Trigeminal neuralgia

Trigeminal neuralgia

Typical trigeminal neuralgia caused by microvascular compression of the trigeminal nerve root in the posterior fossa may become transformed over time into atypical trigeminal neuralgia, if left untreated. This transformation involves change in the character of pain and development of sensory impairment. Two representative cases are presented to support this theory.

If the theory of progressive change in character of pain and degree of sensory impairment in the course of otherwise typical trigeminal neuralgia is correct, trigeminal neuralgia, atypical neuralgia, and trigeminal neuropathic pain may represent different degrees of injury to the trigeminal nerve, therefore comprising a continuous spectrum rather than discrete diagnoses 2).

Barrow Neurological Institute Pain Scale.

Barrow Neurological Facial Numbness Scale.

Slavin KV. Commentary: Development and Evaluation of a Preoperative Trigeminal Neuralgia Scoring System to Predict Long-Term Outcome Following Microvascular Decompression. Neurosurgery. 2019 Dec 9. pii: nyz540. doi: 10.1093/neuros/nyz540. [Epub ahead of print] PubMed PMID: 31813971.


1)

Lewy FH: The first authentic case of major trigeminal neuralgia and some comments on the history of this disease. Ann Med Hist 10:247–250, 1938.
2)

Burchiel KJ, Slavin KV. On the natural history of trigeminal neuralgia. Neurosurgery. 2000 Jan;46(1):152-4; discussion 154-5. Review. PubMed PMID: 10626945.

Condoliase for lumbar disc herniation

Condoliase for lumbar disc herniation


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 However, since chymopapain was withdrawn from the market in 2002 for non-scientific commercial reasons, chemonucleolysis has not been a therapeutic option for LDH.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).

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).

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).

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).


1)

Matsuyama Y, Chiba K. Condoliase for treatment of lumbar disc herniation. Drugs Today (Barc). 2019 Jan;55(1):17-23. doi: 10.1358/dot.2019.55.1.2899445. PMID: 30740609.
2)

Takaki S, Miyama H, Iwasaki M. Cost-effectiveness analysis of intradiscal condoliase injection vs. surgical or conservative treatment for lumbar disc herniation. J Med Econ. 2023 Jan-Dec;26(1):233-242. doi: 10.1080/13696998.2023.2173465. PMID: 36794375.
3)

Matsuyama Y, Chiba K, Iwata H, Seo T, Toyama Y. A multicenter, randomized, double-blind, dose-finding study of condoliase in patients with lumbar disc herniation. J Neurosurg Spine. 2018 May;28(5):499-511. doi: 10.3171/2017.7.SPINE161327. Epub 2018 Feb 9. PMID: 29424676.
4)

Ohtonari T, Torii R, Noguchi S, Kitagawa T, Nishihara N. Short-term clinical and radiographic outcomes of chemonucleolysis with condoliase for painful lumbar disc herniation and analysis regarding intradiscal injection area. Neurosurg Rev. 2023 Feb 23;46(1):59. doi: 10.1007/s10143-023-01966-w. PMID: 36813932.
5)

Takeuchi S, Hanakita J, Takahashi T, Inoue T, Minami M, Suda I, Nakamura S, Kanematsu R. Predictive Factors for Poor Outcome following Chemonucleolysis with Condoliase in Lumbar Disc Herniation. Medicina (Kaunas). 2022 Dec 18;58(12):1868. doi: 10.3390/medicina58121868. PMID: 36557070; PMCID: PMC9781337.
6)

Banno T, Hasegawa T, Yamato Y, Yoshida G, Arima H, Oe S, Ide K, Yamada T, Kurosu K, Nakai K, Matsuyama Y. Condoliase therapy for lumbar disc herniation -2 year clinical outcome. J Orthop Sci. 2022 Nov 21:S0949-2658(22)00317-7. doi: 10.1016/j.jos.2022.11.005. Epub ahead of print. PMID: 36424250.
7)

Oshita Y, Matsuyama D, Sakai D, Schol J, Shirasawa E, Emori H, Segami K, Takahashi S, Yagura K, Miyagi M, Saito W, Imura T, Nakazawa T, Inoue G, Hiyama A, Katoh H, Akazawa T, Kanzaki K, Sato M, Takaso M, Watanabe M. Multicenter Retrospective Analysis of Intradiscal Condoliase Injection Therapy for Lumbar Disc Herniation. Medicina (Kaunas). 2022 Sep 15;58(9):1284. doi: 10.3390/medicina58091284. PMID: 36143959; PMCID: PMC9501482.
8)

Kobayashi K, Sato K, Ando T. Factors associated with disc degeneration based on Pfirrmann criteria after condoliase treatment for lumbar disc herniation. J Orthop Sci. 2022 Aug 24:S0949-2658(22)00230-5. doi: 10.1016/j.jos.2022.08.001. Epub ahead of print. PMID: 36030156.
9)

Okada E, Suzuki S, Nori S, Tsuji O, Nagoshi N, Yagi M, Fujita N, Nakamura M, Matsumoto M, Watanabe K. The effectiveness of chemonucleolysis with condoliase for treatment of painful lumbar disc herniation. J Orthop Sci. 2021 Jul;26(4):548-554. doi: 10.1016/j.jos.2020.06.004. Epub 2020 Jul 23. PMID: 32713796.
10)

Banno T, Hasegawa T, Yamato Y, Yoshida G, Yasuda T, Arima H, Oe S, Ushirozako H, Yamada T, Ide K, Watanabe Y, Matsuyama Y. Clinical outcome of condoliase injection treatment for lumbar disc herniation: Indications for condoliase therapy. J Orthop Sci. 2021 Jan;26(1):79-85. doi: 10.1016/j.jos.2020.02.002. Epub 2020 Feb 25. PMID: 32111547.
11)

Hirai T, Takahashi T, Tanaka T, Motoyoshi T, Matsukura Y, Yuasa M, Inose H, Yoshii T, Okawa A. Intradiscal Injection with Condoliase (Chondroitin Sulfate ABC Endolyase) for Painful Radiculopathy Caused by Lumbar Disc Herniation. Spine Surg Relat Res. 2021 Oct 11;6(3):252-260. doi: 10.22603/ssrr.2021-0151. PMID: 35800623; PMCID: PMC9200423.
12)

Inoue M, Sainoh T, Kojima A, Yamagata M, Morinaga T, Mannoji C, Ataka H, Yamashita M, Takahashi H, Saito J, Fujiyoshi T, Ishikawa T, Eguchi Y, Kato K, Orita S, Inage K, Shiga Y, Norimoto M, Umimura T, Shiko Y, Kawasaki Y, Aoki Y, Ohtori S. Efficacy and Safety of Condoliase Disc Administration as a New Treatment for Lumbar Disc Herniation. Spine Surg Relat Res. 2021 Jun 11;6(1):31-37. doi: 10.22603/ssrr.2021-0035. PMID: 35224244; PMCID: PMC8842352.
13)

Ishibashi K, Fujita M, Takano Y, Iwai H, Inanami H, Koga H. Chemonucleolysis with Chondroitin Sulfate ABC Endolyase for Treating Lumbar Disc Herniation: Exploration of Prognostic Factors for Good or Poor Clinical Outcomes. Medicina (Kaunas). 2020 Nov 19;56(11):627. doi: 10.3390/medicina56110627. PMID: 33228119; PMCID: PMC7699387.
14)

Nakajima H, Kubota A, Maezawa Y, Watanabe S, Honjoh K, Ohmori H, Matsumine A. Short-Term Outcome and Predictors of Therapeutic Effects of Intradiscal Condoliase Injection for Patients with Lumbar Disc Herniation. Spine Surg Relat Res. 2020 Nov 20;5(4):264-271. doi: 10.22603/ssrr.2020-0126. PMID: 34435150; PMCID: PMC8356240.
15)

Chiba K, Matsuyama Y, Seo T, Toyama Y. Condoliase for the Treatment of Lumbar Disc Herniation: A Randomized Controlled Trial. Spine (Phila Pa 1976). 2018 Aug 1;43(15):E869-E876. doi: 10.1097/BRS.0000000000002528. PMID: 29257028.
16)

Funayama T, Setojima Y, Shibao Y, Noguchi H, Miura K, Eto F, Sato K, Kono M, Asada T, Takahashi H, Tatsumura M, Koda M, Yamazaki M. A Case of Postoperative Recurrent Lumbar Disc Herniation Conservatively Treated with Novel Intradiscal Condoliase Injection. Case Rep Orthop. 2022 Feb 15;2022:3656753. doi: 10.1155/2022/3656753. PMID: 35211348; PMCID: PMC8863464.

