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Regorafenib side effects

Regorafenib side effects

 

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Some of the most common side effects of regorafenib include:

Fatigue

Diarrhea

Nausea and vomiting

Loss of appetite

Hand-foot syndrome (redness, swelling, and pain on the palms of the hands and soles of the feet)

High blood pressure

Abdominal pain

Headache

Weight loss

Infections

Extensive coagulative necrosis 1).

One patient experienced, after reintervention and during Regorafenib treatment (administered 40 days after surgery), dehiscence of the surgical wound 2)

In patients with progressive WHO grade 3 or 4 gliomas, predominantly with two pretreatment lines or more, regorafenib seems to be effective despite considerable grade 3 or 4 side effects 3).

Treiber et al. described 11 consecutive patients with high-grade glioma recurrence treated with regorafenib at the university medical center in Göttingen. The majority of patients had MGMT promoter methylation (9/11 cases). Regorafenib was given as 2nd line systemic treatment in 6/11 patients and 3rd or higher line treatment in 5/11 patients. The median number of applied cycles was 2 with dosage reductions on 5/11. Response to treatment was observed on 4/11 (PR on 1/11, and SD on 3/11). The Median overall survival for the cohort was 16.1 months, median progression-free survival was 9.0 months, and median time to treatment failure was 3.3 months. Side effects of any CTCAE grade were noted in all patients, hereby 6/11 with CTCAE °III-IV reactions. High-grade side effects were of dermatologic, cardiovascular, and hematologic nature. A mean treatment delay of 57.5 days (range 23-119) was noted between tumor board recommendation and treatment initiation due to the application process for off-label use in this indication. In conclusion, treatment with regorafenib in relapsed high-grade glioma is a feasible treatment option but has to be considered carefully due to the significant side effect profile 4).

Within 12-months of regorafenib treatment, and 16-years since SRS, the patient developed ipsilateral House-Brackmann Grade IV facial weakness. Dramatic VS expansion from 14 to 25 mm in maximum diameter, with new brain stem compression, was seen on MRI. Due to poor prognosis of his gastrointestinal malignancy, he declined surgical resection, and elected for palliative salvage SRS 5).

1) 
Werner JM, Wollring MM, Tscherpel C, Rosen EK, Werr L, Stetter I, Rueß D, Ruge MI, Brunn A, Al Shughri A, Kabbasch C, Fink GR, Langen KJ, Galldiks N. Multimodal imaging findings in patients with glioblastoma with extensive coagulative necrosis related to regorafenib. Neuro Oncol. 2023 Mar 24:noad051. doi: 10.1093/neuonc/noad051. Epub ahead of print. PMID: 36960770.
2) 
Gregucci F, Surgo A, Carbonara R, Laera L, Ciliberti MP, Gentile MA, Caliandro M, Sasso N, Bonaparte I, Fanelli V, Tortora R, Paulicelli E, Surico G, Lombardi G, Signorelli F, Fiorentino A. Radiosurgery and Stereotactic Brain Radiotherapy with Systemic Therapy in Recurrent High-Grade Gliomas: Is It Feasible? Therapeutic Strategies in Recurrent High-Grade Gliomas. J Pers Med. 2022 Aug 20;12(8):1336. doi: 10.3390/jpm12081336. PMID: 36013284; PMCID: PMC9410141.
3) 
Werner JM, Wolf L, Tscherpel C, Bauer EK, Wollring M, Ceccon G, Deckert M, Brunn A, Pappesch R, Goldbrunner R, Fink GR, Galldiks N. Efficacy and tolerability of regorafenib in pretreated patients with progressive CNS grade 3 or 4 gliomas. J Neurooncol. 2022 Jun 18. doi: 10.1007/s11060-022-04066-9. Epub ahead of print. PMID: 35716310.
4) 
Treiber H, von der Brelie C, Malinova V, Mielke D, Rohde V, Chapuy CI. Regorafenib for recurrent high-grade glioma: a unicentric retrospective analysis of feasibility, efficacy, and toxicity. Neurosurg Rev. 2022 Jun 20. doi: 10.1007/s10143-022-01826-z. Epub ahead of print. PMID: 35725846.
5) 
Carlstrom LP, Muñoz-Casabella A, Perry A, Graffeo CS, Link MJ. Dramatic Growth of a Vestibular Schwannoma After 16 Years of Postradiosurgery Stability in Association With Exposure to Tyrosine Kinase Inhibitors. Otol Neurotol. 2021 Dec 1;42(10):e1609-e1613. doi: 10.1097/MAO.0000000000003304. PMID: 34766951; PMCID: PMC8597893.

Corpus callosum

Corpus callosum

The corpus callosum (from Latin: “tough body”), also known as the colossal commissure, is a wide, flat bundle of neural fibers beneath the cortex in the eutherian brain at the longitudinal fissure. It connects the left and right cerebral hemispheres and facilitates interhemispheric communication. It is the largest white matter structure in the brain, consisting of 200–250 million contralateral axonal projections.

The band of white matter connecting the two cerebral hemispheres.

Plays a crucial role in interhemispheric communication.

Parts

see Genu.

see Splenium.

Importance

It is particularly important because various tumors and vascular lesions can be located in and around the corpus callosum, and it is a route through which pass several surgical approaches. Performing accurate surgery in this region and avoiding damage to normal structures require that the neurosurgeon have adequate knowledge of the anatomy of the intricate blood supply to this area.

see Callosotomy

Callosal disconnection syndrome, or split brain is an example of a disconnection syndrome from damage to the corpus callosum between the two hemispheres of the brain. Disconnection syndrome can also lead to aphasia, left-sided apraxia, and tactile aphasia, among other symptoms.

Arterial supply

The pericallosal and posterior pericallosal arteries were found to be the main sources of blood supply to the corpus callosum. In 80% of the specimens, the anterior communicating artery gave rise to either a subcallosal artery or a median callosal artery, each of which made a substantial contribution to the blood supply of the corpus callosum 1).

see Pericallosal pial plexus.

Short callosal arteries were present in 58 hemispheres (96.6%) and supplied the superficial surface of the corpus callosum along its midline and were a primary arterial source to this structure. Long callosal arteries were found in 28 hemispheres (46.6%) and contributed to the pial plexus. The cingulocallosal arteries were present in all hemispheres and supplied the corpus callosum, cingulate gyrus, and also contributed to the pericallosal pial plexus. The recurrent cingulocallosal arteries were present in 17 hemispheres (28.3%) and also contributed to the pericallosal pial plexus. The median callosal artery, an anatomical variation, was present in 10 brains (33.3%). This vessel supplied the corpus callosum and the cingulate gyrus 2).

Morphometry

Variations in morphometry exist. There is a paucity of data on CC dimensions in Nigeria, and no standardized reference is available. The study aimed to determine the CC dimensions among the adult population in southeast Nigeria. The result will provide reference ranges and form a benchmark for comparisons of CC-related pathologies. A retrospective study of CC morphometric dimensions in normal subjects who had cranial MRI over two years in Memfys Hospital, Enugu, Southeast Nigeria, using a 1.5T GE© 16 channel machine. The CC was segmentalized into seven subregions using the modified Witelson method with special computer software. All measurements were taken twice from the T1 mid-sagittal image, and the mean was used for computation. The results were analyzed using descriptive and inferential statistics. A total of 200 subjects were recruited for the study. The mean length and height of the CC were 75.58 ± 4.52 mm and 24.64 ± 3.40 mm, respectively. The width dimensions of the genu, body, rostrum and splenium were 10.88 ± 1.81 mm, 5.66 ± 1.32 mm, 3.65 ± 1.25 mm, and 10.02 ± 1.70 mm, respectively. No gender variations were noted among the different dimensions of CC (P = 0.90). The length and height of CC increase gradually with age and show a positive correlation. The width dimensions of the genu and splenium increase till middle age and subsequently decreases in line with brain atrophy (p = 0.0000& p = 0.004). Using Pearson’s correlation test, no correlation was noted in the dimensions of the body and rostrum of the corpus callosum when related to age and sex. (P = 0.92 & p = 0.66). Reference ranges of CC dimensions in the subregion were presented, and variations exist in its different morphometric dimensions which are affected by brain atrophy. Gender does not influence the dimensions in these subpopulations 3)

Corpus callosum abnormality

Corpus callosum abnormality.

Corpus callosum and epilepsies

Epilepsies are reported in up to two thirds of patients with complete or partial CC agenesis (AgCC). However, AgCC per se is not indicative for seizure disorders. Moreover, additional malformations of cortical development (MCD) are causal. Microstructural CC abnormalities are detected by advanced imaging techniques, are part of diffuse white matter disturbances and are related to cognitive deficits. The etiological significance remains unexplained. However, they are also found in non-epileptic benign and transient disorders. In drug-resistant epilepsies with violent drops to the floor (“drop seizures”) callosotomy may be beneficial in seizure reduction. Since the EEG after callosotomy exhibits a single seizure focus in up to 50% of patients, consecutive resective surgical methods might be successful.

CC is part of cerebral white matter and anomalies cannot act per se as seizure onset zone. Imaging techniques demonstrate additional lesions in patients with epilepsies. CC is the major pathway for seizure generalization. Therefore, callosotomy is used to prevent generalized drop seizures 4).

Corpus callosum lesion

Corpus callosum lesion.

