); therefore, an endoscopic approach was performed in order to remove the purulent collection under direct vision. This material was aspirated with the help of an endoscopic ultrasonic aspirator. The outcome was favorable, with a resolution of infection and re-implantation of the ventriculo-peritoneal shunt. Surprisingly, post-operative radiological examination showed substantial modification of the anatomy of the posterior fossa with disappearing of the Dandy-Walker cyst. To the best of our knowledge, this is the first documented report of a true Dandy-Walker malformation that modified its anatomical appearance over time. DISCUSSION AND CONCLUSION: Endoscopic aspiration of intracranial purulent collection should be considered a valid option to manage complicated cases. An endoscopic ultrasonic aspirator may make the procedure more effective and faster.

Psychiatric Symptoms in Parkinson's Disease Patients before and One Year after Subthalamic Nucleus Deep Brain Stimulation Therapy: Role of Lead Positioning and Not of Total Electrical Energy Delivered.

Parkinson's disease (PD) patients may experience neuropsychiatric symptoms, including depression, anxiety, sleep disturbances, psychosis, as well as behavioral and cognitive symptoms during all the different stages of the illness. Deep Brain Stimulation (DBS) therapy has proven to be successful in controlling the motor symptoms of PD and its possible correlation with the occurrence or worsening of neuropsychiatric symptoms has been reported. We aimed to assess the neuropsychiatric symptoms of 14 PD patients before and after one year of Subthalamic Nucleus (STN)-DBS and to correlate the possible changes to the lead placement and to the total electrical energy delivered. We assessed PD motor symptoms, depression, anxiety, apathy, impulsivity, and suicidality using clinician- and/or self-administered rating scales and correlated the results to the lead position using the Medtronic SuretuneTM software and to the total electrical energy delivered (TEED). At the 12-month follow-up, the patients showed a significant improvement in PD symptoms on the UPDRS (Unified Parkinson's disease Rating Scale) (−38.5%; p < 0.001) and in anxiety on the Hamilton Anxiety Rating Scale (HAM-A) (−29%; p = 0.041), with the most significant reduction in the physiological anxiety subscore (−36.26%; p < 0.001). A mild worsening of impulsivity was detected on the Barratt Impulsiveness Scale (BIS-11) (+9%; p = 0.048), with the greatest increase in the attentional impulsiveness subscore (+13.60%; p = 0.050). No statistically significant differences were found for the other scales. No correlation was found between TEED and scales' scores, while the positioning of the stimulating electrodes in the different portions of the STN was shown to considerably influence the outcome, with more anterior and/or medial lead position negatively influencing psychiatric symptoms.

Acute ischemic stroke secondary to ventriculoperitoneal shunt dysfunction in a child with Moyamoya syndrome.

Background: Patients with brain vascular disease and hydrocephalus may be predisposed to acute ischemic stroke in case of shunt dysfunction and subsequent increased intracranial pression. Patients with brain tumor may develop hydrocephalus as a consequence of obstruction of cerebrospinal fluid pathways and radiation-induced moyamoya syndrome secondary (RIMS) to radiotherapy (RT). Case Description: A 15-year-old male patient, affected by hydrocephalus and RIMS, presented acute cerebral ischemia after an episode of shunt malfunction. The shunt was promptly revised and the areas of ischemia visible at magnetic resonance imaging significantly decreased. Conclusion: Children who receive RT for brain tumor, particularly if the circle of Willis region is involved, require close surveillance for the development of vasculopathy and consequent stroke. This surveillance must be even tighter if the patient has been treated with ventricular shunt for the possible synergistic interaction between the two causes on reducing cerebral perfusion and increasing the risk of acute ischemic events.

Evolution in endoscopic endonasal approach for the management of hypothalamic-pituitary region metastasis: A single-institution experience.