Tranexamic acid for intracranial meningioma

Tranexamic acid for intracranial meningioma

Based upon Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Wijaya et al. from the Universitas Pelita Harapan, Tangerang, BantenIndonesia, Cedars-Sinai Medical Center, Los Angeles, CES University, El Poblado, Medellín, Antioquia, Colombia. collected fully published English literature on the administration of tranexamic acid for patients undergoing intracranial meningioma surgery using the keywords [“tranexamic acid” and “meningioma”] and its synonyms from Cochrane Central Register of Controlled Trials Database, the WHO International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, and PubMed. The primary outcome of the current study was total blood loss. The secondary outcomes include individuals requiring blood transfusionanesthesia duration, surgical duration, and complication rate. Each included study’s quality was assessed using the JADAD scale.

For qualitative and quantitative data synthesis, they included five RCTs (n = 321) with a mean age was 47.5 ± 11.9 years for the intervention group and 47.2 ± 11.9 years for the control group. The meta-analysis showed that the administration of TXA is associated with decreased total blood loss of standardized mean difference (SMD) of -1.40 (95% CI [-2.49, -0.31]), anesthetic time SMD -0.36 (95% CI [-0.63, -0.09]), and blood transfusion requirements RR 0.58 (95% CI [0.34, 0.99]).

The current study showed that TXA was associated with reduced intraoperative blood loss and intraoperative and postoperative blood transfusion. However, the studies are small. More RCT studies with a greater sample size are favorable 1).

Patients with supratentorial meningiomas and deemed suitable for surgical resection will be recruited in the trial. Patients will be randomized to receive either a single administration of 20 mg/kg TXA or a placebo of the same volume with a 1:1 allocation ratio after anesthesia induction. The primary endpoint is the cumulative incidence of early postoperative seizures within 7 days after craniotomy. Secondary outcomes include the incidence of non-seizure complications, changes in hemoglobin level from baseline, intraoperative blood loss, erythrocyte transfusion volume, Karnofsky Performance Status, all-cause mortality, length of stay, and total hospitalization cost.

Ethics and dissemination: This trial is registered at ClinicalTrial.gov and approved by the Chinese Ethics Committee of Registering Clinical Trials (ChiECRCT20200224). The findings will be disseminated in peer-reviewed journals and presented at national or international conferences relevant to the subject fields.

Trial registration number: NCT04595786 2).


conducted a prospective, randomized double-blind clinical study. The patient scheduled to undergo excision of intracranial meningioma were randomly assigned to receive intraoperatively either intravenous TXA or placebo. Patients in the TXA group received an intravenous bolus of 20 mg/kg over 20 min followed by an infusion of 1 mg/kg/h up to surgical wound closure. Efficacy was evaluated based on total blood loss and transfusion requirements. Postoperatively, thrombotic complications, convulsive seizure, and hematoma formation were noted.

Ninety-one patients were enrolled and randomized: 45 received TXA (TXA group) and 46 received placebo (group placebo). Total blood loss was significantly decreased in the TXA group compared to the placebo (283 ml vs. 576 ml; P < 0.001). Transfusion requirements were comparable in the two groups (P = 0.95). The incidence of thrombotic complications, convulsive seizure, and hematoma formation were similar in the two groups.

TXA significantly reduces intraoperative blood loss but did not significantly reduce transfusion requirements in adults undergoing resection of intracranial meningioma 3).

Thirty patients aged 18-65 years undergoing elective meningioma resection surgery were given either tranexamic acid or placebo (0.9% saline), tranexamic acid at a loading dose of 20 mg/kg, and infusion of 1 mg/kg/h during surgery. The intraoperative blood loss, coagulation profile, and the surgical field using the Likert scale were assessed.

The patients in the tranexamic group had significantly decreased intraoperative blood loss compared to the placebo group (616.42 ± 393.42 ml vs. 1150.02 ± 416.1 ml) (P = 0.02). The quality of the surgical field was better in the tranexamic group (median score 4 vs. 2 on Likert Scale) (P < 0.001). Patients in the tranexamic group had an improved coagulation profile and decreased blood transfusion requirement (p=0.016). The blood collected in the closed suction drain in 24 h postsurgery was less in the tranexamic acid group compared to the placebo group (84.7 ± 50.4 ml vs. 127.6 ± 62.2 ml) (P = 0.047).

Tranexamic acid bolus followed by infusion reduces perioperative blood loss by 46.43% and blood transfusion requirement with improved surgical field and coagulation profile in patients undergoing intracranial meningioma resection surgery 4).


In the Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, India, Sixty adults undergoing elective craniotomy for meningioma excision were randomized to receive either tranexamic acid or placebo, initiated prior to skin incision. Patients in the tranexamic acid group received an intravenous bolus of 20mg/kg over 20min followed by an infusion of 1mg/kg/h till the conclusion of surgery. Intraoperative blood loss, transfusion requirements, and estimating surgical hemostasis using a 5-grade scale were noted. Postoperatively, the extent of tumor excision on CT scan and complications were observed. Demographics, tumor characteristics, amount of fluid infusion, and duration of surgery and anesthesia were comparable between the two groups. The amount of blood loss was significantly less in the tranexamic acid group compared to the placebo (830mlvs 1124ml; p=0.03). The transfusion requirement was less in the tranexamic acid group (p>0.05). The patients in the tranexamic acid group fared better on a 5-grade surgical hemostasis scale with more patients showing good hemostasis (p=0.007). There were no significant differences between the groups regarding the extent of tumor removal, perioperative complications, hospital stay, or neurologic outcome. To conclude, the administration of tranexamic acid significantly reduced blood loss in patients undergoing excision of meningioma. Fewer patients in the tranexamic acid group received blood transfusions. Surgical field hemostasis was better achieved in patients who received tranexamic acid 5).

A man in his 40s with a history of coronary artery disease previously treated with a drug-eluting stent presented for elective craniotomy and resection of an asymptomatic but enlarging meningioma. During his craniotomy, he received desmopressin and tranexamic acid for surgical bleeding. Postoperatively, the patient developed chest pain and was found to have an ST-elevation myocardial infarction (MI). Because of the patient’s recent neurosurgery, standard post-MI care was contraindicated and he was managed symptomatically in the intensive care unit. The echocardiogram on a postoperative day 1 demonstrated no regional wall motion abnormalities and an ejection fraction of 60%. His presentation was consistent with the thrombosis of his diagonal stent. He was transferred out of the intensive care unit on postoperative day 1 and discharged home on postoperative day 3 6).


Raghavendra et al. report the intraoperative use of tranexamic acid to secure complete hemostasis as a rescue measure in intracranial meningioma resection in uncontrollable bleeding 7).