Agenesis of the corpus callosum

Agenesis of the corpus callosum.

Corpus callosum dysgenesis

Corpus callosum dysgenesis.

Arteriovenous malformation of the corpus callosum

Arteriovenous malformation of the corpus callosum.

Corpus callosum tumor

Corpus callosum tumor

1) 

Türe U, Yaşargil MG, Krisht AF. The arteries of the corpus callosum: a microsurgical anatomic study. Neurosurgery. 1996 Dec;39(6):1075-84; discussion 1084-5. PubMed PMID: 8938760.

2) 

Kahilogullari G, Comert A, Arslan M, Esmer AF, Tuccar E, Elhan A, Tubbs RS, Ugur HC. Callosal branches of the anterior cerebral artery: an anatomical report. Clin Anat. 2008 Jul;21(5):383-8. doi: 10.1002/ca.20647. PubMed PMID: 18521950.

3) 

Ajare EC, Campbell FC, Mgbe EK, Efekemo AO, Onuh AC, Nnamani AO, Okwunodulu O, Ohaegbulam SC. MRI-based morphometric analysis of corpus callosum dimensions of adults in Southeast Nigeria. Libyan J Med. 2023 Dec;18(1):2188649. doi: 10.1080/19932820.2023.2188649. PMID: 36946121.

4) 

Unterberger I, Bauer R, Walser G, Bauer G. Corpus callosum and epilepsies. Seizure. 2016 Apr;37:55-60. doi: 10.1016/j.seizure.2016.02.012. Epub 2016 Mar 3. Review. PubMed PMID: 27010176.

Microvascular Decompression Complications

Microvascular Decompression Complications

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Microvascular decompression (MVD) has a satisfactory safety, and it is the only surgical treatment for neurovascular compression diseases, such as hemifacial spasm, trigeminal neuralgia, and glossopharyngeal neuralgia, from the perspective of etiology.

Microvascular decompression (MVD) is a surgical procedure used to relieve pressure on a nerve root in the brainstem. While the procedure has a high success rate, like all surgeries, it does carry some risks and potential complications.

Some possible complications of microvascular decompression include:

Bleeding: Bleeding can occur during or after the surgery, which may require additional medical intervention.

Infection: Infection can occur at the site of the surgery or in the brain, which can lead to serious complications.

Nerve damage: Nerve damage can occur during the surgery, which may lead to a range of symptoms, including weakness, numbness, and paralysis.

Hearing loss: MVD can lead to hearing loss in some cases, particularly if the acoustic nerve is damaged during the procedure.

Balance problems: MVD can cause balance problems or vertigo, which may persist for several weeks or months after the surgery.

Cerebrospinal fluid leak: In rare cases, MVD can cause a cerebrospinal fluid leak, which may require further medical intervention.

It’s important to note that while these complications are possible, they are relatively rare.

Bilateral dilated and fixed pupils have long been regarded as a sign of life threatening, which is common in patients with brain herniation due to intracranial hypertension. However, transient dilated pupils after MVD have not been previously reported.

Wang et al. presented 2 patients with bilateral transient dilated and fixed pupils after MVD and discussed the possible etiologies through the literature review. Physical examination of both patients showed bilateral pupils were normal and without a medical history of pupil dilation. They underwent MVD under general anesthesia and used propofol and sevoflurane. In both cases, the vertebral artery was displaced, and Teflon pads were inserted between the vertebral artery and the brain stem. Postoperation, we found transient bilateral mydriasis without light reflection in both patients. The emergency head computed tomography revealed no obvious signs of hemorrhage and cerebral herniation. About 1 hour later, this phenomenon disappeared. Therefore, the authors think if MVD is successfully carried out, bilateral transient mydriasis may not necessarily indicate brain stem hemorrhage, cerebral herniation, and other emergency conditions, which can be recovered within a short time. The causes could be related to stimulation of the sympathetic pathway in the brain stem during MVD and side effects of anesthetics 1).

Microvascular decompression for trigeminal neuralgia complications

see Microvascular decompression for trigeminal neuralgia complications.

1)

Wang L, Fan H, Xu X, Su S, Feng W, Wu C, Chen Y. Bilateral Transient Dilated and Fixed Pupils After Microvascular Decompression: Rare Clinical Experience. J Craniofac Surg. 2023 Mar 21. doi: 10.1097/SCS.0000000000009293. Epub ahead of print. PMID: 36941233.

Neurosurgical Residency Away Rotation

Neurosurgical Residency Away Rotation

Neurosurgical Residency Away Rotation is an important component in the education of a neurosurgical resident. Subspecialization of physicians and regional centers concentrate the volume of certain rare cases into fewer hospitals. Consequently, the primary institution of a Neurosurgical Resident Training Program may not have sufficient case volume to meet the current Residency Review Committee case minimum requirements in some areas. To ensure the competency of graduating residents through comprehensive neurosurgical education, programs may need residents to travel to outside institutions for exposure to cases that are either less common or more regionally focused.

Harvey Williams Cushing 14-month Wanderjahr had a profound effect on his subsequent personal career, which in turn ushered in the modern age of American neurosurgery. From July 1900 to August 1901, he traveled to European neurosurgical centers in England, France, Switzerland, Italy, and Germany. His excursion happened at a crucial moment in his trajectory; it was built on his existing foundation of Halstedian surgical training and occurred at a time when interest in the special field of neurological surgery was emerging. The research and clinical experiences on his journey-good and bad-undoubtedly informed his fledgling neurosurgical practice. Salwi et al. present a concise account of Harvey Cushing’s time in Europe that consolidates accounts from Cushing’s travel journals, biographers, and other neurosurgeons.

The article of Salwi et al. highlights tensions in prior works and reveals new insights into the transformative nature of his Wanderjahr. Furthermore, he contextualizes his travels and achievements within the broader transformation of American medical education at the turn of the 20th century to elucidate how Europe influenced American medicine. They briefly consider the parallel benefits of Harvey Cushing’s Wanderjahr and modern domestic or international training opportunities and present potential areas of implementation 1)

Selection of the area of research

The selection of the area of research is essential. There are many arguments in favor of selecting research projects to be close to the individual trainee‘s clinical interest. Studies far away from the individual’s clinical interest in most cases are less productive and will not be pursued later. There are also many advantages if cooperation is planned with other institutions. The residency program director or staff members play an important role in the selection of the research project, of an appropriate laboratory or institution, and in the process of financing a research rotation 2)

Advantages

A neurosurgical residency away rotation allows a neurosurgical resident to spend time at another institution, usually for several weeks or months, to gain additional experience and training in the field of neurosurgery. Some potential benefits of a neurosurgical away rotation may include:

Exposure to a different patient population: Away rotations can expose neurosurgical residents to a different patient population, which may help broaden their clinical skills and experience.

Exposure to different surgical techniques and approaches: The host institution may use different surgical techniques and approaches than the resident’s home institution, which can broaden the resident’s skill set and knowledge of neurosurgery.

Access to specialized equipment and resources: The host institution may have access to specialized equipment or resources that are not available at the resident’s home institution. This can provide a unique learning opportunity and exposure to cutting-edge technology.

Networking opportunities: Away rotations provide opportunities to build relationships with faculty members, residents, and other medical professionals at the host institution. This can be valuable for future job opportunities or collaborations.

Improved residency application: Completing an away rotation at a program of interest can provide neurosurgical residents with an opportunity to showcase their skills and abilities, potentially improving their chances of being accepted into the program.

Overall, a neurosurgical residency away rotation can provide valuable learning experiences, networking opportunities, and exposure to different clinical scenarios and surgical techniques, which can help to enhance the skills and knowledge of neurosurgical residents.

Disadvantages

While there are many potential benefits to a neurosurgical residency away rotation, there are also some potential disadvantages to consider. These may include:

Disruption of continuity of care: When neurosurgical resident is away from their home institution, they may miss out on some aspects of patient care and continuity of care. This can lead to challenges in communication and follow-up for patients.

Potential differences in practice style: The host institution may have different practice styles, expectations, or protocols than the resident’s home institution. This can create confusion or challenges for the resident in terms of adapting to a new environment and different expectations.

Financial costs: Neurosurgical residents may need to bear the costs of travel, lodging, and other expenses associated with completing an away rotation. This can be a significant financial burden, particularly for residents with limited financial resources.

Challenges adapting to a new environment: Moving to a unique institution, even temporarily, can be stressful and challenging for neurosurgical residents. They may need to adapt to new living arrangements, a new hospital system, and new colleagues.

Limited time for exploration: While an away rotation can provide exposure to a different patient population and clinical setting, the limited amount of time can make it difficult to fully explore and understand the nuances of the institution and its practice.

Overall, a neurosurgical residency away rotation can be a valuable experience, but residents should carefully consider the potential disadvantages before making the decision to participate. It’s important to weigh the potential benefits against the costs and challenges to determine if an away rotation is a right choice for the individual resident.

