Endoscopic third ventriculostomy and choroid plexus cauterization

Endoscopic third ventriculostomy and choroid plexus cauterization

Endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC) offers an alternative to shunt.


While ventriculoperitoneal shunt (VPS) insertion is the standard treatment for myelomeningocele-associated hydrocephalus (MAH), it can be complicated by shunt infection and shunt malfunction. As such, endoscopic third ventriculostomy (ETV), with or without choroid plexus coagulation (CPC), has been proposed as an alternative.

ETV+CPC was associated with a higher success rate than ETV alone for MAH in a meta-analysis of published studies. ETV, with or without CPC, was technically feasible and safe for this patient population 1).


In the twenty-first century, choroid plexus cauterization (CPC) in combination with endoscopic third ventriculostomy (ETV) has emerged as an effective treatment for some infants with hydrocephalus, leading to the favourable condition of ‘shunt independence‘.

Coulter et al. provide a narrative technical review considering the indications, procedural aspects, morbidity and its avoidance, postoperative care and follow-up. The CP has been the target of hydrocephalus treatment for more than a century. Early eminent neurosurgeons including Dandy, Putnam and Scarff performed CPC achieving generally poor results, and so the procedure fell out of favour. In recent years, the addition of CPC to ETV was one of the reasons greater ETV success rates were observed in Africa, compared to developed nations, and its popularity worldwide has since increased. Initial results indicate that when ETV/CPC is performed successfully, shunt independence is more likely than when ETV is undertaken alone. CPC is commonly performed using a flexible endoscope via septostomy and aims to maximally cauterize the CP. Success is more likely in infants aged >1 month, those with hydrocephalus secondary to myelomeningocele and aqueductal obstruction and those with >90% cauterized CP. Failure is more likely in those with post-haemorrhagic hydrocephalus of prematurity (PHHP), particularly those <1 month of corrected age and those with prepontine scarring. High-quality evidence comparing the efficacy of ETV/CPC with shunting is emerging, with data from ongoing and future trials offering additional promise to enhance our understanding of the true utility of ETV/CPC 2).


In the quest to identify the optimal means of cerebrospinal fluid diversion free of shunt dependency, endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) has been proposed as a promising procedure in select children. Supplementing traditional ETV with obliteration of the choroid plexus has been shown to decrease the likelihood of ultimate shunt dependency by roughly 20%. Originally devised to treat hydrocephalus in infants in sub-Saharan Africa, ETV/CPC has gained eager attention and cautious support in the developed world 3).

Diagnosing treatment failure is dependent on infantile hydrocephalus metrics, including head circumference, fontanel quality, and ventricle size.

Systematic review was performed using four electronic databases and bibliographies of relevant articles, with no language or date restrictions. Cohort studies of participants undergoing ETV/CPC that reported outcome were included using MOOSE guidelines. The outcome was time to repeat CSF diversion or death. Forest plots were created for pooled mean and its 95 % CI of outcome and morbidity.

Of 78 citations, 11 retrospective reviews (with 524 total participants) were eligible. Efficacy was achieved in 63 % participants at follow-up periods between 6 months and 8 years. Adverse events and mortality was reported in 3.7 and 0.4 % of participants, respectively. Publication bias was detected with respect to efficacy and morbidity of the procedure. A large discrepancy in success was identified between ETV/CPC in six studies from sub-Saharan Africa (71 %), compared to three studies from North America (49 %).

The reported success of ETV/CPC for infantile hydrocephalus is higher in sub-Saharan Africa than developed nations. Large long-term prospective multi-center observational studies addressing patient-important outcomes are required to further evaluate the efficacy and safety of this re-emerging procedure 4).

2016

It is not clear to what degree these metrics should be expected to change after ETV/CPC. Using these clinical metrics, Dewan et al., present and analyze the decision making in cases of ETV/CPC failure.

Infantile hydrocephalus metrics, including bulging fontanel, head circumference z-score, and frontal and occipital horn ratio (FOHR), were compared between ETV/CPC failures and successes. Treatment outcome predictive values of metrics individually and in combination were calculated.