Three of 13 patients with intracranial meningiomas showed the pre-and postoperative elevation of tissue-type plasminogen activator (t-PA) related fibrinolytic activity in euglobulin fractions (EFA). During the operation, two of these three patients showed a significant elevation of the level of fibrinogen degradation products and oozing in the operating field. However, oozing was not observed in the third patient who had been given tranexamic acid preoperatively. Fibrin autography revealed that a broad lytic band of mol wt 50-60 kDa, probably free t-PA, appeared in the plasma obtained from two of the three patients after the operation when EFA elevated significantly. In all patients studied, the t-PA antigen levels were normal preoperatively but increased both during and after the operation, and correlated mainly with the intensities of a lytic band of mol wt 110 kDa, probably t-PA complexed with its major inhibitor (PAI-1). These results suggest that excessive fibrinolysis can induce local hemorrhagic diathesis during operation and may be related to t-PA function in plasma 8).


1)

Wijaya JH, July J, Quintero-Consuegra M, Chadid DP. A systematic review and meta-analysis of the effects of tranexamic acid in surgical procedure for intracranial meningioma. J Neurooncol. 2023 Jan 12. doi: 10.1007/s11060-023-04237-2. Epub ahead of print. PMID: 36633801.
2)

Li S, Yan X, Li R, Zhang X, Ma T, Zeng M, Dong J, Wang J, Liu X, Peng Y. Safety of intravenous tranexamic acid in patients undergoing supratentorial meningiomas resection: protocol for a randomized, parallel-group, placebo control, non-inferiority trial. BMJ Open. 2022 Feb 2;12(2):e052095. doi: 10.1136/bmjopen-2021-052095. PMID: 35110315; PMCID: PMC8811564.
3)

Rebai L, Mahfoudhi N, Fitouhi N, Daghmouri MA, Bahri K. Intraoperative tranexamic acid use in patients undergoing excision of intracranial meningioma: Randomized, placebo-controlled trial. Surg Neurol Int. 2021 Jun 14;12:289. doi: 10.25259/SNI_177_2021. PMID: 34221620; PMCID: PMC8247750.
4)

Ravi GK, Panda N, Ahluwalia J, Chauhan R, Singla N, Mahajan S. Effect of tranexamic acid on blood loss, coagulation profile, and quality of the surgical field in intracranial meningioma resection: A prospective randomized, double-blind, placebo-controlled study. Surg Neurol Int. 2021 Jun 7;12:272. doi: 10.25259/SNI_296_2021. PMID: 34221603; PMCID: PMC8247710.
5)

Hooda B, Chouhan RS, Rath GP, Bithal PK, Suri A, Lamsal R. Effect of tranexamic acid on intraoperative blood loss and transfusion requirements in patients undergoing excision of intracranial meningioma. J Clin Neurosci. 2017 Mar 7. pii: S0967-5868(16)31491-6. doi: 10.1016/j.jocn.2017.02.053. [Epub ahead of print] PubMed PMID: 28283245.
6)

Westfall KM, Ramcharan RN, Anderson HL 3rd. Myocardial infarction after craniotomy for asymptomatic meningioma. BMJ Case Rep. 2022 Dec 29;15(12):e252256. doi: 10.1136/bcr-2022-252256. PMID: 36581354; PMCID: PMC9806024.
7)

Raghavendra H, Varsha KS, Reddy MA, Kumar SS, Sunanda G, Nagarjuna T, Latha S. Rescue Measure in Giant Intracranial Meningioma Resection by Tranexamic Acid. J Neurosci Rural Pract. 2017 Aug;8(Suppl 1):S127-S129. doi: 10.4103/jnrp.jnrp_198_17. PMID: 28936089; PMCID: PMC5602238.
8)

Tsuda H, Oka K, Noutsuka Y, Sueishi K. Tissue-type plasminogen activator in patients with intracranial meningiomas. Thromb Haemost. 1988 Dec 22;60(3):508-13. PMID: 3149049.

Linezolid in Neurosurgery

Linezolid in Neurosurgery

Relevant studies were identified through searches of the PubMed, Current Contents, and Cochrane databases (publications archived until October 2006).

Case reports, case series, prospective and retrospective studies, and randomized controlled trials were eligible for inclusion in our review if they evaluated the effectiveness and safety of linezolid for the treatment of patients with CNS infections.

In 18 (42.9%) of the 42 relevant cases identified, patients had undergone neurosurgical operations and/or had prosthetic devices. Meningitis was the most common CNS infection, accounting for 20 (47.6%) cases. Other CNS infections included brain abscesses (14; 33.3%), ventriculitis (5; 11.9%), and ventriculo-peritoneal shunt infection (3; 7.1%). In the 39 patients in whom the responsible pathogen was isolated, those predominantly responsible for the CNS infections were: penicillin-nonsusceptible Streptococcus pneumoniae (7; 17.9%), vancomycin-resistant enterococci (6; 15.4%), Nocardia spp. (5; 12.8%), methicillin-resistant Staphylococcus epidermidis (4; 10.3%), and methicillin-resistant Staphylococcus aureus (3; 7.7%). Of the 42 patients who received linezolid for the treatment of CNS infections, 38 (90.5%) were either cured or showed clinical improvement of the infection. The mean duration of follow-up was 7.2 months; no recurrent CNS infection was reported.

The limited published data suggest that linezolid may be considered for the treatment of patients with CNS infections in cases of failure of previously administered treatment or limited available options 2).

To evaluate the efficacy and safety of SAT with oral linezolid in patients with NSI and to analyse the cost implications, an observational, non-comparative, prospective cohort study was conducted on clinically stable consecutive adult patients at the Neurosurgical Service. Following intravenous treatment, patients were discharged with SAT with oral linezolid.

A total of 77 patients were included. The most common NSIs were: 41 surgical wound infections, 20 subdural empyemas, 18 epidural abscesses, and 16 brain abscesses. Forty-four percent of patients presented two or more concomitant NSIs. Aetiological agents commonly isolated were: Propionibacterium acnes (36 %), Staphylococcus aureus (23 %), Staphylococcus epidermidis (21 %) and Streptococcus spp. (13 %). The median duration of the SAT was 15 days (range, 3-42). The SAT was interrupted in five cases due to adverse events. The remainder of the patients were cured at the end of the SAT. A total of 1,163 days of hospitalisation were saved. An overall cost reduction of €516,188 was attributed to the SAT. Eight patients with device infections did not require removal of the device, with an additional cost reduction of €190,595. The mean cost saving per patient was €9,179.

SAT with linezolid was safe and effective for the treatment of NSI. SAT reduces hospitalisation times, which means significant savings of health and economic resources 3).


Seventeen patients were included in the study. The main comorbidities among these patients included one or more of the following: subarachnoidal or intraventricular hemorrhage (n=8), solid neurological cancer (n=7), corticosteroids(n=9), and hydrocephalus (n=6). Eight patients underwent a craniotomy and fourteen patients had external ventricular drainage (EVD) as a predisposing factor for infection. Meningitis was the most common infection (11; 64.7%), followed by ventriculitis (4; 23.5%) and brain abscesses (2;11.8%). The main causative organisms were coagulase-negative Staphylococcus spp. (13; 76.5%). Linezolid was used as the initial therapy in 8 episodes, after therapy failure in 6, and for other reasons in 3. The oral route was used in 9 (52.9%) episodes; linezolid was initiated orally in 2 cases. The mean duration of treatment was 26.5 days (range 15-58). No adverse events were reported. Sixteen (94.1%) patients were considered cured. There was one recurrence. The mean length of hospital stay was 45.6 (range 15-112) days and the mean duration of follow-up was 7.2 (range 0.4-32) months. No related deaths occurred during active episodes.