ACGME rules regarding away rotations

Gephart et al. sought to evaluate off-site rotations to better understand the changing demographics and needs of resident education. This would also allow prospective monitoring of modifications to the neurosurgery training landscape. They completed a survey of neurosurgery program directors and a query of data from the Accreditation Council of Graduate Medical Education to characterize the current use of away rotations in the neurosurgical education of residents. They found that 20% of programs have mandatory away rotations, most commonly for exposure to a pediatric, functional, peripheral nerve, or trauma cases. Most of these rotations are done during postgraduate years 3 to 6, lasting 1 to 15 months. Twenty-six programs have 2 to 3 participating sites and 41 have 4 to 6 sites distinct from the host program. Programs frequently offset potential financial harm to residents rotating at a distant site by the support of housing and transportation costs. As medical systems experience fluctuating treatment paradigms and demographics, over time, more residency programs may adapt to meet the Accreditation Council of Graduate Medical Education case minimum requirements through the implementation of away rotations 3).

In 2019, the ACGME implemented new rules regarding away rotations, in an effort to promote resident well-being, reduce the burden of travel and expense associated with away rotations, and improve the quality of the educational experience for residents. Under these new rules, the ACGME now requires that:

Residency programs must limit the number of away rotations to no more than four weeks per year, per resident. Programs must have a written policy that outlines the process for selecting and approving away rotations, and must ensure that residents receive appropriate supervision and support during their away rotations. Programs must ensure that away rotations do not interfere with resident education and training, and that residents have adequate time to meet program requirements and prepare for board exams. The ACGME’s requirements related to away rotations are part of a larger effort to improve the quality of graduate medical education in the United States, and to ensure that residents receive the training and support they need to become competent and compassionate physicians.

1)

Salwi S, Chitale RV, Kelly PD. Harvey Cushing’s Wanderjahr (1900-1901). World Neurosurg. 2020 Oct;142:476-480. doi: 10.1016/j.wneu.2020.07.034. Epub 2020 Jul 19. PMID: 32698081; PMCID: PMC8048037.
2)

Reulen HJ. Basic research vs. applied research. Acta Neurochir Suppl. 2002;83:45-8. doi: 10.1007/978-3-7091-6743-4_8. PMID: 12442620.
3)

Gephart MH, Derstine P, Oyesiku NM, Grady MS, Burchiel K, Batjer HH, Popp AJ, Barbaro NM. Resident away rotations allow adaptive neurosurgical training. Neurosurgery. 2015 Apr;76(4):421-5; discussion 425-6. doi: 10.1227/NEU.0000000000000661. PMID: 25635889.

Neurosurgical Training in Germany

Neurosurgical Training in Germany

There has been a fivefold increase in neurosurgeons over the last three decades in Germany, despite a lesser increase in operations. Currently, there are approximately 1000 neurosurgical residents employed at training hospitals.

Neurosurgery remains an attractive specialty in Germany, but there are two concerns that may impede its appeal in the near future. The administrative burden for a neurosurgeon is onerous: Perhaps 50 percent of a neurosurgeon’s time is spent on administrative responsibilities such as coding and other tasks not involving patient care. Of perhaps greater concern is the limited pay. An international ranking of physicians’ pay published in Der Spiegel magazine in 2006 showed German doctors at the bottom, below their colleagues in other European countries as well as those in the U.S. and Australia. Physician pay in Germany increased by 10 percent after physician strikes in 2006, but the dissatisfaction with pay remains, as was evidenced in September by protests for higher physician pay and increased hospital funding. Neurosurgery is a hospital-based specialty, and most neurosurgeons are salaried employees of hospitals. Neurosurgeons, like most physicians, see private patients to supplement their income.

These concerns are likely to negatively influence the recruitment to neurosurgical training programs in the future. This problem is compounded by the fact that approximately 70 percent of medical students are women, to whom other specialties have appealed more than neurosurgery. Roughly one-third of all neurosurgeons in Germany, including those already certified and those in training, are women.

The neurosurgical training program lasts six years, and trainees work 40 to 48 hours or 50 to 66 hours per week, depending on the state and local hospital arrangements. Providing adequate training within the prescribed time frame remains a challenge 1)

Little is known about the overall training experience and career opportunities for these trainees.

Stienen et al. evaluated the current status of neurosurgical training of residents in Germany.

An electronic survey was sent to European neurosurgical trainees between June 2014 and March 2015. The responses of German trainees were compared with those of trainees from other European countries. Logistic regression analysis was performed to assess the effect size of the relationship between a trainee being from Germany and the outcome (e.g., satisfaction, working time). Results Of 532 responses, 95 were from German trainees (17.8%). In a multivariate analysis corrected for baseline group differences, German trainees were 29% as likely as non-German trainees to be satisfied with clinical lectures given at their teaching facility (odds ratio [OR]: 0.29; 95% confidence interval [CI]: 0.18-0.49; p < 0.0001). The satisfaction rate with hands-on operating room exposure was 73.9% and equal to the rate in Europe (OR: 0.94; 95% CI, 0.56-1.59; p = 0.834). German trainees were 2.3 times as likely to perform a lumbar spine intervention as the primary surgeon within the first year of training (OR: 2.27; 95% CI, 1.42-3.64; p = 0.001). However, they were less likely to perform a cervical spine procedure within 24 months of training (OR: 0.38; 95% CI, 0.17-0.82; p = 0.014) and less likely to perform a craniotomy within 36 months of training (OR: 0.49; 95% CI, 0.31-0.79; p = 0.003). Only 25.6% of German trainees currently adhere to the weekly limit of 48 hours as requested from the European Working Time Directive 2003/88/EC, and in an international comparison, German trainees were twice as likely to work > 50 hours per week (OR: 2.13; 95% CI, 1.25-3.61; p = 0.005). This working time, however, is less spent in the operating suite (OR: 0.26; 95% CI, 0.11-0.59; p = 0.001) and more doing administrative work (OR: 1.83; 95% CI, 1.13-2.96; p = 0.015).

Some theoretical and practical aspects of neurosurgical training are superior, but a considerable proportion of relevant aspects are inferior in Germany compared with other European countries. This analyses provide the opportunity for a critical review of the local conditions in German training facilities 2).

Survey on training satisfaction

As a resident representative, Lawson McLean et al. implemented a mailing list for interested German neurosurgical trainees. Thereafter, they created a survey including 25 items to assess the trainees’ satisfaction with their training and their perceived career prospects, which they then distributed through the mailing list. The survey was open from 1st April until 31st May 2021.

90 trainees were enrolled in the mailing list and they received 81 completed responses to the survey. Overall, 47% of trainees were very dissatisfied or dissatisfied with their training. 62% of trainees reported a lack of neurosurgical training. 58% of trainees found it difficult to attend courses or classes and only 16% had consistent mentoring. There was an expressed desire for a more structured Neurosurgical Resident Training Program and mentoring projects. In addition, 88% of trainees were willing to relocate for fellowships outside their current hospitals.

Half of the responders were dissatisfied with their neurosurgical training. There are various aspects that require improvement, such as the training curriculum, the lack of structured mentoring, and the amount of administrative work. They propose the implementation of a modernized structured curriculum, which addresses the mentioned aspects, in order to improve neurosurgical training and, consecutively, patient care 3).

1)

https://aansneurosurgeon.org/practicing-neurosurgery-in-germany/
2)

Stienen MN, Gempt J, Gautschi OP, Demetriades AK, Netuka D, Kuhlen DE, Schaller K, Ringel F. Neurosurgical Resident Training in Germany. J Neurol Surg A Cent Eur Neurosurg. 2017 Jul;78(4):337-343. doi: 10.1055/s-0036-1594012. Epub 2016 Nov 30. PubMed PMID: 27903015.
3)

Lawson McLean A, Maurer S, Nistor-Gallo D, Moritz I, Tourbier M. Survey on training satisfaction among German neurosurgical trainees. J Neurol Surg A Cent Eur Neurosurg. 2023 Mar 13. doi: 10.1055/a-2053-3108. Epub ahead of print. PMID: 36914157.

Olfactory groove meningioma

Olfactory groove meningioma

Olfactory groove meningiomas (OGMs) are arachnoid cell neoplasms of the frontoethmoidal suture and lamina cribrosa, 1) and may involve any part of the area from the crista galli to the planum sphenoidale 2) 3) 4).

Epidemiology

Olfactory groove meningioma epidemiology

Classification

Olfactory groove meningioma classification

Clinical features

Olfactory groove meningioma clinical features

Diagnosis

Olfactory groove meningioma diagnosis.

Differential diagnosis

Tuberculum sellae meningioma

Planum sphenoidale meningioma

Treatment

Olfactory groove meningioma treatment.

Complications

Olfactory groove meningioma complications

Books

The Meningiomas Arising from the Olfactory Groove and Their Removal by the Aid of Electro-surgery By Harvey Cushing · 1927

Cushing H, Eisenhardt L (1938) The olfactory meningiomas with primary anosmia. In: Cushing H, Eisenhardt L (eds) Meningiomas: their classification, regional behavior, life history, and surgical results. Charles C Thomas, Springfield, pp 250–282

Ojemann RG (1991) Olfactory groove meningiomas. In: Al-Mefty O (ed) Meningiomas. Raven Press, New York, pp 383–393

Al-Mefty O (1993) Tuberculum sellae and olfactory groove meningioma. In: Sekhar LN, Janecka IP (eds) Surgery of cranial base tumors. Raven Press, New York, pp 507–519

Surgery of Skull Base Meningiomas: With a Chapter Madjid Samii, ‎Mario Ammirati · 2012

Meningiomas of the Skull Base Treatment Nuances in Contemporary Neurosurgery 2018

Videos

Olfactory groove meningioma videos.