Introduction: Endonasal endoscopic surgery has changed the treatment perspectives for different lesions of the hypothalamic-pituitary region. The metastases of the hypothalamic-pituitary region represent 0.4% of all intracranial metastatic tumors and account for only 1.8% of surgically managed pituitary lesions. The aim of tshis study is to describe a single-center institutional experience with 13 cases of hypothalamic-pituitary metastasis focused on presurgical workup, the evolution of the surgical technique, and postsurgical management according to our protocols, showing effects on progression-free and overall survival rates for this relatively uncommon location. Material and Methods: We retrospectively reviewed the whole series of patients that received the endoscopic endonasal approach at the Division of Neurosurgery at the University of Naples "Federico II" undergoing surgery from January 1997 to December 2021. We identified 13 cases whose pathology reports revealed a metastatic lesion. Statistical analysis was performed to determine the Kaplan-Meier survival function and assess for log-rank differences in survival based on gender, surgical treatment, and postoperative therapy (p-value < 0.02*). Results: The pathology report disclosed lung adenocarcinoma (six cases, 46%), breast adenocarcinoma (two cases, 15.4%), clear cell renal carcinoma (one case, 7%), melanoma (one case, 7%), colorectal adenocarcinoma (one case, 7%), uterine cervix carcinoma (one case, 7%), and follicular thyroid carcinoma (one case, 7%). A standard endoscopic endonasal approach was performed in 10 patients (76.9%), while an extended endonasal procedure was performed in only three cases (23%). Biopsy was the surgical choice in five patients with infiltrative and invasive lesions and a poor performance status (38%), while in the cases where neurovascular decompression was necessary, a subtotal resection was achieved in five patients (38%) and partial resection in three patients (23%). Recovery of visual field defect was observed in six of seven patients with visual loss (85.7%), improvement of oculomotor nerve palsy occurred in four of seven patients with this defect (57.1%), while the impairment of oculomotor palsy was observed in three patients (42.9%). Visual function was stable in the other patients. The median progression-free survival and overall survival were 14 and 18 months, respectively. There were statistically significant differences in PFS and OS in patients who underwent adjuvant radiotherapy (p=0.019 is referred to OS and p=0.017 to PFS, respectively; p-value = 0.02). Conclusions: The endoscopic endonasal approach is a viable approach for the management of hypothalamic-pituitary metastases as this surgery provides an adequate opportunity to obtain tissue sample and neurovascular decompression, both being crucial for continuing the integrated adjuvant therapy protocols.

Endoscopic ultrasonic aspiration as alternative to more invasive surgery in initial management of optic pathway gliomas in children.

INTRODUCTION: Optic pathway gliomas (OPGs) presenting with acute hydrocephalus represent a true neurosurgical and neurooncological challenge. Two main strategies are currently used: microsurgical removal of the tumor, restoring CSF pathways, and endoscopic biopsy associated with ventriculo-peritoneal shunt implantation. Since the availability of an ultrasonic aspirator handpiece, that can be used inside the working channel of a neuroendoscope, a different less invasive surgical strategy can be used. METHODS: Four pediatric patients were treated by endoscopic ultrasonic aspiration, in order to remove the upper pole of the tumor, obtaining tissue for diagnosis and restoring CSF pathways as initial treatment of OPG invading the third ventricle and causing hydrocephalus due to simultaneous blockage of both Monro foramina and of the Sylvian aqueduct. Surgical technique is described. Pre-operative and post-operative volumes were calculated on magnetic resonance imaging. RESULTS: In all cases, the surgical procedure was uneventful, the biopsy was diagnostic, and CSF pathways were restored. The amount of tumor removed ranged between 31 and 76%. All patients underwent oncological treatment of their tumors. One patient received V-P shunt only 1 year after endoscopic decompression due to tumor progression. CONCLUSION: Our preliminary results show that the use of endoscopic cavitron aspirator is safe and effective to obtain CSF flow restoration and tumor biopsy (for histological and molecular purposes), avoiding CSF shunt implant in the acute phase and offering the chance to obtain a consistent tumor debulking in a minimally invasive fashion. Neuroendoscopic approach together with modern target therapy offers the opportunity to avoid or delay major surgery.

Primary leptomeningeal medulloblastoma: a case-based review.

