5-aminolevulinic-acid guided resection

5-aminolevulinic-acid guided resection

In addition to stereotactic localization as well as intraoperative brain mapping, techniques to enhance visual identification of tumor intraoperatively may be used and include 5-aminolevulinic-acid (5-ALA). 5-ALA is metabolized into fluorescent porphyrins, which accumulate in malignant glioma cells. These property permits use of ultraviolet illumination during surgery as an adjunct to map out the tumor. This has been proven with RCT where the use of 5-ALA leads to more complete resection (65% vs. 36%, p < 0.0001), which translates into a higher 6-month progression-free survival (41% vs. 21.1%, p = 0.0003) but no effect on OS 1).


Fluorescein can be used as a viable alternative to 5-ALA for intraoperative fluorescent guidance in brain tumor surgery. Comparative, prospective, and randomized studies are much needed 2)

Indications

Doses

The highest visible and measurable fluorescence was yielded by 20 mg/kg. No fluorescence was elicited at 0.2 mg/kg. Increasing 5-ALA doses did not result in proportional increases in tissue fluorescence or PPIX accumulation in plasma, indicating that doses higher than 20 mg/kg will not elicit useful increases in fluorescence 3).


Application of 5mg/kg ALA was evaluated as equally reliable as the higher dose regarding the diagnostic performance when guidance was performed using a spectroscopic system. Moreover, no PpIX was detected in the skin of the patients 4).

Over time, several other tumour entities have been identified to metabolize 5-ALA and show a similar fluorescence pattern during surgical resection.

Further research is warranted to determine the role of 5-ALA accumulation in post-ischaemic and inflammatory brain tissue 5).

The positive predictive values (PPVs), of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the negative predictive values (NPVs), of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence 6).

Reviews

Senders et al., systematically review all clinically tested fluorescent agents for application in fluorescence guided surgery (FGS) for glioma and all preclinically tested agents with the potential for FGS for glioma.

They searched the PubMed and Embase databases for all potentially relevant studies through March 2016.

They assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.

The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5 aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.

5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives. 7).

Complications

Despite its benefits, 5-ALA has not reached widespread popularity in the United States, primarily because of lack of Food and Drug Administration (FDA) approval. Even if it were approved, 5-ALA does have specific limitations including low depth of penetration, autofluorescence of background parenchyma


Findings suggest that the administration of 5-ALA or the combined effect of 5-ALA, anaesthesia and tumour resection can cause a mild and reversible elevation in liver enzymes. It therefore appears safe to change the regime of monitoring. Routine blood samples are thus abolished, though caution remains necessary in patients with known liver impairment 8).

For near infrared imaging, additional investigators have explored fluorescein as well as novel near-infrared (NIR) agents 9) 10) 11)

Stummer et al. showed that 5–ALA guided resections carry a higher risk of post-operative neurological deterioration than conventional resections (26% vs 15%, respectively), even though the difference vanished within weeks 12).

Just as tumour tissue is often indiscernible from normal brain tissue, functionally critical tissues are indistinguishable from tissues with less clinically relevant functions.

Thus, knowing when to stop a resection due to proximity to areas of crucial neurological functions is of obvious and utmost importance. Detailed knowledge of the normal brain anatomy and distribution of function is not sufficient during glioma resection. Interindividual variability and functional relocation (i.e., plasticity) induced by the presence of an infiltrating tumour 13) requires an exact functional brain map at the site of surgery in order to spare areas involved in crucial (so-called eloquent) functions. Preoperative localisation of function, either with functional MRI (fMRI) or navigated transcranial magnetic stimulation (nTMS), provides an approximate map 14) 15).

Furthermore, intra-operative direct cortical and subcortical electrical stimulation (DCS) for functional analysis of the tissue in the tumour’s infiltration zone is required for accurate identification of areas that need to be spared in order to retain the patient’s functional integrity 16) 17). Motor evoked potentials (MEP) provide real-time information on the integrity of the primary motor cortex and the corticospinal tract 18). Direct cortical mapping and phase reversal identify the primary motor and sensory cortices. Subcortical mapping can estimate the distance to the pyramidal tract, acting as guidance close to functionally critical areas 19). When integrated into the existing surgical tools, continuous and dynamic mapping enables more extensive resection while simultaneously protecting motor function 20). Using these techniques and a detailed electrophysiological “Bern-concept”, a group achieved complete motor function protection in 96% of patients with high-risk motor eloquent tumours 21). Furthermore, localisation of cortical and subcortical regions relevant to language function is essential for speech preservation during resection of gliomas in proximity to presumed speech areas 22) and requires the patient to be awake during the brain mapping part of surgery. Similarly, intra-operative mapping of visual functions may contribute to increased resections while avoiding tissue essential for vision within the temporal and occipital lobes 23).