Systematic Reviews

A systematic review was performed to identify studies that compared outcomes following EEA and TCA for OGMs. Data extracted from each study included gross total resection (GTR), the incidence of cerebrospinal fluid (CSF) leaks, and post-operative complications including anosmia. The results of the search yielded 5 studies that met the criteria for inclusion and analysis. All studies compared TCA (n = 922) with EEA (n = 141) outcomes for OGMs. Overall, the rate of gross total resection (GTR) was lower among the endoscopic group (70.9%) relative to the transcranial group (91.5%). The rate of postoperative CSF leak was 6.3% vs. 25.5% for the transcranial and endoscopic groups, respectively. Post-operative anosmia was higher for patients undergoing EEA (95.9%) compared with patients in the transcranial group (37.4%). In this analysis, EEA was associated with a lower rate of GTR and higher incidences of CSF leaks and post-operative anosmia. However, with increasing surgeon familiarity with the endoscopic anatomy and technique for managing ASB pathologies, a nuanced approach may be used to minimize patient morbidity and widen the spectrum of skull base surgery 5).

Electronic databases were searched from inception until December 2019 for studies delineating TCAs for OGM patients. Patient demographics, pre-operative symptoms, surgical outcomes, and complications were evaluated and analyzed with a meta-analysis of proportions. Results: A total of 27 observational case series comparing 554 unilateral vs. 451 bilateral TCA patients were eligible for review. The weighted pooled incidence of gross total resection is 94.6% (95% CI, 90.7-97.5%; I 2 = 59.0%; p = 0.001) for unilateral and 90.9% (95% CI, 85.6-95.4%; I 2 = 58.1%; p = 0.003) for bilateral cohorts. Similarly, the incidence of OGM recurrence is 2.6% (95% CI, 0.4-6.0%; I 2 = 53.1%; p = 0.012) and 4.7% (95% CI, 1.4-9.2%; I 2 = 55.3%; p = 0.006), respectively. Differences in oncologic outcomes were not found to be statistically significant (p = 0.21 and 0.35, respectively). Statistically significant differences in complication rates in bilateral vs. unilateral TCA cohorts include meningitis (1.0 vs. 0.0%; p = 0.022) and mortality (3.2 vs. 0.2%; p = 0.007). Conclusions: While both cohorts have similar oncologic outcomes, bilateral TCA patients exhibit higher postoperative complication rates. This may be explained by underlying tumor characteristics necessitating more radical resection but may also indicate increased morbidity with bilateral approaches. However, evidence from more controlled, comparative studies is warranted to further support these findings 6).

A PubMed search of the recent literature (2011-2016) was performed to examine outcomes following EEA and TCA for OGM. The extent of resection, visual outcome, postoperative complications, and recurrence rates were analyzed using percentages and proportions, the Fischer exact test, and the Student’s t-test using GraphPad PRISM 7.0Aa (San Diego, CA) software.

Results: There were 444 patients in the TCA group with a mean diameter of 4.61 (±1.17) cm and 101 patients in the EEA group with a mean diameter of 3.55 (± 0.58) cm (p = 0.0589). GTR was achieved in 90.9% (404/444) in the TCA group and 70.2% (71/101) in the EEA group (p < 0.0001). Of the patients with preoperative visual disturbances, 80.7% (21/26) of patients in the EEA cohort had an improvement in vision compared to 12.83%(29/226) in the TCA group (p < 0.0001). Olfaction was lost in 61% of TCA and in 100% of EEA patients. CSF leaks and meningitis occurred in 25.7% and 4.95% of EEA patients and 6.3% and 1.12% of TCA patients, respectively (p < 0.0001; p = 0.023).

The updated literature review demonstrates that despite more experience with endoscopic resection and skull base reconstruction, the literature still supports TCA over EEA with respect to the extent of resection and complications. EEA may be an option in selected cases where visual improvement is the main goal of surgery and postoperative anosmia is acceptable to the patient or in medium-sized tumors with existing preoperative anosmia. Nevertheless, based on our results, it seems more prudent at this time to use TCA for the majority of OGMs 7).

Case series

Olfactory groove meningioma case series

Case reports

Olfactory groove meningioma case reports.

1)

Guinto G. Olfactory Groove Meningiomaas. World Neurosurg. 2015 Jun;83(6):1046-7. doi: 10.1016/j.wneu.2014.12.044. Epub 2015 Jan 14. PMID: 25596435.
2)

Hentschel SJ, DeMonte F, Olfactory groove meningiomas. DeMonte F, McDermott MW, Al-Mefty O: Al-Mefty’s Meningiomas 2New York, Thieme, 2011. 196–205
3)

Nakamura M, Struck M, Roser F, Vorkapic P, Samii M: Olfactory groove meningiomas: clinical outcome and recurrence rates after tumor removal through the frontolateral and bifrontal approach. Neurosurgery 62:6 Suppl 31224–1232, 2008
4)

Pepper J, Hecht SL, Gebarski SS, Lin EM, Sullivan SE, Marentette LJ. Olfactory groove meningioma: discussion of clinical presentation and surgical outcomes following excision via the subcranial approach. Laryngoscope. 2011;121:2282–2289.
5)

Purohit A, Jha R, Khalafallah AM, Price C, Rowan NR, Mukherjee D. Endoscopic endonasal versus transcranial approach to resection of olfactory groove meningiomas: a systematic review. Neurosurg Rev. 2020 Dec;43(6):1465-1471. doi: 10.1007/s10143-019-01193-2. Epub 2019 Nov 10. PMID: 31709465.
6)

Feng AY, Wong S, Saluja S, Jin MC, Thai A, Pendharkar AV, Ho AL, Reddy P, Efron AD. Resection of Olfactory Groove Meningiomas Through Unilateral vs. Bilateral Approaches: A Systematic Review and Meta-Analysis. Front Oncol. 2020 Oct 22;10:560706. doi: 10.3389/fonc.2020.560706. PMID: 33194626; PMCID: PMC7642686.
7)

Shetty SR, Ruiz-Treviño AS, Omay SB, Almeida JP, Liang B, Chen YN, Singh H, Schwartz TH. Limitations of the endonasal endoscopic approach in treating olfactory groove meningiomas. A systematic review. Acta Neurochir (Wien). 2017 Oct;159(10):1875-1885. doi: 10.1007/s00701-017-3303-0. Epub 2017 Aug 22. PMID: 28831590.

3D Exoscope for Vascular neurosurgery

3D Exoscope for Vascular neurosurgery

3D Exoscope for Intracranial aneurysm clipping

In aneurysm clipping, three-dimensional exoscopes are noninferior to operating microscopes in terms of surgery duration, safety, and outcomes, based on limited series. Progressive experience enables the surgeon to perform significantly more device adjustments within the same amount of surgical time 1)

Visualization and Maneuverability Features of a Robotic Arm Three-Dimensional Exoscope and Operating Microscope for Clipping an Unruptured Intracranial Aneurysm: Video Comparison and Technical Evaluation 2).

A case of a 11-year-old male with Alagille syndrome, pancytopenia, and peripheral pulmonary stenosis found to have a 12 × 13 × 7 mm distal left M1 aneurysm arising from the inferior M1/M2 junction. The patient was neurologically intact without evidence of rupture. In order to prevent catastrophic rupture, the decision was made to treat the lesion. Due to the patients underlying medical conditions including baseline coagulopathy, surgical management was felt to be superior to an endovascular reconstruction, which would require long-term antiplatelet therapy. Thus the patient underwent a left-sided pterional craniotomy with exoscopic 3D ICG-VA. As demonstrated in Video 1, ICG-VA was performed before definitive clip placement in order to understand flow dynamics with particular emphasis on understanding the middle cerebral artery outflow. Postoperatively, the patient remained at his neurologic baseline and subsequent imaging demonstrated complete obliteration of the aneurysm without any neck remnant. The patient continues to follow and remains asymptomatic and neurologically intact without radiographic evidence of residual or recurrence 3)

Cerebral revascularization

3D Exoscope for cerebral revascularization.

Case reports

The Kinevo 900 exoscope was used in 3 patients with cerebral (2) and spinal (1) vascular pathology, we evaluated the image quality, equipment management, ergonomics, educational utility, 3D glasses, we recorded the characteristics of the cases. and we show a review of the experience of other authors.

Results: 3 patients underwent surgery: one occipital cavernoma, one cerebral dural fistula, and 1 spinal dural fistula. Excellent 3D visualization with Zeiss Kinevo 900 exoscope (Carl Zeiss, Germany), surgical comfort, and educational utility is shown. There were no complications.

The experience and that of other authors suggests that the 3D exoscope shows excellent visualization, better ergonomics, and an innovative educational experience. Vascular microsurgery can be performed safely and effectively 4).