BACKGROUND: Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for 40% of childhood tumors in posterior fossa. Metastatic disease, occurring in 20-30% of all medulloblastoma cases at diagnosis, is largely exclusive to the leptomeninges. On the contrary, primary leptomeningeal medulloblastoma or so-called chameleon medulloblastoma, defined by the absence of a detectable intraparenchymal lesion with a widespread diffusion along leptomeninges, is a rare entity of difficult diagnosis with only a few cases reported in literature. METHODS AND RESULTS: A comprehensive literature search of three databases (PubMed, Ovid Medline, and Ovid Embase) have been conducted to identify pertinent papers focusing on the diagnostic process, management, and treatment of primary leptomeningeal medulloblastoma and its peculiar features. To our knowledge, only eight cases are described in literature, including five pediatric patients and three adults, two of which with the initial involvement of the spinal cord. In addition, we report another two pediatric cases, showing widespread primary diffusion along leptomeninges of brain and spinal cord. Finally, we analyze in-depth the peculiar morphological MRI features of this tumor. CONCLUSION: The classification and treatment of medulloblastomas are likely to change in the coming years due to new insights into the molecular biology of medulloblastoma. Primary leptomeningeal medulloblastoma could represent another potential challenge for biologists to start exploring the underlying mechanisms of this different clinical and pathological entity, with different implications for diagnosis and its management.

Malignant cerebral infarction associated with COVID-19 in a child.

Neurological manifestations, such as encephalitis, meningitis, ischemic, and hemorrhagic strokes, are reported with increasing frequency in patients affected by Coronavirus disease 2019 (COVID-19). In children, acute ischemic stroke is usually multifactorial: viral infection is an important precipitating factor for stroke. We present a case of a child with serological evidence of SARS-CoV-2 infection whose onset was a massive right cerebral artery ischemia that led to a malignant cerebral infarction. The patient underwent a life-saving decompressive hemicraniectomy, with good functional recovery, except for residual hemiplegia. During rehabilitation, the patient also developed a lower extremity peripheral nerve neuropathy, likely related to a long-Covid syndrome.

Prenatal diagnosis and postnatal management of congenital unilateral hydrocephalus for stenosis of the foramen of Monro.

Congenital hydrocephalus and ventriculomegaly can be diagnosed reliably with prenatal ultrasound and Magnetic Resonance Imaging (MRI). Unilateral hydrocephalus is uncommon, and the prognosis depends on etiology and postnatal management. Here, we present a case of a 32-years-old woman with prenatal diagnosis of unilateral hydrocephalus associated with stenosis of the foramen of Monro. Unilateral hydrocephalus is an uncommon feature that can be detected prenatally on ultrasound and MRI. In case of isolated stenosis of the foramen of Monro prognosis is good.

The gender impact in the era of COVID-19: an Italian neurosurgical perspective.

BACKGROUND: The aim of this study was to understand the impact of SARS-COVID-19 disease on neurosurgeons and our profession; specifically, to trace the role of women, in particular young neurosurgeons, in addressing this health emergency. METHODS: This cross-sectional study evaluated the impact of SARS-COVID-19 disease on Italian neurosurgeons stratified by gender [44 (49.9%) males and 49 (52,1%) females] enrolled through a questionnaire-based online survey. RESULTS: Ninety-three Italian neurosurgeons were included in this study. The percentage of female participants was 52,1%(49) and 53%(50) were younger than 40 years. Men were significantly more affected than women by complications (14 versus 3), while there was no gender difference in the Covid infection rate. Furthermore the social impact of the Pandemia was the same between men and women. CONCLUSIONS: Our analysis did not show significant differences between the two genders in the susceptibility, and mortality from COVID-19. The possible and immediate implementation of anti-COVID-19 measures and devices, associated with a lower risk of transmission in the treatment of neurosurgical pathologies, has likely, moderated and disregarded the socio-psychological "gender gap" of the Covid-19 pandemic.

Fat and Fibrin Glue: Quo Vadis?