References

1)

Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ; ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006 May;7(5):392-401. PubMed PMID: 16648043.
2)

Hansen RW, Pedersen CB, Halle B, Korshoej AR, Schulz MK, Kristensen BW, Poulsen FR. Comparison of 5-aminolevulinic acid and sodium fluorescein for intraoperative tumor visualization in patients with high-grade gliomas: a single-center retrospective study. J Neurosurg. 2019 Oct 4:1-8. doi: 10.3171/2019.6.JNS191531. [Epub ahead of print] PubMed PMID: 31585425.
3)

Stummer W, Stepp H, Wiestler OD, Pichlmeier U. Randomized, Prospective Double-Blinded Study Comparing 3 Different Doses of 5-Aminolevulinic Acid for Fluorescence-Guided Resections of Malignant Gliomas. Neurosurgery. 2017 Apr 1. doi: 10.1093/neuros/nyx074. [Epub ahead of print] PubMed PMID: 28379547.
4)

Haj-Hosseini N, Richter J, Hallbeck M, Wårdell K. Low dose 5-aminolevulinic acid: Implications in spectroscopic measurements during brain tumor surgery. Photodiagnosis Photodyn Ther. 2015 Mar 25. pii: S1572-1000(15)00031-9. doi: 10.1016/j.pdpdt.2015.03.004. [Epub ahead of print] PubMed PMID: 25818546.
5)

Behling F, Hennersdorf F, Bornemann A, Tatagiba M, Skardelly M. 5-Aminolevulinic acid accumulation in a cerebral infarction mimicking high-grade glioma, a case report. World Neurosurg. 2016 May 10. pii: S1878-8750(16)30271-6. doi: 10.1016/j.wneu.2016.05.009. [Epub ahead of print] PubMed PMID: 27178236.
6)

Lau D, Hervey-Jumper SL, Chang S, Molinaro AM, McDermott MW, Phillips JJ, Berger MS. A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas. J Neurosurg. 2015 Nov 6:1-10. [Epub ahead of print] PubMed PMID: 26544781.
7)

Senders JT, Muskens IS, Schnoor R, Karhade AV, Cote DJ, Smith TR, Broekman ML. Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results. Acta Neurochir (Wien). 2017 Jan;159(1):151-167. doi: 10.1007/s00701-016-3028-5. Review. PubMed PMID: 27878374; PubMed Central PMCID: PMC5177668.
8)

Offersen CM, Skjoeth-Rasmussen J. Evaluation of the risk of liver damage from the use of 5-aminolevulinic acid for intra-operative identification and resection in patients with malignant gliomas. Acta Neurochir (Wien). 2016 Nov 10. [Epub ahead of print] PubMed PMID: 27832337.
9)

Shinoda J, Yano H, Yoshimura SI, et al. Fluorescence-guided resection of glioblastoma multiforme by using high-dose fluorescein sodium. Technical note. J Neurosurg. 2003;99(3):597–603.
10)

Rey-Dios R, Cohen-Gadol AA. Technical principles and neurosurgical applications of fluorescein fluorescence using a microscope-integrated fluorescence module. Acta Neurochir (Wien). 2013;155(4):701–706.
11)

Swanson KI, Clark PA, Zhang RR, et al. Fluorescent cancer-selective alkylphosphocholine analogs for intraoperative glioma detection. Neurosurgery. 2015;76(2):115–123.
12)

Stummer W1, Tonn JC, Mehdorn HM, Nestler U, Franz K, Goetz C, et al. ALA-Glioma Study Group. Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5–aminolevulinic acid glioma resection study. J Neurosurg. 2011;114(3):613–23. doi: 10.3171/2010.3
13)

Ojemann G, Ojemann J, Lettich E, Berger M. Cortical language localization in left, dominant hemisphere. An electrical stimulation mapping investigation in 117 patients. J Neurosurg. 1989;71(3):316–26.
14)

Seghier ML, Lazeyras F, Pegna AJ, Annoni JM, Zimine I, Mayer E, et al. Variability of fMRI activation during a phonological and semantic language task in healthy subjects. Hum Brain Mapp. 2004;23(3):140–55.
15)

Krieg SM, Shiban E, Buchmann N, Gempt J, Foerschler A, Meyer B, et al. Utility of presurgical navigated transcranial magnetic brain stimulation for the resection of tumors in eloquent motor areas. J Neurosurg. 2012;116(5):994–1001. doi: 10.3171/2011.12.JNS111524
16) , 22)

Duffau H, Capelle L, Sichez N, Denvil D, Lopes M, Sichez JP, et al. Intraoperative mapping of the subcortical language pathways using direct stimulations. An anatomo-functional study. Brain. 2002;125(1):199–214.
17)