1)

Rossmann T, Veldeman M, Nurminen V, Huhtakangas J, Niemelä M, Lehecka M. 3D Exoscopes are Noninferior to Operating Microscopes in Aneurysm Surgery: Comparative Single-Surgeon Series of 52 Consecutive Cases. World Neurosurg. 2023 Feb;170:e200-e213. doi: 10.1016/j.wneu.2022.10.106. Epub 2022 Nov 9. PMID: 36334715.
2)

Haeren R, Hafez A, Lehecka M. Visualization and Maneuverability Features of a Robotic Arm Three-Dimensional Exoscope and Operating Microscope for Clipping an Unruptured Intracranial Aneurysm: Video Comparison and Technical Evaluation. Oper Neurosurg (Hagerstown). 2022 Jan 1;22(1):28-34. doi: 10.1227/ONS.0000000000000060. Erratum in: Oper Neurosurg (Hagerstown). 2022 Aug 1;23(2):e157. PMID: 34982902.
3)

Wali AR, Kang KM, Rennert R, Santiago-Dieppa D, Khalessi AA, Levy M. First-in-Human Clinical Experience Using High-Definition Exoscope with Intraoperative Indocyanine Green for Clip Reconstruction of Unruptured Large Pediatric Aneurysm. World Neurosurg. 2021 Jul;151:52. doi: 10.1016/j.wneu.2021.04.019. Epub 2021 Apr 17. PMID: 33872836.
4)

Acha JL, Contreras L, Lopez K, Azurin M, Cueva M, Bellido A, Contreras S, Santos O. Neurovascular microsurgical experience through 3D exoscopy. Case report and literature review. World Neurosurg. 2023 Mar 3:S1878-8750(23)00270-X. doi: 10.1016/j.wneu.2023.02.120. Epub ahead of print. PMID: 36871654.

Parkinson’s disease

Parkinson’s disease

James Parkinson was the first to describe Parkinson’s disease (PD) in 1817; he described it as a combination of tremor, rigidity, postural abnormalities, and bradykinesia.

Definition

Parkinson’s disease is a progressive neurological disorder characterized by the preferential loss of dopaminergic neurons in the substantia nigra, which project to the striatum.

Parkinson’s disease (PD) is a neurodegenerative disease involving the basal ganglia, resulting in motor and extra-motor deficits. These extra-motor deficits may be reflective of a self-regulatory deficit impacting patients’ ability to regulate cognitive processes, thoughts, behaviors, and emotions.

With advances in knowledge disease, boundaries may change. Occasionally, these changes are of such a magnitude that they require redefinition of the disease. In recognition of the profound changes in our understanding of Parkinson’s disease (PD), the International Parkinson and Movement Disorders Society (MDS) commissioned a task force to consider a redefinition of PD.

Several critical issues were identified that challenge current PD definitions. First, new findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. Second, the increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. Third, there is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. Fourth, the recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early-stage and prodromal PD should be created; here, essential features of these criteria are proposed. Finally, there is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration 1).

see Parkinson’s Disease Dementia

Classification

Idiopathic Parkinson’s disease

Current subtype classifications may not be sufficiently robust to warrant formal delineation.

see also Tremor predominant Parkinson’s disease.

Sporadic Parkinson’s disease and some genetic forms such as GBA1-associated parkinsonism, LRRK2-associated Parkinson’s disease

Natural History

The natural history of PD may follow a more benign motor-predominant course in some patients, while in others the disabling non-motor features predominate. The underlying basis of the clinical heterogeneity is poorly understood, but it is becoming clear that this is, at least in part, due to genetic factors 2) 3) 4). One of these genetic risk factors is mutation in the GBA1 gene, which has emerged numerically as the most important genetic abnormality associated with PD 5) 6), being found in about 5% of patients with the so-called sporadic PD

Scales

UPDRS

Epidemiology

Parkinson’s Disease Epidemiology.

Etiology

see Parkinson’s disease etiology.

Pathogenesis

Parkinson’s disease Pathogenesis.

Pathophysiology

see Parkinson’s disease pathophysiology.

Pathology

The main neuropathological finding is Alpha-synuclein-containing Lewy bodies and loss of dopaminergic neurons in the substantia nigra, manifesting as reduced facilitation of voluntary movements. With progression of PD, Lewy body pathology spreads to neocortical and cortical regions. Several environmental factors are associated with increased risk of PD. Autopsy studies show that the clinical diagnosis of PD is not confirmed at autopsy in a significant proportion of patients. Revised diagnostic criteria are expected to improve the clinician´s accuracy in diagnosing PD. Increasing knowledge on genetic and environmental risk factors of PD will probably elucidate the cause of this disease within the near future 7)

Clinical Features

see Parkinson’s disease clinical features.

Diagnosis

Parkinson’s disease diagnosis.

Treatment

see Parkinson’s disease treatment.

Outcome

Parkinson’s disease outcome

Parkinson’s disease complications.

Research

Open science and collaboration are necessary to facilitate the advancement of Parkinson’s disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities, thus we coordinated a virtual 3-day hackathon event, during which 49 early-career scientists from 12 countries built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. Each team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. Hackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early-career researchers. The resources generated can be used to accelerate research on the genetics of PD 8).

Meta-analysis

A meta-analysis investigated the effectiveness of short pulse width DBS (spDBS) versus conventional DBS (cDBS) in patients with Parkinson’s disease.

Four databases (PubMed, Cochrane, Web of Science, and Embase) were independently searched until October 2021 by two reviewers. They utilized the following scales and items: therapeutic windows (TW), efficacy threshold, side effect threshold, Movement Disorder Society-Sponsored Revision Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III off-medication score, Speech Intelligence Test (SIT), and Freezing of Gait Questionnaire (FOG-Q).

The analysis included seven studies with a total of 87 patients. The results indicated that spDBS significantly widened the therapeutic windows (0.99, 95% CI = 0.61 to 1.38) while increasing the threshold amplitudes of side effects (2.25, 95% CI = 1.69 to 2.81) and threshold amplitudes of effects (1.60, 95% CI = 0.84 to 2.36). There was no statistically significant difference in UPDRS part III, SIT, and FOG-Q scores between spDBS and cDBS groups, suggesting that treatment with both cDBS and spDBS may result in similar effects of improved dysarthria and gait disorders.

Compared with cDBS, spDBS is effective in expanding therapeutic windows (TW). Both types of deep brain stimulation resulted in improved gait disorders and speech intelligibility 9)

Case series

see Parkinson’s disease case series.

Case reports

Parkinson´s disease case reports.

1)

Berg D, Postuma RB, Bloem B, Chan P, Dubois B, Gasser T, Goetz CG, Halliday GM, Hardy J, Lang AE, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov Disord. 2014 Apr;29(4):454-62. doi: 10.1002/mds.25844. Epub 2014 Mar 11. PubMed PMID: 24619848.
2)

Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386(9996):896–912.
3)

Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet. 2014;46(9):989–93.
4)

Williams-Gray CH, Goris A, Saiki M, Foltynie T, Compston DA, Sawcer SJ, et al. Apolipoprotein E genotype as a risk factor for susceptibility to and dementia in Parkinson’s disease. J Neurol. 2009;256(3):493–8.
5)

Gan-Or Z, Giladi N, Rozovski U, Shifrin C, Rosner S, Gurevich T, et al. Genotype-phenotype correlations between GBA mutations and Parkinson’s disease risk and onset. Neurology. 2008;70(24):2277–83.
6)

Migdalska-Richards A, Schapira AH. The relationship between glucocerebrosidase mutations and Parkinson’s disease. J Neurochem. 2016 Oct;1(139 Suppl):77–90.
7)

Tysnes OB, Storstein A. Epidemiology of Parkinson’s disease. J Neural Transm (Vienna). 2017 Aug;124(8):901-905. doi: 10.1007/s00702-017-1686-y. Epub 2017 Feb 1. PMID: 28150045.
8)

Leonard HL, Murtadha R, Martinez-Carrasco A, Jama A, Müller-Nedebock AC, Gil-Martinez AL, Illarionova A, Moore A, Bustos BI, Jadhav B, Huxford B, Storm C, Towns C, Vitale D, Chetty D, Yu E, Grenn FP, Salazar G, Rateau G, Iwaki H, Elsayed I, Foote IF, Jansen van Rensburg Z, Kim JJ, Yuan J, Lake J, Brolin K, Senkevich K, Wu L, Tan MMX, Periñán MT, Makarious MB, Ta M, Pillay NS, Betancor OL, Reyes-Pérez PR, Alvarez Jerez P, Saini P, Al-Ouran R, Sivakumar R, Real R, Reynolds RH, Hu R, Abrahams S, Rao SC, Antar T, Leal TP, Iankova V, Scotton WJ, Song Y, Singleton A, Nalls MA, Dey S, Bandres-Ciga S, Blauwendraat C, Noyce AJ; International Parkinson Disease Genomics Consortium (IPDGC) and The Global Parkinson’s Genetics Program (GP2). The IPDGC/GP2 Hackathon – an open science event for training in data science, genomics, and collaboration using Parkinson’s disease data. NPJ Parkinsons Dis. 2023 Mar 4;9(1):33. doi: 10.1038/s41531-023-00472-6. PMID: 36871034.
9)

Zou X, Shi Y, Wu X, Ye Q, Lin F, Cai G. Efficacy of short pulse and conventional deep brain stimulation in Parkinson’s disease: a systematic review and meta-analysis. Neurol Sci. 2022 Nov 16. doi: 10.1007/s10072-022-06484-z. Epub ahead of print. PMID: 36383263.