Forty-four patients (57% males, median age 1.2 months) underwent ETV/CPC for hydrocephalus; of these patients, 25 (57%) experienced failure at a median time of 51 days postoperatively. Patients experiencing failure were younger than those experiencing successful treatment (0.8 vs 3.9 months, p = 0.01). During outpatient follow-up, bulging anterior fontanel, progressive macrocephaly, and enlarging ventricles each demonstrated a positive predictive value (PPV) of no less than 71%, but a bulging anterior fontanel remained the most predictive indicator of ETV/CPC failure, with a PPV of 100%, negative predictive value of 73%, and sensitivity of 72%. The highest PPVs and specificities existed when the clinical metrics were present in combination, although sensitivities decreased expectedly. Only 48% of failures were diagnosed on the basis all 3 hydrocephalus metrics, while only 37% of successes were negative for all 3 metrics. In the remaining 57% of patients, a diagnosis of success or failure was made in the presence of discordant data.

Successful ETV/CPC for infantile hydrocephalus was evaluated in relation to fontanel status, head growth, and change in ventricular size. In most patients, a designation of failure or success was made in the setting of discordant data 5).

2014

A study retrospectively reviewed medical records of 27 premature infants with intraventricular hemorrhage (IVH) and hydrocephalus treated with ETV and CPC from 2008 to 2011. All patients were evaluated using MRI before the procedure to verify the anatomical feasibility of ETV/CPC. Endoscopic treatment included third ventriculostomy, septostomy, and bilateral CPC. After ETV/CPC, all patients underwent follow-up for a period of 6-40 months (mean 16.2 months). The procedure was considered a failure if the patient subsequently required a shunt. The following factors were analyzed to determine a relationship to patient outcomes: gestational age at birth, corrected age and weight at surgery, timing of surgery after birth, grade of IVH, the status of the prepontine cistern and cerebral aqueduct on MRI, need for a ventricular access device prior to the endoscopic procedure, and scarring of the prepontine cistern noted at surgery.

Seventeen (63%) of 27 patients required a shunt after ETV/CPC, and 10 patients did not require further CSF diversion. Several factors studied were associated with a higher rate of ETV/CPC failure: Grade IV hemorrhage, weight 3 kg or less and age younger than 3 months at the time of surgery, need for reservoir placement, and presence of a normal cerebral aqueduct. Two factors were found to be statistically significant: the patient’s corrected gestational age of less than 0 weeks at surgery and a narrow prepontine cistern on MRI. The majority (83%) of ETV/CPC failures occurred in the first 3 months after the procedure. None of the patients had a complication directly related to the procedure.

Endoscopic third ventriculostomy/CPC is a safe initial procedure for hydrocephalus in premature infants with IVH and hydrocephalus, obviating the need for a shunt in selected patients. Even though the success rate is low (37%), the lower rate of complications in comparison with shunt treatment may justify this procedure in the initial management of hydrocephalus. As several of the studied factors have shown influence on the outcome, patient selection based on these observations might increase the success rate 6).

2005

A total of 710 children underwent ventriculoscopy as candidates for ETV as the primary treatment for hydrocephalus. The ETV was accomplished in 550 children: 266 underwent a combined ETV-CPC procedure and 284 underwent ETV alone. The mean and median ages were 14 and 5 months, respectively, and 443 patients (81%) were younger than 1 year of age. The hydrocephalus was postinfectious (PIH) in 320 patients (58%), nonpostinfectious (NPIH) in 152 (28%), posthemorrhagic in five (1%), and associated with myelomeningocele in 73 (13%). The mean follow up was 19 months for ETV and 9.2 months for ETV-CPC. Overall, the success rate of ETV-CPC (66%) was superior to that of ETV alone (47%) among infants younger than 1 year of age (p < 0.0001). The ETV-CPC combined procedure was superior in patients with a myelomeningocele (76% compared with 35% success, p = 0.0045) and those with NPIH (70% compared with 38% success, p = 0.0025). Although the difference was not significant for PIH (62% compared with 52% success, p = 0.1607), a benefit was not ruled out (power = 0.3). For patients at least 1 year of age, there was no difference between the two procedures (80% success for each, p = 1.0000). The overall surgical mortality rate was 1.3%, and the infection rate was less than 1%.