AIM: To analyze the effectiveness of fat and fibrin glue to prevent postoperative cerebrospinal fluid (CSF) leak in pituitary surgery. MATERIAL AND METHODS: Two hundred and eleven patients affected by pituitary adenoma entered this study. Patients that underwent a microscopic transsphenoidal approach between January 2013 and April 2019 were included. All the patients that developed intraoperative CSF leak were treated with fat and fibrin glue. The presence or absence of postoperative CSF leak was considered as a parameter to test the effectiveness of the intraoperative reconstruction technique used. RESULTS: Postoperative CSF leak was observed in 5 patients (2.4%). Among patients with an intraoperative low- grade CSF leak (1 or 2), 97.9% did not develop a postoperative CSF leak. In contrast, those who presented an intraoperative CSF leak of grade 3, had a worse prognosis. CONCLUSION: Fat and fibrin glue is currently an effective method in the treatment of low-grade intraoperative CSF leak. In case of intraoperative CSF leak of grade 3, it should be used combined with the nasoseptal flap technique to obtain a safer reconstruction.

Interhemispheric transcallosal transchoroidal approach to a pineal teratoma in a 15-year-old boy.

In this video, the authors present an interhemispheric transcallosal transchoroidal approach to a pineal mass in a 15-year-old boy. He received emergency endoscopic third ventriculostomy (ETV), then an endoscopic biopsy that revealed an immature teratoma. Surgical removal was selected. The mass was located very high in the posterior third ventricle, hidden behind the splenium of the corpus callosum and the vein of Galen, so an interhemispheric transcallosal approach followed by a complete dissection of the whole choroidal fissure was chosen and allowed complete removal of the tumor. Microsurgical dissection is presented, showing clearly in detail all the neurovascular structures encountered. The video can be found here: https://stream.cadmore.media/r10.3171/2021.4.FOCVID2126.

Removal of Koos IV acoustic neuroma and auditory brainstem implant in NF2 patient.

The authors present the case of removal of a Koos grade IV right acoustic neuroma in a neurofibromatosis type 2 (NF2) patient, already operated on for left cerebellopontine angle meningioma at 7 years of age and a left acoustic neuroma at 16 years of age. A transpetrosal approach allowed cochlear sensor implantation to detect residual hearing. An enlarged retrosigmoid approach then allowed subtotal microsurgical removal of the lesion; consequently, the authors illustrate the technical nuances of an auditory brainstem implant (ABI). One month after surgery, the ABI was successfully switched on, giving back hearing perception to the patient. The video can be found here: https://stream.cadmore.media/r10.3171/2021.7.FOCVID2188.

Early vascular modifications after endoscopic endonasal pituitary surgery: The role of OCT-angiography.

PURPOSE: The aim of the present study is to analyze the changes in retinal vessel density (VD), using Optical Coherence Tomography Angiography (OCT-A), in patients that received endoscopic endonasal approach for the removal of an intra-suprasellar pituitary adenoma compressing optic chiasm. METHODS: We evaluated the VD in Superficial Capillary Plexus (SCP), Deep Capillary Plexus (DCP), Radial Peripapillary Capillary (RPC) and the Foveal Avascular Zone (FAZ) area in a series of fourteen patients (7 males, 7 females, mean age 56 ± 13 years), as compared to healthy controls. We also detected the structural Spectral Domain (SD)-OCT parameters: Ganglion Cell Complex (GCC), Retinal Nerve Fiber Layer (RNFL), visual field parameters (Mean Deviation, Pattern Standard Deviation) and Best Corrected Visual Acuity (BCVA). These measurements were performed prior than surgery and 48 hours after. RESULTS: The patients showed a significant decrease in VD of the macular and papillary regions, a significant increase in FAZ area, a significant impairment in SD-OCT, VF parameters and BCVA respect to 14 eyes of 14 healthy controls (p<0.05), at pre-op evaluation. In patients group the VD in SCP, DCP and RPC increased after surgery respect to baseline but the difference turned to be out statistically significant only in RPC (p = 0.003). Also the BCVA (p = 0.040) and the Mean Deviation at visual field (p = 0.015) significantly improved after surgery. While there was a reduction in structural OCT parameters but it was statistically significant only in GCC (p = 0.039). A positive correlation was found between the preoperative VD of the RPC, Mean Deviation, BCVA and the postoperative Mean Deviation (r = 0.426 p = 0.027; r = 0.624 p = 0.001; r = 0.515 p = 0.006). CONCLUSION: OCT-A allows to detect the early changes occurring within 48 hours after surgery showing that the improvement in retinal vessel density could occur before the recovery of the structural OCT parameters and can be a positive predictive factor for the functional recovery.