Norwegian Registry for Spine Surgery (NORspine)

Norwegian Registry for Spine Surgery (NORspine)

https://helsedata.no/en/forvaltere/university-hospital-of-north-norway/norwegian-registry-for-spine-surgery/

Latest Pubmed Related Articles

Loss to follow-up may bias outcome assessments in medical registries. A cohort study aimed to analyze and compare patients who failed to respond with those that responded to the Norwegian Registry for Spine Surgery (NORspine).

They analyzed a cohort of 474 consecutive patients operated for lumbar spinal stenosis at four public hospitals in Norway during a two-year period. These patients reported sociodemographic data, preoperative symptoms, and Oswestry Disability Index (ODI), numerical rating scales (NRS) for back and leg pain to NORspine at baseline and 12 months postoperatively. They contacted all patients who did not respond to NORspine after 12 months. Those who responded were termed responsive non-respondents and compared to 12 months respondents.

One hundred forty (30%) did not respond to NORspine 12 months after surgery and 123 were available for additional follow-up. Sixty-four of the 123 non-respondents (52%) responded to a cross-sectional survey done at a median of 50 (36-64) months after surgery. At baseline, non-respondents were younger 63 (SD 11.7) vs. 68 (SD 9.9) years (mean difference (95% CI) 4.7 years (2.6 to 6.7); p = < 0.001) and more frequently smokers 41 (30%) vs. 70 (21%) RR (95%CI) = 1.40 (1.01 to 1.95); p = 0.044. There were no other relevant differences in other sociodemographic variables or preoperative symptoms. We found no differences in the effect of surgery on non-respondents vs. respondents (ODI (SD) = 28.2 (19.9) vs. 25.2 (18.9), MD (95%CI) = 3.0 ( -2.1 to 8.1); p = 0.250).

Kaur et al. found that 30% of patients did not respond to NORspine at 12 months after spine surgery. Non-respondents were somewhat younger and smoked more frequently than respondents; however, there were no differences in patient-reported outcome measures. The findings suggest that attrition bias in NORspine was random and due to non-modifiable factors. 1).

Data were obtained from the Norwegian Registry for Spine Surgery. The primary outcome was change in the neck disability index (NDI) 1 yr after surgery. Secondary endpoints were the European myelopathy score (EMS), quality of life (EuroQoL 5D [EQ-5D]), numeric rating scales (NRS) for headache, neck pain, and arm pain, complications, and perceived benefit of surgery assessed by the Global Perceived Effect (GPE) scale.

They included 905 patients operated between January 2012 and June 2018. There were significant improvements in all patient-reported outcome measures (PROMs) including NDI (mean -10.0, 95% CI -11.5 to -8.4, P < .001), EMS (mean 1.0, 95% CI 0.8-1.1, P < .001), EQ-5D index score (mean 0.16, 95% CI 0.13-0.19, P < .001), EQ-5D visual analogue scale (mean 13.8, 95% CI 11.7-15.9, P < .001), headache NRS (mean -1.1, 95% CI -1.4 to -0.8, P < .001), neck pain NRS (mean -1.8, 95% CI -2.0 to -1.5, P < .001), and arm pain NRS (mean -1.7, 95% CI -1.9 to -1.4, P < .001). According to GPE scale assessments, 229/513 patients (44.6%) experienced “complete recovery” or felt “much better” at 1 yr. There were significant improvements in all PROMs for both mild and moderate-to-severe DCM. A total of 251 patients (27.7%) experienced adverse effects within 3 mo.

Surgery for DCM is associated with significant and clinically meaningful improvement across a wide range of PROMs 2).

multicenter cohort study included 11,081 patients operated with lumbar microdiscectomy, registered at the Norwegian Registry for Spine Surgery. Follow-up was 1 year. Uni- and multivariate logistic regression analyses were used to assess potential prognostic factors for previously defined cut-offs for failure and worsening on the Oswestry Disability Index scores 12 months after surgery. Since the cut-offs for failure and worsening are different for patients with low, moderate, and high baseline ODI scores, the multivariate analyses were run separately for these subgroups. Data were split into a training (70%) and a validation set (30%). The model was developed in the training set and tested in the validation set. A prediction (%) of an outcome was calculated for each patient in a risk matrix.

Results: The prognostic model produced six risk matrices based on three baseline ODI ranges (low, medium, and high) and two outcomes (failure and worsening), each containing 7 to 11 prognostic factors. Model discrimination and calibration were acceptable. The estimated preoperative probabilities ranged from 3 to 94% for failure and from 1 to 72% for worsening in our validation cohort.

Conclusion: We developed a prognostic model for failure and worsening 12 months after surgery for lumbar disc herniation. The model showed acceptable calibration and discrimination, and could be useful in assisting physicians and patients in clinical decision-making process prior to surgery 3).

A study is based on data from the Norwegian Registry for Spine Surgery (NORspine). Patients who had decompressive surgery in the period from 7/1-2007 to 11/3-2013 at 31 hospitals were included. The patients was divided into four groups based on preoperative Numeric Rating Scale (NRS)-score for lower extremity pain. Patients in group 1 had insignificant pain, group 2 had mild or moderate pain, group 3 severe pain and group 4 extremely severe pain. The primary outcome was change in the Oswestry Disability Index (ODI). Successfully treated patients were defined as patients reporting at least 30% reduction of baseline ODI, and the number of successfully treated patients in each group were recorded.

Results: In total, 3181 patients were eligible; 154 patients in group 1; 753 in group 2; 1766 in group 3; and 528 in group 4. Group 1 had significantly less improvement from baseline in all the clinical scores 12 months after surgery compared to the other groups. However, with a mean reduction of 8 ODI points and 56% of patients showing a reduction of at least 30% in their ODI score, the proportion of patients defined as successfully treated in group 1, was not significantly different from that of other groups.

Conclusion: This national register study shows that patients with insignificant lower extremity pain had less improvement in primary and secondary outcome parameters from baseline to follow-up compared to patients with more severe lower extremity pain 4).

A total of 6840 patients with lumbar disc herniation were operated and followed for 12 months, according to the standard protocol of the Norwegian Registry for Spine Surgery (NORspine). Patients reporting to be unchanged or worse on the Global Perceived Effectiveness (GPE) scale at 12-month follow-up were classified as “failure”, and those considering themselves “worse” or “worse than ever” after surgery were classified as “worsening”. These two dichotomous outcomes were used as anchors in analyses of receiver operating characteristics (ROC) to define cutoffs for failure and worsening on commonly used PROMs, namely, the Oswestry Disability Index (ODI), the EuroQuol 5D (EQ-5D), and Numerical Rating Scales (NRS) for back pain and leg pain.

Results: “Failure” after 12 months for each PROM, as an insufficient improvement from baseline, was (sensitivity and specificity): ODI change <13 (0.82, 0.82), ODI% change <33% (0.86, 0.86), ODI final raw score >25 (0.89, 0.81), NRS back-pain change <1.5 (0.74, 0.86), NRS back-pain % change <24 (0.85, 0.81), NRS back-pain final raw score >5.5 (0.81, 0.87), NRS leg-pain change <1.5 (0.81, 0.76), NRS leg-pain % change <39 (0.86, 0.81), NRS leg-pain final raw score >4.5 (0.91, 0.85), EQ-5D change <0.10 (0.76, 0.83), and EQ-5D final raw score >0.63 (0.81, 0.85). Both a final raw score >48 for the ODI and an NRS >7.5 were indicators for “worsening” after 12 months, with acceptable accuracy.

Conclusion: The criteria with the highest accuracy for defining failure and worsening after surgery for lumbar disc herniation were an ODI percentage change score <33% for failure and a 12-month ODI raw score >48. These cutoffs can facilitate shared decision-making among doctors and patients, and improve quality assessment and comparison of clinical outcomes across surgical units. In addition to clinically relevant improvements, we propose that rates of failure and worsening should be included in reporting from clinical trials 5).

1)

Kaur S, Alhaug OK, Dolatowski FC, Solberg TK, Lønne G. Characteristics and outcomes of patients who did not respond to a national spine surgery registry. BMC Musculoskelet Disord. 2023 Mar 4;24(1):164. doi: 10.1186/s12891-023-06267-3. PMID: 36871007.
2)

Gulati S, Vangen-Lønne V, Nygaard ØP, Gulati AM, Hammer TA, Johansen TO, Peul WC, Salvesen ØO, Solberg TK. Surgery for Degenerative Cervical Myelopathy: A Nationwide Registry-Based Observational Study With Patient-Reported Outcomes. Neurosurgery. 2021 Jul 29:nyab259. doi: 10.1093/neuros/nyab259. Epub ahead of print. PMID: 34325471.
3)

Werner DAT, Grotle M, Småstuen MC, Gulati S, Nygaard ØP, Salvesen Ø, Ingebrigtsen T, Solberg TK. A prognostic model for failure and worsening after lumbar microdiscectomy: a multicenter study from the Norwegian Registry for Spine Surgery. Acta Neurochir (Wien). 2021 Jul 10. doi: 10.1007/s00701-021-04859-3. Epub ahead of print. PMID: 34245366.
4)

Hermansen E, Myklebust TÅ, Austevoll IM, Rekeland F, Solberg T, Storheim K, Grundnes O, Aaen J, Brox JI, Hellum C, Indrekvam K. Clinical outcome after surgery for lumbar spinal stenosis in patients with insignificant lower extremity pain. A prospective cohort study from the Norwegian registry for spine surgery. BMC Musculoskelet Disord. 2019 Jan 22;20(1):36. doi: 10.1186/s12891-019-2407-5. PMID: 30669998; PMCID: PMC6343340.
5)

Werner DAT, Grotle M, Gulati S, Austevoll IM, Lønne G, Nygaard ØP, Solberg TK. Criteria for failure and worsening after surgery for lumbar disc herniation: a multicenter observational study based on data from the Norwegian Registry for Spine Surgery. Eur Spine J. 2017 Oct;26(10):2650-2659. doi: 10.1007/s00586-017-5185-5. Epub 2017 Jun 14. PMID: 28616747.