The ETV-CPC was more successful than ETV alone in infants younger than 1 year of age. In developing countries in which a dependence on shunts is dangerous, ETV-CPC may be the best option for treating hydrocephalus in infants, particularly for those with NPIH and myelomeningocele 7).


1)

Omar AT, Espiritu AI, Spears J. Endoscopic third ventriculostomy with or without choroid plexus coagulation for myelomeningocele-associated hydrocephalus: systematic review and meta-analysis. J Neurosurg Pediatr. 2022 Jan 21:1-9. doi: 10.3171/2021.11.PEDS21505. Epub ahead of print. PMID: 35061994.
2)

Coulter IC, Dewan MC, Tailor J, Ibrahim GM, Kulkarni AV. Endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC) for hydrocephalus of infancy: a technical review. Childs Nerv Syst. 2021 May 15. doi: 10.1007/s00381-021-05209-5. Epub ahead of print. PMID: 33991213.
3)

Dewan MC, Naftel RP. The Global Rise of Endoscopic Third Ventriculostomy with Choroid Plexus Cauterization in Pediatric Hydrocephalus. Pediatr Neurosurg. 2016 Dec 22. doi: 10.1159/000452809. [Epub ahead of print] PubMed PMID: 28002814.
4)

Weil AG, Westwick H, Wang S, Alotaibi NM, Elkaim L, Ibrahim GM, Wang AC, Ariani RT, Crevier L, Myers B, Fallah A. Efficacy and safety of endoscopic third ventriculostomy and choroid plexus cauterization for infantile hydrocephalus: a systematic review and meta-analysis. Childs Nerv Syst. 2016 Nov;32(11):2119-2131. PubMed PMID: 27613635.
5)

Dewan MC, Lim J, Morgan CD, Gannon SR, Shannon CN, Wellons JC 3rd, Naftel RP. Endoscopic third ventriculostomy with choroid plexus cauterization outcome: distinguishing success from failure. J Neurosurg Pediatr. 2016 Dec;25(6):655-662. PubMed PMID: 27564786.
6)

Chamiraju P, Bhatia S, Sandberg DI, Ragheb J. Endoscopic third ventriculostomy and choroid plexus cauterization in posthemorrhagic hydrocephalus of prematurity. J Neurosurg Pediatr. 2014 Apr;13(4):433-9. doi: 10.3171/2013.12.PEDS13219. PubMed PMID: 24527862.
7)

Warf BC. Comparison of endoscopic third ventriculostomy alone and combined with choroid plexus cauterization in infants younger than 1 year of age: a prospective study in 550 African children. J Neurosurg. 2005 Dec;103(6 Suppl):475-81. PubMed PMID: 16383244.

Posterior cervical decompression

Posterior cervical decompression

Not typically used for a herniated cervical disc, more common for cervical spinal stenosisOPLL

● without posterior fusion

● with lateral mass fusion

b) keyhole laminotomy: sometimes permits removal of disc fragment

Usually reserved for the following conditions:

multiple cervical discs or osteophytes (anterior cervical discectomy (ACD) is usually used to treat only 2, or possibly 3, levels without) with myelopathy.

where the anterior pathology is superimposed on cervical stenosis, and the latter is more diffuse and/or more significant

in professional speakers or singers where the 4% risk of permanent voice change due to recurrent laryngeal nerve injury with ACD may be unacceptable.


Laminectomy and facetectomy are commonly used surgical procedures for decompressing cervical spinal stenosis. Resection of the posterior structures causes instability and affects the internal stresses of the cervical spinal components. However, the influence of these surgical procedures on the biomechanical responses of the cervical spine has not been studied.