Linezolid was mainly indicated in post-neurosurgical EVD-associated infections due to coagulase-negative Staphylococcus spp. It was used as initial therapy in most cases. A high rate of clinical cure was observed and no related adverse events were reported. More than half of the patients benefited from the advantages of the oral route of administration 4).


In order to study the penetration of this antimicrobial into the cerebrospinal fluid (CSF) of such patients, the disposition of linezolid in serum and CSF was studied in 14 neurosurgical patients given linezolid at 600 mg twice daily (1-h intravenous infusion) for the treatment of CNS infections caused by gram-positive pathogens or for prophylactic chemotherapy. Serum and CSF linezolid steady-state concentrations were analyzed by high-pressure liquid chromatography, and the concentration-time profiles obtained were analyzed to estimate pharmacokinetic parameters. The mean +/- standard deviation (SD) linezolid maximum and minimum measured concentrations were 18.6 +/- 9.6 microg/ml and 5.6 +/- 5.0 microg/ml, respectively, in serum and 10.8 +/- 5.7 microg/ml and 6.1 +/- 4.2 microg/ml, respectively, in CSF. The mean +/- SD areas under the concentration-time curves (AUCs) were 128.7 +/- 83.9 microg x h/ml for serum and 101.6 +/- 59.6 microg x h/ml for CSF, with a mean penetration ratio for the AUC for CSF to the AUC for serum of 0.66. The mean elimination half-life of linezolid in CSF was longer than that in serum (19.1 +/- 19.0 h and 6.5 +/- 3.6 h, respectively). The serum and CSF linezolid concentrations exceeded the pharmacodynamic breakpoint of 4 microg/ml for susceptible target pathogens for the entire dosing interval in the majority of patients. These findings suggest that linezolid may achieve adequate concentrations in the CSF of patients requiring antibiotics for the management or prophylaxis of CNS infections caused by gram-positive pathogens 5).


1)

Jahoda D, Nyc O, Pokorný D, Landor I, Sosna A. [Linezolid in the treatment of antibiotic-resistant gram-positive infections of the musculoskeletal system]. Acta Chir Orthop Traumatol Cech. 2006 Oct;73(5):329-33. Czech. PubMed PMID: 17140514.
2)

Ntziora F, Falagas ME. Linezolid for the treatment of patients with central nervous system infection. Ann Pharmacother. 2007 Feb;41(2):296-308. Epub 2007 Feb 6. Review. PubMed PMID: 17284501.
3)

Martín-Gandul C, Mayorga-Buiza MJ, Castillo-Ojeda E, Gómez-Gómez MJ, Rivero-Garvía M, Gil-Navarro MV, Márquez-Rivas FJ, Jiménez-Mejías ME. Sequential antimicrobial treatment with linezolid for neurosurgical infections: efficacy, safety and cost study. Acta Neurochir (Wien). 2016 Oct;158(10):1837-43. doi: 10.1007/s00701-016-2915-0. Epub 2016 Aug 13. PubMed PMID: 27520361.
4)

Sousa D, Llinares P, Meijide H, Gutiérrez JM, Miguez E, Sánchez E, Castelo L, Mena A. Clinical experience with linezolid for the treatment of neurosurgical infections. Rev Esp Quimioter. 2011 Mar;24(1):42-7. PMID: 21412669.
5)

Myrianthefs P, Markantonis SL, Vlachos K, Anagnostaki M, Boutzouka E, Panidis D, Baltopoulos G. Serum and cerebrospinal fluid concentrations of linezolid in neurosurgical patients. Antimicrob Agents Chemother. 2006 Dec;50(12):3971-6. doi: 10.1128/AAC.00051-06. Epub 2006 Sep 18. PMID: 16982782; PMCID: PMC1694012.

ShuntScope

ShuntScope

Autoclavable reusable SHUNTSCOPE® is designed to facilitate the endoscopic ventricular drainage placement during shunt surgery.

A retrospective analysis of all pediatric patients undergoing ventricular catheter placement using the ShuntScope from 01/2012 to 01/2022 in the Department of Neurosurgery, Saarland University Medical Center, Homburg was performed. Demographic, clinical, and radiological data were evaluated. The visualization quality of the intraoperative endoscopy was stratified into the categories of excellent, medium, and poor and compared to the postoperative catheter tip placement. Follow-up evaluation included the surgical revision rate due to proximal catheter occlusion.

A total of 65 ShuntScope-assisted surgeries have been performed on 51 children. The mean age was 5.1 years. The most common underlying pathology was a tumor- or cyst-related hydrocephalus in 51%. Achieved image quality was excellent in 41.5%, medium in 43%, and poor in 15.5%. Ideal catheter placement was achieved in 77%. There were no intraoperative ventricular catheter placement complications and no technique-related morbidity associated with the ShuntScope. The revision rate due to proximal occlusion was 4.61% during a mean follow-up period of 39.7 years. No statistical correlation between image grade and accuracy of catheter position was observed (p-value was 0.290).

The ShuntScope can be considered a valuable addition to standard surgical tools in pediatric hydrocephalus treatment. Even suboptimal visualization contributes to high rates of correct catheter placement and, thereby, to a favorable clinical outcome 1).


The purpose of the study is to compare the accuracy of catheter placement and the complication and revision rates between SG and freehand (FH) techniques.

A retrospective study based on a prospectively acquired database of patients who underwent VC placement between September 2018 and July 2021. The accuracy of catheter placement was graded on postoperative imaging using a three-point Hayhurst grading system. Complication and revision rates were documented and compared between both groups with an average follow-up period of 20.84 months.

Results: Fifty-seven patients were included. SG technique was used in 29 patients (mean age was 6.3 years, 1.4 -27.7 years, 48.1% females), and FH technique was used in 28 patients (mean age was 26.7 years, 0.83 – 79.5 years, 67.9% female). The success rate for the optimal placement of the VC with a grade I on the Hayhurst scale was significantly higher in the SG group (93.1%) than in the FH group (60.7%), P = 0.012. The revision rate was higher in the FH group with 35.7% vs. 20.7% of in the SG group, P = 0.211.

Conclusion: VC placement using the SG technique is a safe and effective procedure, which enabled a significantly higher success rate and lower revision and complication rate. Accordingly, we recommend using the SG technique especially in patients with difficult anatomy 2)


The experience of shuntscope-guided ventriculoperitoneal shunt in 9 cases done from June 2015 to April 2016. Shuntscope is a 1 mm outer diameter semi-rigid scope from Karl Storz with 10000 pixels of magnification. It has a fiber optic lens system with a camera and light source attachment away from the scope to make it lightweight and easily maneuverable.

Results: In all cases, VC was placed in the ipsilateral frontal horn away from choroid plexuses, septae, or membranes. Septum pellucidum perforation and placement to the opposite side of the ventricle was identified with shunt scope assistance and corrected.

Conclusion: Although our initial results are encouraging, larger case series would be helpful. Complications and cost due to shunt dysfunction can thus be reduced to a great extent with shuntscope 3)


The semi-rigid ShuntScope (Karl Storz GmbH & Co.KG, Tuttlingen, Germany) with an outer diameter of 1.0 mm and an image resolution of 10,000 pixels was used in a series of 27 children and adolescents (18 males, 9 females, age range 2 months-18 years). Indications included catheter placement in aqueductal stenting (n = 4), first-time shunt placement (n = 5), burr hole reservoir insertion (n = 4), catheter placement after endoscopic procedures (n = 7) and revision surgery of the ventricle catheter (n = 7).