Condoliase for lumbar disc herniation

Condoliase for lumbar disc herniation

Latest Pubmed Related Articles

Percutaneous chemonucleolysis with condoliase has been available for painful lumbar disc herniation since 2018 in Japan.

In the 1980s, chemonucleolysis with chymopapain, a protease, was widely used as the intermediate treatment between conservative therapy and surgical therapy in Western countries. However, since chymopapain was withdrawn from the market in 2002 for non-scientific commercial reasons, chemonucleolysis has not been a therapeutic option for LDH. Condoliase (chondroitin sulfate ABC endolyase), a glycosaminoglycan-degrading enzyme, was approved by the drug regulatory authority in Japan as a newer intradiscal therapy for LDH after clinical studies conducted in Japan demonstrated efficacy and safety for patients with LDH 1)

Condoliase as a first-line treatment option ahead of surgical treatment for LDH is superior, from a cost perspective to surgical treatment from the beginning. Condoliase is also a cost-effective alternative to non-surgery conservative treatment 2).

Multicenter, randomized, double-blind, dose-finding studies

Patients between 20 and 70 years of age with unilateral leg pain, positive findings on the straight leg raise test, and LDH were recruited. All eligible patients were randomly assigned to receive condoliase (1.25, 2.5, or 5 U) or placebo. The primary end point was a change in the worst leg pain from preadministration (baseline) to week 13. The secondary end points were changes from baseline in the following items: worst back pain, Oswestry Disability Index (ODI), SF-36, and neurological examination. For pharmacokinetic and pharmacodynamic analyses, plasma condoliase concentrations and serum keratan sulfate concentrations were measured. The safety end points were adverse events (AEs) and radiographic and MRI parameters. Data on leg pain, back pain, abnormal neurological findings, and imaging parameters were collected until week 52. RESULTS A total of 194 patients received an injection of condoliase or placebo. The mean change in worst leg pain from baseline to week 13 was -31.7 mm (placebo), -46.7 mm (1.25 U), -41.1 mm (2.5 U), and -47.6 mm (5 U). The differences were significant at week 13 in the 1.25-U group (-14.9 mm; 95% CI -28.4 to -1.4 mm; p = 0.03) and 5-U group (-15.9 mm; 95% CI -29.0 to -2.7 mm; p = 0.01) compared with the placebo group. The dose-response improvement in the worst leg pain at week 13 was not significant (p = 0.14). The decrease in the worst leg pain in all 3 condoliase groups was observed from week 1 through week 52. Regarding the other end points, the worst back pain and results of the straight leg raise test, ODI, and SF-36 showed a tendency for sustained improvement in each of the condoliase groups until week 52. In all patients at all time points, plasma condoliase concentrations were below the detectable limit (< 100 μU/ml). Serum keratan sulfate concentrations significantly increased from baseline to 6 hours and 6 weeks after administration in all 3 condoliase groups. No patient died or developed anaphylaxis or neurological sequelae. Five serious AEs occurred in 5 patients (3 patients in the condoliase groups and 2 patients in the placebo group), resolved, and were considered unrelated to the investigational drug. Severe AEs occurred in 10 patients in the condoliase groups and resolved or improved. In the condoliase groups, back pain was the most frequent AE. Modic type 1 change and decrease in disc height were frequent imaging findings. Dose-response relationships were observed for the incidence of adverse drug reactions and decrease in disc height. CONCLUSIONS Condoliase significantly improved clinical symptoms in patients with LDH and was well tolerated. While all 3 doses had similar efficacy, the incidence of adverse drug reactions and decrease in disc height were dose dependent, thereby suggesting that 1.25 U would be the recommended clinical dose of condoliase. Clinical trial registration no.: NCT00634946 (clinicaltrials.gov) 3).

Case series

Ohtonari et al. investigated clinical and radiographic outcomes three months after the administration because secondary surgical removal is most required during this period for insufficient pain relief, and analyzed whether the differences in intradiscal injection areas affected the clinical outcomes. They retrospectively investigated 47 consecutive patients (males, 31; median age, 40 years) three months after the administration. Clinical outcomes were evaluated using the Japanese Orthopaedic Association Back Pain Questionnaire (JOABPEQ), a visual analog scale (VAS) score for low back pain, and VAS scores for pains and numbness in the lower limbs. Radiographic outcomes were analyzed in 41 patients, using parameters such as mid-sagittal disc height and maximal protrusion length of herniation on MRI preoperatively and at the final follow-up. The postoperative median evaluation period was 90 days. The effective rate of low back pain based on the pain-related disorders at baseline and the last follow-up in the JOABPEQ reached 79.5%. The postoperative proportion of VAS scores recovery ≥ 2 points and ≥ 50% for pains in the lower limbs were 80.9% and 66.0%, respectively, revealing satisfactory effectiveness. Preoperative median mid-sagittal disc height significantly reduced from 9.5 to 7.6 mm postoperatively. There were no significant differences in pain relief in the lower limbs by injection areas in the center and the dorsal 1/3rd near the herniation of the nucleus pulposus. Chemonucleolysis with condoliase revealed satisfactory short-term outcomes after the administration regardless of intradiscal injection areas 4).

101 patients who underwent chemonucleolysis with condoliase from January 2019 to December 2021. Patients were divided into good outcome (i.e., favorable outcome) and poor outcome (i.e., requiring additional surgical treatment) groups. Patient demographics and imaging findings were collected. Clinical outcomes were evaluated using the numerical rating scale and Japanese Orthopaedic Association scores at baseline and at 1- and 3-month follow-up. Pretreatment indicators for additional surgery were compared between the 2 groups. Results: There was a significant difference in baseline leg numbness between the good outcome and poor outcome groups (6.27 ± 1.90 vs. 4.42 ± 2.90, respectively; p = 0.033). Of the 101 included patients, 32 received a preoperative computed tomography scan. In those patients, the presence of calcification or ossification in disc hernia occurred more often in the poor outcome group (61.5% vs. 5.3%, respectively; p &lt; 0.001; odds ratio = 22.242; p = 0.014). Receiver-operating characteristics curve analysis for accompanying calcification or ossification showed an area under the curve of 0.858 (95% confidence interval, 0.715-1.000; p = 0.001). Conclusions: Calcified or ossified disc herniation may be useful predictors of unsuccessful treatment in patients with condoliase administration 5).

Sixty-seven patients (44 men, 23 women; mean age, 46.7 ± 18.0 years) were analyzed. Time-course changes in disc height, disc degeneration, and herniation size were assessed. For clinical outcomes assessment, visual analog scale (VAS) scores for leg and back pain and the Oswestry disability index (ODI) were obtained at baseline and the 3-month, 1-year, and 2-year follow-ups. We obtained a questionnaire from these patients at two years to assess satisfaction and recommendation. Condoliase therapy was considered to be effective in patients whose VAS score for leg pain improved by ≥ 50% at 2 years from baseline and who did not require surgery.

Results: Condoliase therapy was effective in 51 patients (76.1%). Eight patients (11.9%) required surgery due to ineffectiveness of the therapy. Condoliase therapy was ineffective in five out of six patients with a history of discectomy. The ODI and VAS scores for leg and back pain significantly improved from three months to two years. Of the patients, 80% satisfied with their outcomes, and 85% recommended this therapy. Progression of disc degeneration was observed in 57.1% of patients at three months; however, 30% recovered to baseline at two years. The mean disc height decreased at three months, but recovered slightly at one year and remained stable until two years. No recurrent disc herniation was observed.

Conclusions: Chemonucleolysis with condoliase was effective in 78% of patients with LDH for 2 years. Chemonucleolysis-induced disc degeneration was slightly recovered and maintained for two years post-injection. This treatment resulted in high patient satisfaction and recommendations 6).

137 LDH patients treated through condoliase at four Japanese institutions and assessed its effectiveness among different age categories on alleviation of visual analog scale (VAS) of leg pain, low back pain and numbness, as well as ODI and JOA scores. Moreover, we divided them into either a “group-A” category if a ≥50% improvement in baseline leg pain VAS was observed or “group-N” if VAS leg pain improved &lt;50%. Next, we assessed the differences in clinical and demographic distribution between group-A and group-N. Results: Fifty-five patients were classified as group-A (77.5%) and 16 patients were allocated to group-N (22.5%). A significant difference in Pfirrmann classification was found between both cohorts, with grade IV suggested to be most receptive. A posterior disc angle &gt; 5° was also found to approach statical significance. In all age groups, average VAS scores showed improvement. However, 75% of adolescent patients showed deterioration in Pfirrmann classification following treatment. Conclusions: Intradiscal condoliase injection is an effective treatment for LDH, even in patients with large vertebral translation and posterior disc angles, regardless of age. However, since condoliase imposes a risk of progressing disc degeneration, its indication for younger patients remains controversial 7).