A nonlinear finite element model of the intact C2-C7 was constructed and validated. Ten surgically altered models were created from the intact model and were tested under physiologic loading. Because of the inclusion of five motion segments, it was possible to determine the intersegmental responses and internal cortical shell and disc stresses in the adjacent altered and unaltered spinal components.

Under combined flexion and extension, intersegmental motions at C4-C5 and C5-C6 increased significantly after C5 laminectomy. Subsequent facetectomy performed at C5 and C6 on the laminectomized model only affected the responses at the C5-C6 segment. Overall, slight intersegmental responses of up to 5% were observed at the adjacent levels of C3-C4 and C6-C7. Laminectomy did not cause any significant increase in the intersegmental motions under lateral bending and axial rotation. Extending the surgical procedures to unilateral and bilateral facetectomy only increased the intersegmental motions slightly. Similar increases in the intervertebral disc and the cortical shell stresses were observed. These findings may partially explain the clinical observations of enhanced osteophytes formation.

This study provides a better understanding of the surgically altered cervical spinal biomechanics and may help formulate treatment strategies such as spinal implants 1).


Its a posterior cervical spine surgery, for cervical spinal stenosis. The spine surgeon removes a small section of the lamina to relieve compression on the nerve. The remaining spinal bones are connected back together with titanium metal rods and screws.

The skin incision is in the midline of the back of the neck and is about 3 to 4 inches long. The paraspinal muscles are then elevated from multiple levels. Removal of the lamina. A high-speed burr can be used to make a trough in the lamina on both sides right before it joins the facet joint. The lamina with the spinous process can then be removed as one piece (like a lobster tail). Removal of the lamina and spinous process allows the spinal cord to float backwards and gives it more room.


Cervical laminectomy resulted in the greatest increase in global cervical ROM. Resection of the intraspinous and supraspinous ligaments [ISLs).ISLs at C2-3 and C7-T1 increased segmental ROM at these specific levels to a similar extent that laminectomy increased ROM at each cervical level. This segmental ROM may contribute to pain or postprocedural deformity and highlights the importance of the ISLs at the terminal ends of the cervical open door laminoplasty (ODL) 2).

Cervical laminectomy complications.

Prone, some use pin head holder

a) C-arm

b) high speed drill

  1. implants: cervical lateral mass screws and rods if fusion is being done

4. neuromonitoring: some surgeons used SSEP/MEP: Use of intra-op EP monitoring during a routine surgery for CSM or cervical radiculopathy is not recommended as an indication to alter the surgical plan or administer steroids since this paradigm has not been observed to reduce the incidence of neurologic injury (Level D Class III).

5. consent (in lay terms for the patient—not all-inclusive):

a) procedure: surgery through the back of the neck to remove the bone over the compressed spinal cord and nerves and possibly to place screws and rods to fuse the boned together

b) alternatives: nonsurgical management, surgery from the front of the neck, posterior surgery without fusion, laminoplasty

c) complications: nerve root weakness (C5 nerve root is the most common), may not relieve symptoms, further surgery may be needed, possible seizures with MEPs. If fusion is not done, there is a risk of progressive bone slippage, which would require further surgery.

Posterior cervical decompression and fusion.

Posterior fossa decompression for Chiari type 1 deformity.


1)

Hong-Wan N, Ee-Chon T, Qing-Hang Z. Biomechanical effects of C2-C7 intersegmental stability due to laminectomy with unilateral and bilateral facetectomy. Spine (Phila Pa 1976). 2004 Aug 15;29(16):1737-45; discussion 1746. PubMed PMID: 15303016.
2)

Healy AT, Lubelski D, West JL, Mageswaran P, Colbrunn R, Mroz TE. Biomechanics of open-door laminoplasty with and without preservation of posterior structures. J Neurosurg Spine. 2016 May;24(5):746-51. doi: 10.3171/2015.7.SPINE15229. Epub 2016 Jan 22. PubMed PMID: 26799115.