ShuntScope-guided precise catheter placement was achieved in 26 of 27 patients. In one case of aqueductal stenting, the procedure had to be abandoned. One single wound healing problem was noted as a complication. Intraventricular image quality was always sufficient to recognize the anatomical structures. In the case of catheter removal, it was helpful to identify adherent vessels or membranes. Penetration of small adhesions or thin membranes was feasible. Postoperative imaging studies demonstrated catheter tip placements analogous to the intraoperative findings.

Misplacements of shunt catheters are completely avoidable with the presented intra-catheter technique including slit ventricles or even aqueductal stenting. Potential complications can be avoided during revision surgery. The implementation of the ShuntScope is recommended in pediatric neurosurgery 4).


1)

Prajsnar-Borak A, Teping F, Oertel J. Image quality and related outcomes of the ShuntScope for catheter implantation in pediatric hydrocephalus-experience of 65 procedures. Childs Nerv Syst. 2022 Dec 2. doi: 10.1007/s00381-022-05776-1. Epub ahead of print. PMID: 36459211.
2)

Issa M, Nofal M, Miotik N, Seitz A, Unterberg A, El Damaty A. ShuntScope®-Guided Versus Free Hand Technique for Ventricular Catheter Placement: A Retrospective Comparative Study of Intra-Ventricular Catheter Tip Position and Complication Rate. J Neurol Surg A Cent Eur Neurosurg. 2022 Feb 10. doi: 10.1055/a-1768-3892. Epub ahead of print. PMID: 35144299.
3)

Agrawal V, Aher RB. Endoluminal Shuntscope-Guided Ventricular Catheter Placement: Early Experience. Asian J Neurosurg. 2018 Oct-Dec;13(4):1071-1073. doi: 10.4103/ajns.AJNS_98_17. PMID: 30459870; PMCID: PMC6208226.
4)

Senger S, Antes S, Salah M, Tschan C, Linsler S, Oertel J. The view through the ventricle catheter – The new ShuntScope for the therapy of pediatric hydrocephalus. J Clin Neurosci. 2018 Feb;48:196-202. doi: 10.1016/j.jocn.2017.10.046. Epub 2017 Nov 6. PubMed PMID: 29102235.

Stenotrophomonas maltophilia meningitis

Stenotrophomonas maltophilia meningitis

Stenotrophomonas maltophilia treatment

The clinical characteristics of six Stenotrophomonas maltophilia ABM cases, collected during a study period of nine years (2001-2009) were included. In the related literature, 13 S. maltophilia ABM cases were reported, and their clinical data were also collected.

The 19 S. maltophilia ABM cases included 11 men and 8 women, aged 28-70 years. Of these 19 cases, 89.5% (17/19) had underlying neurosurgical (NS) conditions as the preceding event. Before the development of S. maltophilia ABM, 52.6% (10/19) of them had long stays in hospital and 63.2% (12/19) had undergone antibiotic treatment. Among the implicated S. maltophilia cases, three strains were found to have a resistance to sulfamethoxazole-trimethoprim (SMZ-TMP). Two of our five cases had resistant strains to levofloxacin. Among the antibiotics chosen for treatment, SMZ-TMP was the most common followed by quinolone (ciprofloxacin, levofloxacin, moxifloxacin). The therapeutic results showed 2 cases expired while the other 17 cases survived.

S. maltophilia ABM usually develops in patients with a preceding neurosurgical condition, a long hospital stay and antibiotic use. SMZ-TMP and quinolones, especially the ciprofloxacin, are the major antibiotic used. This study also shows the emergence of clinical S. maltophilia strains which are not susceptible to SMZ-TMP and quinolones and this development may pose a more serious threat in the near future because treatment options may become depleted and limited despite the mortality rate of this specific group of ABM not being high at this time 1).

A young female patient with history of multiple shunt revisions in the past, came with shunt dysfunction and exposure of the ventriculoperitoneal shunt tube in the neck. The abdominal end of the shunt tube was seen migrating into the bowel during shunt revision. The cerebrospinal fluid analysis showed evidence of Stenotrophomonas maltophilia growth. This is the first reported case of Stenotrophomonas maltophilia meningitis associated with ventriculoperitoneal shunt migration into the bowel. 2).


A patient who developed C. utilis and S. maltophilia after undergoing neurosurgery and received effective nosocomial meningitis treatment. Multiple neurosurgeries were required for a 16-year-old girl due to complications. For probable nosocomial meningitis, she was treated with cefepime with vancomycin. Meropenem and liposomal amphotericin B were prescribed after her seizure and positive CSF culture for Candida utilis. Consequently, S. maltophilia was discovered in the CSF, and ceftazidime and trimethoprim-sulfamethoxazole were prescribed. The patient has been hemodynamically stable for the past two months, and consecutive CSF cultures have been negative. To the best of our knowledge, this is the first case of C. utilis and S. maltophilia co-infection that has been successfully handled. 3).


Two cases of S. maltophilia meningitis following neurosurgical procedures. The first patient was a 60-year-old female. She was admitted to the hospital with a left basal ganglia bleed and underwent placement of an external ventricular drain for the treatment of hydrocephalus. She developed S. maltophilia meningitis 20 days after surgery. She was successfully treated with a combination of trimethoprim-sulfamethoxazole and intravenous colistin and the removal of the drain. She successfully underwent a ventriculoperitoneal (VP) shunt placement at the therapeutic midway point. The second patient was a 35-year-old male with a history of intracranial aneurysm bleeding. He had undergone a craniotomy and placement of a ventriculoperitoneal shunt two years previously. His shunt was replaced twice due to blockage. The last replacement had occurred 15 days prior to the development of meningitis. He was treated with a combination of trimethoprim-sulfamethoxazole and ceftazidime (as well as undergoing another shunt replacement) and experienced an excellent recovery. S. maltophilia is a rare but important cause of nosocomial meningitis. It is strongly associated with prior hospitalization and neurosurgical intervention, which is also found in our case series. The management of S. maltophilia meningitis is a therapeutic challenge due to its high resistance to multiple antibiotics. Optimal therapy is based on antimicrobial sensitivity, and the trimethoprim-sulfamethoxazole-based combination has been shown to be successful. The duration of therapy is debatable, but like most gram-negative meningitis infections, therapy lasting up to three weeks appears to be adequate. 4).


Stenotrophomonas maltophilia CSF infection in infants after neurosurgery 5).


A 4-year-old boy who developed meningitis associated with this organism, after several neurosurgical procedures and previous treatment with a broad-spectrum antibiotic. He was treated successfully with a combination of trimethoprim-sulfamethoxazole, ceftazidime and levofloxacin. Stenotrophomonas maltophilia should be considered as a potential cause of meningitis, especially among severely debilitated or immunosuppressed patients. Antimicrobial therapy is complicated by the high resistance of the organism to multiple antibiotics. 6).


A case of a six months old, male child who developed meningitis caused by Stenotrophomonas maltophilia, after he underwent a neurosurgical procedure. 7).


A 30-year-old male patient who developed meningitis associated with this organism after several neurosurgical procedures. A review of the literature revealed only 15 previous reports. Most cases were associated with neurosurgical procedures. Antimicrobial therapy is complicated by multiple drug resistance of the organism, and trimethoprim-sulfamethoxazole is the recommended agent for treatment. 8).


A case of generalized infection by S. maltophilia, including meningitis, bacteremia and respiratory tract infection, in a patient who had undergone multiple neurosurgical procedures and who was treated with trimethoprim-sulphamethoxazole 9).