Medical records and radiographic findings were reviewed retrospectively for 127 patients with LDH (88 male, 39 female, mean age: 46.6 ± 17.1 years, mean follow-up: 9.8 ± 7.8 months) who underwent chemonucleolysis with intradiscal condoliase injection at our center since September 2018. Condoliase (1.25 U/mL; 1 mL volume) was injected toward the middle of the affected intervertebral nucleus pulposus using a 21-gauge disc-puncture needle.

Results: Cases in which the Pfirrmann grade did and did not progress in the 3 months after the injection were included in groups P (progression, n = 49) and NP (non-progression, n = 78), respectively. Logistic regression analysis of progression of Pfirrmann grade post-injection showed significant associations with age <40 years (p = 0.013, odds ratio (OR): 3.69, 95% confidence interval (CI): 1.32-10.31), Pfirrmann Grade II or III at baseline (p = 0.021, OR: 3.51, 95% CI: 1.24-9.64), and a high-intensity MRI signal in the herniation (p = 0.047, OR: 2.97, 95% CI: 1.03-8.87). Patients in group P had significantly higher rates of disc height decrease ≥20%, reduced herniated disc size, and improved VAS for pain, but both groups had significant decreases in pain. No cases had an anaphylactic shock or neurologic sequelae.

Conclusions: These results show the safety and efficacy of chemonucleolysis with condoliase for treatment of painful LDH. Progression of Pfirrmann criteria on MRI at 3 months after injection was significantly associated with an improved clinical outcome 8).

Seventy patients (85.4%) were classified into the effective (E) group and 12 patients (14.6%) into the less-effective (L) group. Surgical treatment was required in four patients. No severe adverse complications were reported; 41.3% of the patients developed disc degeneration of Pfirrmann grade 1 or more at the injected disc level. Univariate analysis revealed that young age (p = 0.036), without history of epidural or nerve root block (p = 0.024), and injection into the central portion of the intervertebral disc (p = 0.014) were significantly associated with clinical effectiveness. A logistic regression analysis revealed that injection into the central portion of the intervertebral disc (p = 0.049; odds ratio, 4.913; 95% confidence interval, 1.006-26.204) was significantly associated with clinical effectiveness.

Conclusions: Chemonucleolysis with condoliase is a safe and effective treatment for painful LDH; 85.4% of the patients showed improvement after the treatment without severe adverse events. To obtain the best outcome, condoliase should be injected into the center of the intervertebral disc 9).

Forty-seven patients (20 women, 27 men; mean age 48 years) were included. The herniation level was L2/3 in one patient, L3/4 in two, L4/5 in 23, and L5/S1 in 21. Median symptom duration was 8 months. The mean VAS and ODI improved significantly from the baseline to 3-month follow-up (p < 0.01). Group E included 33 patients (70.2%) and group I included 14, three of whom had a history of discectomy. The rates of spondylolisthesis and posterior intervertebral angle ≥5° were significantly higher in group I than in group E. However, the rates of trans-ligamentous type and herniation with high signal intensity on T2-weighted images (highT2) were significantly higher in group E. Reduction of disc herniation was more frequently observed in group E.

Conclusions: Condoliase injection resulted in significantly improved symptoms in patients with LDH. Condoliase therapy was less effective for patients with a history of discectomy, spondylolisthesis, or those with a posterior intervertebral angle ≥5°, while trans-ligamentous type and high T2 herniation were associated with increased efficacy 10)

A total of 52 patients (mean age, 45.0 years) were enrolled and classified according to whether the injection was effective (E group, n=40, 76.9%) or less effective (L group, n=9, 17.3%). Three patients (5.8%) underwent herniotomy for residual pain within 6 months of the injection. There were no severe adverse events. Reduction of herniation was seen on MRI more often in the E group than in the L group. The effectiveness in patients with transligamentous LDH was similar to that in patients with subligamentous LDH. High-intensity signal change in the area of LDH on pretreatment T2-weighted MRI was a significant predictor of successful leg pain relief.

Conclusions: An intradiscal condoliase injection was a safe and effective treatment for painful radiculopathy caused by LDH. Leg pain was more likely to improve in patients with high-intensity signal change in the area of LDH before treatment 11).

In total, 84 patients were recruited (52 men, 32 women; mean age, 44.2 ± 17.1 [16-86 years]). The duration of illness was 6.7 ± 6.8 (1.5-30) months. All patient-based outcomes significantly improved at 4 weeks after the administration compared with pretreatment. The intervertebral disc height decreased significantly at four weeks after condoliase administration compared with that before administration. Progression of intervertebral disc degeneration occurred in 50% of the patients. Eleven patients underwent herniotomy due to poor treatment effects. Moreover, treatment in 77.4% of the patients was considered effective. A logistic regression analysis revealed that L5/S1 disk administration (p = 0.029; odds ratio, 5.94; 95% confidence interval, 1.20-29.45) were significantly associated with clinical effectiveness.

Conclusions: Condoliase disk administration improved pain and quality of life over time. Condoliase disk administration was more effective in L5/S1 intervertebral administration 12).

47 patients who received condoliase, 34 were enrolled in this study. The mean age of the patients was 33 years. The average duration since the onset of disease was 8.6 months. We evaluated patients’ low back and leg pain using a numerical rating scale (NRS) score at two time points (before therapy and 3 months after therapy). We divided the patients into two groups (good group (G): NRS score improvement ≥ 50%, poor group (P): NRS score improvement < 50%). The parameters evaluated were age, disease duration, body mass index (BMI), and positive or negative straight leg raising test results. In addition, the loss of disc height and preoperative radiological findings were evaluated. Results: In terms of low back and leg pain, the G group included 9/34 (26.5%) and 21/34 (61.8%) patients, respectively. Patients’ age (low back pain G/P, 21/36.5 years) was significantly lower in the G group for low back pain (p = 0.001). High-intensity change in the protruded nucleus pulposus (NP) and spinal canal occupancy by the NP ≥ 40% were significantly high in those with leg pain in the G groups (14/21, p = 0.04; and 13/21, p = 0.03, respectively). Conclusions: The efficacy of improvement in leg pain was significantly correlated with high-intensity change and size of the protruded NP. Condoliase was not significantly effective for low back pain but could have an effect on younger patients 13).

42 patients with LDH who underwent intradiscal condoliase injection. Patients with and without a ≥50% improvement from baseline of leg pain at 3 months after injection were defined as responders and non-responders, respectively. Clinical features and radiological findings were compared between these groups.

Results: Of the 42 patients, 32 (76.2%) were responders and 10 (23.8%) were non-responders. Of 8 patients with a history of discectomy at the same level as LDH, 6 (75.0%) were responders. Non-responders had a significantly longer time from onset to treatment, smaller herniated volume before treatment, lower percentage reduction of herniated mass, and less intervertebral disc degeneration before treatment. There were no significant differences in LDH types (subligamentous extrusion or transligamentous extrusion types), high-intensity area within the herniation, changes in disc height, and region of condoliase injection between the two groups.

Conclusions: Intradiscal condoliase injection had a good short-term therapeutic effect in patients with LDH, including in transligamentous extrusion-type and revision cases as well as subligamentous extrusion-type cases. Administration of intradiscal condoliase injection may be most effective in patients with a larger herniated mass volume before treatment, and least effective in cases with a longer time and less intervertebral disc degeneration before treatment 14).

A total of 82 and 81 patients received an injection of condoliase and placebo, respectively. The average changes in worst leg pain from baseline to week 13 (primary endpoint) were -49.5 mm in the condoliase group and -34.3 mm in the placebo group, and the difference of -15.2 mm was significant (95% confidence interval, -24.2 to -6.2; P = 0.001). Significant improvements were observed in the condoliase groups, compared with the placebo group, in most secondary endpoints at 1 year after administration. In the condoliase group, back pain, Modic type 1 change, and decrease in disc height were frequently reported, without any clinically relevant consequences.

Conclusion: Condoliase significantly improved symptoms in patients with LDH and was well tolerated. Condoliase is a novel and potent chemonucleolytic drug for the treatment of LDH 15).

Case reports

It has been available for painful lumbar disc herniation since 2018 in Japan.

A 25-year-old man with a history of LDH in L4/5, who underwent transforaminal full endoscopic lumbar discectomy when he was 17 years old, complained of severe pain radiating to his left leg for 1 month. The straight leg-raising test was limited to 25° on the left side. Lumbar T2-weighted magnetic resonance imaging (MRI) showed intracanal, left-sided transligamentous disc herniation at L4/5 with high-signal intensity. Because the conservative treatment with oral analgesics and selective left L5 nerve root block failed, the patient requested intradiscal condoliase injection instead of revision surgery. There were no adverse events reported after the condoliase treatment, and the pain radiating to the left leg improved within 2 weeks. A lumbar MRI performed 2 months after treatment revealed that the disc herniation had significantly decreased in size. The straight leg-raising test examined 3 months after treatment was negative. In this case, the disc herniation was of the transligamentous type and showed a high-signal intensity on T2-weighted MRI which could be suitably treated by condoliase injection therapy. This case report is the first to suggest that intradiscal condoliase injection could be a useful and novel conservative treatment option to treat postoperative rec-LDH 16).

References

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