Diffuse midline glioma H3 K27M-mutant treatment

Diffuse midline glioma H3 K27M-mutant treatment

Stereotactic biopsy is being performed in some centers, and may become routine when therapies specifically targeted to these mutations become available.

Diffuse midline glioma H3 K27M-mutant have no effective treatment, and their location and diffuse nature render them inoperable. Radiation therapy remains the only standard of care for this devastating disease.

Until recently biopsies were considered not informative enough and therefore not recommended.


Systemic administration of chemotherapeutic agents is often hindered by the blood brain barrier (BBB), and even drugs that successfully cross the barrier may suffer from unpredictable distributions. The challenge in treating this deadly disease relies on effective delivery of a therapeutic agent to the bulk tumor as well as infiltrating cells. Therefore, methods that can enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a strategy that bypasses the BBB entirely and enhances drug distribution by applying hydraulic pressure to deliver agents directly and evenly into a target region. This technique reliably distributes infusate homogenously through the interstitial space of the target region and achieves high local drug concentrations in the brain. Moreover, recent studies have also shown that continuous delivery of drug over an extended period of time is safe, feasible, and more efficacious than standard single session CED. Therefore, CED represents a promising technique for treating midline tumors with the H3K27M mutation 1).


Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma 2).


Although GD2CAR T-cells demonstrated significant anti-tumor activity against Diffuse midline glioma H3 K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. de Billy et al. investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.

Immunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.

GD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual Insulin-like growth factor 1 receptor( IGF1R/IR) antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo and in vivo.

The study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for Diffuse midline glioma H3 K27M-mutant treatment and, potentially, by pHGG 3).


Findings suggest that targeting PLK1 with small-molecule inhibitors, in combination with radiation therapy, will hold a novel strategy in the treatment of Diffuse intrinsic pontine glioma (DIPG) that warrants further investigation 4).


1)

Himes BT, Zhang L, Daniels DJ. Treatment Strategies in Diffuse Midline Gliomas With the H3K27M Mutation: The Role of Convection-Enhanced Delivery in Overcoming Anatomic Challenges. Front Oncol. 2019 Feb 8;9:31. doi: 10.3389/fonc.2019.00031. PMID: 30800634; PMCID: PMC6375835.
2)

Gojo J, Pavelka Z, Zapletalova D, Schmook MT, Mayr L, Madlener S, Kyr M, Vejmelkova K, Smrcka M, Czech T, Dorfer C, Skotakova J, Azizi AA, Chocholous M, Reisinger D, Lastovicka D, Valik D, Haberler C, Peyrl A, Noskova H, Pál K, Jezova M, Veselska R, Kozakova S, Slaby O, Slavc I, Sterba J. Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities. Front Oncol. 2020 Jan 10;9:1436. doi: 10.3389/fonc.2019.01436. PMID: 31998633; PMCID: PMC6965319.
3)

de Billy E, Pellegrino M, Orlando D, Pericoli G, Ferretti R, Businaro P, Ajmone-Cat MA, Rossi S, Petrilli LL, Maestro N, Diomedi-Camassei F, Pezzullo M, De Stefanis C, Bencivenga P, Palma A, Rota R, Del Bufalo F, Massimi L, Weber G, Jones C, Carai A, Caruso S, De Angelis B, Caruana I, Quintarelli C, Mastronuzzi A, Locatelli F, Vinci M. Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant. Neuro Oncol. 2021 Dec 29:noab300. doi: 10.1093/neuonc/noab300. Epub ahead of print. PMID: 34964902.
4)

Amani V, Prince EW, Alimova I, Balakrishnan I, Birks D, Donson AM, Harris P, Levy JM, Handler M, Foreman NK, Venkataraman S, Vibhakar R. Polo-like Kinase 1 as a potential therapeutic target in Diffuse Intrinsic Pontine Glioma. BMC Cancer. 2016 Aug 18;16:647. doi: 10.1186/s12885-016-2690-6. PubMed PMID: 27538997.
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