Two cases of meningitis caused by Stenotrophomonas maltophilia in cancer patients following placement of an Ommaya reservoir for treatment of meningeal carcinomatosis. In addition, they review eight other cases of S. maltophilia that have been reported to date. Stenotrophomonas maltophilia meningitis is often associated with neurosurgical procedures; however, spontaneous infection may also occur, mainly in neonates. The disease’s clinical presentation is similar to that of other forms of meningitis caused by Gram-negative bacilli. The overall mortality rate of this disease is 20% and is limited to neonates with spontaneous meningitis in whom effective antibiotic therapy is delayed. Meningitis caused by S. maltophilia in the modern era should be considered in immunocompromised hosts with significant central nervous system disease who have undergone neurosurgical procedures and who do not readily respond to broad-spectrum antimicrobial coverage. 10).


1)

Huang CR, Chen SF, Tsai NW, Chang CC, Lu CH, Chuang YC, Chien CC, Chang WN. Clinical characteristics of Stenotrophomonas maltophilia meningitis in adults: a high incidence in patients with a postneurosurgical state, long hospital staying and antibiotic use. Clin Neurol Neurosurg. 2013 Sep;115(9):1709-15. doi: 10.1016/j.clineuro.2013.03.006. Epub 2013 Apr 20. PMID: 23611735.
2)

Manuel A, Jayachandran A, Harish S, Sunil T, K R VD, K R, Jo J, Unnikrishnan M, George K, Bahuleyan B. <i>Stenotrophomonas maltophilia</i> as a rare cause of meningitis and ventriculoperitoneal shunt infection. Access Microbiol. 2021 Oct 7;3(10):000266. doi: 10.1099/acmi.0.000266. PMID: 34816086; PMCID: PMC8604181.
3)

Mohzari Y, Al Musawa M, Asdaq SMB, Alattas M, Qutub M, Bamogaddam RF, Yamani A, Aldabbagh Y. Candida utilis and Stenotrophomonas maltophilia causing nosocomial meningitis following a neurosurgical procedure: A rare co-infection. J Infect Public Health. 2021 Nov;14(11):1715-1719. doi: 10.1016/j.jiph.2021.10.004. Epub 2021 Oct 13. PMID: 34700290.
4)

Khanum I, Ilyas A, Ali F. Stenotrophomonas maltophilia Meningitis – A Case Series and Review of the Literature. Cureus. 2020 Oct 28;12(10):e11221. doi: 10.7759/cureus.11221. PMID: 33269149; PMCID: PMC7704165.
5)

Mukherjee S, Zebian B, Chandler C, Pettorini B. Stenotrophomonas maltophilia CSF infection in infants after neurosurgery. Br J Hosp Med (Lond). 2017 Dec 2;78(12):724-725. doi: 10.12968/hmed.2017.78.12.724. PMID: 29240495.
6)

Correia CR, Ferreira ST, Nunes P. Stenotrophomonas maltophilia: rare cause of meningitis. Pediatr Int. 2014 Aug;56(4):e21-2. doi: 10.1111/ped.12352. PMID: 25252064.
7)

Sood S, Vaid VK, Bhartiya H. Meningitis due to Stenotrophomonas maltophilia after a Neurosurgical Procedure. J Clin Diagn Res. 2013 Aug;7(8):1696-7. doi: 10.7860/JCDR/2013/5614.3248. Epub 2013 Aug 1. PMID: 24086879; PMCID: PMC3782936.
8)

Yemisen M, Mete B, Tunali Y, Yentur E, Ozturk R. A meningitis case due to Stenotrophomonas maltophilia and review of the literature. Int J Infect Dis. 2008 Nov;12(6):e125-7. doi: 10.1016/j.ijid.2008.03.028. Epub 2008 Jun 24. PMID: 18579427.
9)

Platsouka E, Routsi C, Chalkis A, Dimitriadou E, Paniara O, Roussos C. Stenotrophomonas maltophilia meningitis, bacteremia and respiratory infection. Scand J Infect Dis. 2002;34(5):391-2. doi: 10.1080/00365540110080520. PMID: 12069028.
10)

Papadakis KA, Vartivarian SE, Vassilaki ME, Anaissie EJ. Stenotrophomonas maltophilia meningitis. Report of two cases and review of the literature. J Neurosurg. 1997 Jul;87(1):106-8. doi: 10.3171/jns.1997.87.1.0106. PMID: 9202275.

Clinically non-functioning pituitary adenoma

Clinically non-functioning pituitary adenoma

Clinically non-functioning pituitary adenoma (CNFPA) is currently the preferred term for designing all the pituitary adenomas which are not hormonally active (in other words, not associated with clinical syndromes such as amenorrheagalactorrhea in the context of Lactotroph adenomas, acromegalyCushing’s disease or hyperthyroidism secondary to TSH secreting pituitary adenoma).

see Clinically non-functioning pituitary adenoma epidemiology.

Clinically non-functioning pituitary adenoma natural history.

Clinically non-functioning pituitary adenoma classification.

Clinically non-functioning pituitary adenoma pathogenesis.

Clinically non-functioning pituitary adenoma clinical features.

Knosp Grade

Clinically non-functioning pituitary adenoma diagnosis.

Clinically non-functioning pituitary adenoma differential diagnosis

see Clinically non-functioning pituitary adenoma treatment.

see Clinically Non-functioning Pituitary Adenoma Outcome.

see Clinically non-functioning pituitary adenoma case series.

Clinically non-functioning pituitary adenoma case reports

Anterior communicating artery aneurysm endovascular treatment complications

Anterior communicating artery aneurysm endovascular treatment complications

Intraprocedural aneurysm rupture and thrombus formation are serious complications during coiling of ruptured intracranial aneurysms, and they more often occur in patients with anterior communicating artery aneurysms.

It is associated with a high rate of complete angiographic occlusion. However, the procedure-related permanent morbidity and mortality are not negligible for aneurysms in this location 1).


Delgado Acosta et al. from Hospital Universitario Reina Sofía aimed to report the characteristics of patients suffering intra- or peri-procedural ruptures during embolization of cerebral aneurysms.

Between March 1994 and October 2021, 648 consecutive cerebral aneurysms were treated by the endovascular procedureMedical records were reviewed retrospectively with emphasis on procedure description, potential risk factors, and clinical outcomes related to intra- or peri-procedural rupture.

Of the 648 patients, 17 (2.6%) suffered an intra- or peri-procedural hemorrhagic event. The most common location was the anterior communicating artery. There was no significant difference between previously ruptured and unruptured aneurysms in the incidence of bleeding. In four patients, bleeding was evident within 24 h after the procedure. The clinical evolution at three months was poor and only four patients presented a positive evolution. There were 11 deaths (64.71%). Balloon remodeling was associated with an increased frequency of ruptures, while stenting was a safer treatment.

Aneurysm rupture during endovascular therapy is unpredictable, and its occurrence can be devastating. The incidence is quite low although the outcome is frequently poor. Early detection and proper management, including prompt occlusion of the aneurysm, are important to achieve a positive outcome. Anterior communicating artery aneurysms and those treated with balloon catheters have a higher incidence of rupture. A small number of ruptures of uncertain origin occur that go unnoticed in digital subtraction angiograms 2).


The immediate and long-term outcomes, complications, recurrences and the need for retreatment were analyzed in a series of 280 consecutive patients with anterior communicating artery aneurysms treated with the endovascular technique. From October 1992 to October 2001 280 patients with 282 anterior communicating artery aneurysms were addressed to our center. For the analysis, the population was divided into two major groups: group 1, comprising 239 (85%) patients with ruptured aneurysms and group 2 comprising of 42 (15%) patients with unruptured aneurysms. In group 1, 185 (77.4%) patients had a good initial pre-treatment Hunt and Hess grade of I-III. Aneurysm size was divided into three categories according to the larger diameter: less than 4 mm, between 4 and 10 mm and larger than 10 mm. The sizes of aneurysms in groups 1 and 2 were identical but a less favorable neck to depth ratio of 0.5 was more frequent in group 2. Endovascular treatment was finally performed in 234 patients in group 1 and 34 patients in group 2. Complete obliteration was more frequently obtained in group 2 unlike a residual neck or opacification of the sac that were more frequently seen in group 1. No peri-treatment complications were recorded in group 2. In group 1 the peri-treatment mortality and overall peri-treatment morbidity were 5.1% and 8.1% respectively. Eight patients (3.4%) in group 1 presented early post treatment rebleeding with a mortality of 88%. The mean time to follow-up was 3.09 years. In group 1, 51 (21.7%) recurrences occurred of which 14 were minor and 37 major. In group 2, eight (23.5%) recurrences occurred, five minor and three major. Two patients (0.8%) presented late rebleeding in group 1. Twenty-seven second endovascular retreatments were performed, 24 (10.2%) in group 1 and three (8.8%) in group 2, seven third endovascular retreatments and two surgical clippings in group 1 only. There was no additional morbidity related to retreatments. Endovascular treatment is an effective method for the treatment of anterior communicating artery aneurysms allowing late rebleeding prevention. Peri-treatment rebleeding warrants caution in anticoagulation management. This is a single center experience and the follow-up period is limited. Patients should be followed-up in the long-term as recurrences may occur and warrant additional treatment 3).


Prolonged anterograde amnesia and disorientation after anterior communicating artery aneurysm coil embolization 4)


LVIS stent-assisted coiling for ruptured wide-necked ACoA aneurysms was safe and effective, with a relatively low rate of perioperative complications and a high rate of complete occlusion at follow-up 5)


1)

Fang S, Brinjikji W, Murad MH, Kallmes DF, Cloft HJ, Lanzino G. Endovascular treatment of anterior communicating artery aneurysms: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2014 May;35(5):943-7. doi: 10.3174/ajnr.A3802. Epub 2013 Nov 28. PMID: 24287090; PMCID: PMC7964525.
2)

Delgado Acosta F, Bravo Rey I, Jiménez Gómez E, Saucedo VR, Toledano A, Oteros Fernández R. Intra- or peri-procedural rupture in the endovascular treatment of intracranial aneurysms. Acta Neurol Scand. 2022 Aug 17. doi: 10.1111/ane.13686. Epub ahead of print. PMID: 35975464.
3)

Finitsis S, Anxionnat R, Lebedinsky A, Albuquerque PC, Clayton MF, Picard L, Bracard S. Endovascular treatment of ACom intracranial aneurysms. Report on series of 280 patients. Interv Neuroradiol. 2010 Mar;16(1):7-16. doi: 10.1177/159101991001600101. Epub 2010 Mar 25. PMID: 20377974; PMCID: PMC3277962.
4)

Al-Atrache Z, Friedler B, Shaikh HA, Kavi T. Prolonged anterograde amnesia and disorientation after anterior communicating artery aneurysm coil embolisation. BMJ Case Rep. 2019 Jul 30;12(7). pii: e230543. doi: 10.1136/bcr-2019-230543. PubMed PMID: 31366616.
5)

Xue G, Liu P, Xu F, Fang Y, Li Q, Hong B, Xu Y, Liu J, Huang Q. Endovascular Treatment of Ruptured Wide-Necked Anterior Communicating Artery Aneurysms Using a Low-Profile Visualized Intraluminal Support (LVIS) Device. Front Neurol. 2021 Jan 28;11:611875. doi: 10.3389/fneur.2020.611875. PMID: 33584512; PMCID: PMC7876256.

terior communicating artery aneurysm endovascular treatment complications

Diffuse midline glioma H3 K27M-altered case series

Diffuse midline glioma H3 K27M-altered case series

Forty-one cases of childhood Diffuse midline glioma H3 K27-altered were collected at Children’s Hospital of Fudan University (39 cases) and Xi’an Children’s Hospital (2 cases), from July 2016 to July 2020. The clinical manifestations, imaging data, histopathology, immunohistochemical phenotype and molecular genetics features, tumor size, site and histological grading were evaluated. Among the 41 cases, 21 were males and 20 females, the age of onset was 3-14 years, the average and median age was 7.6 years and 7.0 years, respectively. The tumor sites were brain stem (n=36) and other locations (n=5). The clinical manifestations were dizzinessgait disturbance, and limb weakness, etc. The MRI features were variable. The histology varied from low-grade to high-grade glioma with neuron differentiation. Immunohistochemistry showed that the tumor cells expressed H3K27MGFAP, and Olig2. Genetic study showed that 76% (16/21) of tumors had H3F3A gene mutation, mostly accompanied by TP53 (62%, 13/21) missense mutation; five tumors (24%, 5/21) had HIST1H3B gene mutation, accompanied by missense mutations in ACVR1 and PI3K pathway-related gene PIK3CA (4/5) and PIK3R1 (1/5) mutations. The prognosis was dismal with only one alive and others died. The average and median overall survival time was 7 months and 4 months, respectively. Cox multivariate regression analysis showed that age, tumor location, radiologically maximum tumor diameter, histologic grading, and surgical methods were not significantly associated with overall survival rate (P>0.05). Pediatric diffuse midline gliomas with H3K27 alteration have unique clinicopathological and genetic characteristics. The prognosis is poor. The tumor location and histopathologic grading are not related to prognosis. New specific drugs and comprehensive treatment are needed to improve the prognosis 1).

Piccardo et al., from Genoa, Italy. retrospectively analyzed 22 pediatric patients with DMG histologically proved and molecularly classified as H3K27M-mutant (12 subjects) and wild-type (10 subjects) who underwent DWIProton magnetic resonance spectroscopic imaging, and ASL performed within 2 weeks of 18F-FDOPA PET. DWI-derived relative minimum apparent diffusion coefficient (rADC min), 1H-MRS data choline/N-acetylaspartate (Cho/NAA), choline/creatine (Cho/Cr), and presence of lactate and relative ASL-derived cerebral blood flow max (rCBF max) were compared with 18F-DOPA uptake Tumor/Normal tissue (T/N) and Tumor/Striatum (T/S) ratios, and correlated with histological and molecular features of DMG. Statistics included Pearson’s chi-square and Mann-Whitney U tests, Spearman’s rank correlation and receiver operating characteristic (ROC) analysis.

The highest degrees of correlation among different techniques were found between T/S, rADC min and Cho/NAA ratio (p < 0.01), and between rCBF max and rADC min (p < 0.01). Significant differences between histologically classified low- and high-grade DMG, independently of H3K27M-mutation, were found among all imaging techniques (p ≤ 0.02). Significant differences in terms of rCBF max, rADC min, Cho/NAA and 18F-DOPA uptake were also found between molecularly classified mutant and wild-type DMG (p ≤ 0.02), even though wild-type DMG included low-grade astrocytomas, not present among mutant DMG. When comparing only histologically defined high-grade mutant and wild-type DMG, only the 18F-DOPA PET data T/S demonstrated statistically significant differences independently of histology (p < 0.003). ROC analysis demonstrated that T/S ratio was the best parameter for differentiating mutant from wild-type DMG (AUC 0.94, p < 0.001).

Advanced MRI and 18F-DOPA PET characteristics of DMG depend on histological features; however, 18F-DOPA PET-T/S was the only parameter able to discriminate H3K27M-mutant from wild-type DMG independently of histology 2).


Baseline diffusion or apparent diffusion coefficient (ADC) characteristics have been shown to predict outcome related to DIPG, but the predictive value of post-radiation ADC is less well understood. ADC parametric mapping (FDM) was used to measure radiation-related changes in ADC and compared these metrics to baseline ADC in predicting progression-free survival and overall survival using a large multi-center cohort of DIPG patients (Pediatric Brain Tumor Consortium-PBTC).

MR studies at baseline and post-RT in 95 DIPG patients were obtained and serial quantitative ADC parametric maps were generated from diffusion-weighted imaging based on T2/FLAIR and enhancement regions of interest (ROIs). Metrics assessed included total voxels with: increase in ADC (iADC); decrease in ADC (dADC), no change in ADC (nADC), fraction of voxels with increased ADC (fiADC), fraction of voxels with decreased ADC (fdADC), and the ratio of fiADC and fdADC (fDM Ratio).

A total of 72 patients were included in the final analysis. Tumors with higher fiADC between baseline and the first RT time point showed a trend toward shorter PFS with a hazard ratio of 6.44 (CI 0.79, 52.79, p = 0.083). In contrast, tumors with higher log mean ADC at baseline had longer PFS, with a hazard ratio of 0.27 (CI 0.09, 0.82, p = 0.022). There was no significant association between fDM derived metrics and overall survival.

Baseline ADC values are a stronger predictor of outcome compared to radiation related ADC changes in pediatric DIPG. We show the feasibility of employing parametric mapping techniques in multi-center studies to quantitate spatially heterogeneous treatment response in pediatric tumors, including DIPG 3).

Meyronet et al., from Lyon analyzed the characteristics of 21 adult H3 K27M-mutant gliomas and compared them with those of 135 adult diffuse gliomas without histone H3 and without isocitrate dehydrogenase (IDH) mutation (IDH/H3 wild type).

The median age at diagnosis in H3 K27M-mutant gliomas was 32 years (range: 18-82 y). All tumors had a midline location (spinal cord n = 6, thalamus n = 5, brainstem n = 5, cerebellum n = 3, hypothalamus n = 1, and pineal region n = 1) and were IDH and BRAF-V600E wild type. The identification of an H3 K27M mutation significantly impacted the diagnosis in 3 patients (14%) for whom the histological aspect initially suggested a diffuse low-grade glioma and in 7 patients (33%) for whom pathological analysis hesitated between a diffuse glioma, ganglioglioma, or pilocytic astrocytoma. Compared with IDH/H3 wild-type gliomas, H3 K27M-mutant gliomas were diagnosed at an earlier age (32 vs 64 y, P < .001), always had a midline location (21/21 vs 21/130, P < .001), less frequently had a methylated MGMT promoter (1/21 vs 52/129, P = .002), and lacked EGFR amplification (0/21 vs 26/128, P = .02). The median survival was 19.6 months in H3 K27M-mutant gliomas and 17 months in IDH/H3 wild-type gliomas (P = .3).

In adults, as in children, H3 K27M mutations define a distinct subgroup of IDH wild-type gliomas characterized by a constant midline location, low rate of MGMT promoter methylation, and poor prognosis 4).

130 cases of DIPG biopsies and previous published data, these procedures appear to have a diagnostic yield and morbidity rates similar to those reported for other brain locations (3.9 % of transient morbidity in our series). In addition, the quality and the quantity of the material obtained allow to (1) confirm the diagnosis, (2) reveal that WHO grading was useless to predict outcome, and (3) perform an extended molecular screen, including biomarkers study and the development of preclinical models. Recent studies reveal that DIPG may comprise more than one biological entity and a unique oncogenesis involving mutations never described in other types of cancers, i.e., histones H3 K27M and activin receptor ACVR1.

Stereotactic biopsies of DIPG can be considered as a safe procedure in well-trained neurosurgical teams and could be incorporated in protocols. It is a unique opportunity to integrate DIPG biopsies in clinical practice and use the biology at diagnosis to drive the introduction of innovative targeted therapies, in combination with radiotherapy 5).

A suboccipital, transcerebellar approach was used to obtain biopsy samples in 24 children.

Two patients suffered deficits. Both had a transient (< 2 months) new cranial nerve palsy; one of these patients also experienced an exacerbation of a preoperative hemiparesis. No patient died during the perioperative period. A histological diagnosis was made in all 24 patients as follows: 22 had a malignant infiltrative astrocytoma, one had a low-grade astrocytoma, and one had a pilocytic astrocytoma. The diagnosis of the latter two patients affected the initial treatment after the biopsy.

The findings of this study imply that stereotactic biopsy sampling of a diffuse pontine tumor is a safe procedure, is associated with minimal morbidity, and has a high diagnostic yield. A nonmalignant tumor was identified in two of the 24 patients in whom the imaging findings were characteristic of a malignant infiltrative astrocytoma. With the advent of new treatment protocols, stereotactic biopsy sampling, which would allow specific tumor characterization of diffuse pontine lesions, may become standard 6).


1)

Li J, Ma YY, Feng J, Zhao D, Ding F, Tian L, Chen R, Zhao R. [Diffuse midline gliomas with H3K27 alteration in children: a clinicopathological analysis of forty-one cases]. Zhonghua Bing Li Xue Za Zhi. 2022 Apr 8;51(4):319-325. Chinese. doi: 10.3760/cma.j.cn112151-20210830-00625. PMID: 35359043.
2)

Piccardo A, Tortora D, Mascelli S, Severino M, Piatelli G, Consales A, Pescetto M, Biassoni V, Schiavello E, Massollo M, Verrico A, Milanaccio C, Garrè ML, Rossi A, Morana G. Advanced MR imaging and (18)F-DOPA PET characteristics of H3K27M-mutant and wild-type pediatric diffuse midline gliomas. Eur J Nucl Med Mol Imaging. 2019 Apr 27. doi: 10.1007/s00259-019-04333-4. [Epub ahead of print] PubMed PMID: 31030232.
3)

Ceschin R, Kocak M, Vajapeyam S, Pollack IF, Onar-Thomas A, Dunkel IJ, Poussaint TY, Panigrahy A. Quantifying radiation therapy response using apparent diffusion coefficient (ADC) parametric mapping of pediatric diffuse intrinsic pontine glioma: a report from the pediatric brain tumor consortium. J Neurooncol. 2019 Feb 27. doi: 10.1007/s11060-019-03133-y. [Epub ahead of print] PubMed PMID: 30810873.
4)

Meyronet D, Esteban-Mader M, Bonnet C, Joly MO, Uro-Coste E, Amiel-Benouaich A, Forest F, Rousselot-Denis C, Burel-Vandenbos F, Bourg V, Guyotat J, Fenouil T, Jouvet A, Honnorat J, Ducray F. Characteristics of H3 K27M-mutant gliomas in adults. Neuro Oncol. 2017 Aug 1;19(8):1127-1134. doi: 10.1093/neuonc/now274. PubMed PMID: 28201752; PubMed Central PMCID: PMC5570304.
5)

Puget S, Beccaria K, Blauwblomme T, Roujeau T, James S, Grill J, Zerah M, Varlet P, Sainte-Rose C. Biopsy in a series of 130 pediatric diffuse intrinsic Pontine gliomas. Childs Nerv Syst. 2015 Oct;31(10):1773-80. doi: 10.1007/s00381-015-2832-1. Epub 2015 Sep 9. PubMed PMID: 26351229.
6)

Roujeau T, Machado G, Garnett MR, Miquel C, Puget S, Geoerger B, Grill J, Boddaert N, Di Rocco F, Zerah M, Sainte-Rose C. Stereotactic biopsy of diffuse pontine lesions in children. J Neurosurg. 2007 Jul;107(1 Suppl):1-4. PubMed PMID: 17647306.