Duffau H, Capelle L, Denvil D, Sichez N, Gatignol P, Taillandier L, et al. Usefulness of intraoperative electrical subcortical mapping during surgery for low-grade gliomas located within eloquent brain regions: functional results in a consecutive series of 103 patients. J Neurosurg. 2003;98(4):764–78.
18)

Seidel K, Beck J, Stieglitz L, Schucht P, Raabe A. The warning-sign hierarchy between quantitative subcortical motor mapping and continuous motor evoked potential monitoring during resection of supratentorial brain tumors. J Neurosurg. 2013;118(2):287–96.
19)

Seidel K, Beck J, Stieglitz L, Schucht P, Raabe A. Low Threshold Monopolar Motor Mapping for Resection of Primary Motor Cortex Tumors. Neurosurgery. 2012;71(1):104–14.
20)

Raabe A, Beck J, Schucht P, Seidel K. Continuous dynamic mapping of the corticospinal tract during surgery of motor eloquent brain tumors: evaluation of a new method. J Neurosurg. 2014;120(5)1015–24. doi: 10.3171/2014.1.JNS13909.
21)

Schucht P, Seidel K. Beck J, Murek M, Jilch A, Wiest R, et al. Intraoperative monopolar mapping during 5-ALA-guided resections of glioblastomas adjacent to motor eloquent areas: evaluation of resection rates and neurological outcome. Neurosurg Focus. 2014;27(6):E16.
23)

Gras-Combe G, Moritz-Gasser S, Herbet G, Duffau H. Intraoperative subcortical electrical mapping of optic radiations in awake surgery for glioma involving visual pathways. J Neurosurg. 2012;117(3):466–73.

Stereoelectroencephalography guided radiofrequency thermocoagulation

Stereoelectroencephalography guided radiofrequency thermocoagulation

stereoelectroencephalography.jpg

Indications

Concerns about the impact of open surgery for drug-resistant mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) have driven interest in minimally invasive techniques. Stereoelectroencephalography guided radiofrequency thermocoagulation (SEEG guided RF-TC) offers an alternative choice but with currently limited efficacy. Fan et al. developed a procedure for optimally extended thermocoagulation lesions and investigated the efficacy and safety of MTLE-HS in a preliminary observational study. Optimized SEEG-guided RF-TC is a promising complementary option for the treatment of MTLE-HS 1).


Despite the increasing number of studies reporting results of stereo-electroencephalography (SEEG)-guided radiofrequency-thermocoagulation (SEEG-guided RF-TC) in the treatment of patients with drug-resistant focal epilepsy, the exact efficacy of this approach remains unclear. The seizure-freedom rate varies greatly across studies and the factors associated with efficacy have not been formally investigated.

All prospective or retrospective studies reporting efficacy and/or safety of SEEG-guided RF-TC in patients with drug-resistant focal epilepsy were included. The primary outcome was the seizure-free rate 1 year after the procedure. Secondary outcomes were (1) the responder rate 1 year after the procedure and (2) the proportion of patients with permanent neurologic deficit 1 year after the procedure. Each outcome was assessed in all patients and in 4 groups of patients defined by the etiology of epilepsy. Each outcome was pooled using inverse variance weighting, logit transformation of proportion, and a random-effects model.

No prospective study was identified and a total of 6 retrospective studies, reporting efficacy and safety data of 296 patients, were included. The pooled rate of permanent neurologic deficit was 2.5% (95% confidence interval [CI] 1.2%-5.3%), without heterogeneity across studies. In contrast, both the seizure-free and responder rates varied greatly across studies, and statistical heterogeneity was high. The pooled seizure-free and responder rates were 23% (95% CI 8%-50%) and 58% (95% CI 36%-77%), respectively. Both for the seizure-free and responder rates, the greatest efficacy was observed in patients with periventricular nodular heterotopia and the lowest in patients with normal magnetic resonance imaging (MRI) findings.

SEEG-guided RF-TC is a safe procedure with low risk of complications. In contrast, the level of evidence regarding its efficacy remains low. Better identification of factors associated with seizure outcome are needed 2).

Case series

From June 2016 to August 2017, twenty-two patients were selected for the present study. They met the criteria of unilateral MTLE-HS after noninvasive evaluation and then underwent implantation of a combination of SEEG electrodes to form a high-density focal stereo-array, including one electrode along the long axis of amygdalohippocampal complex and three orthogonal electrodes to widely sample mesial temporal structures. A unilateral epileptogenic zone of mesial temporal structures was confirmed in these 21 patients. SEEG-guided bipolar coagulations were performed between two contiguous contacts of the same electrode, or between two adjacent contacts of different electrodes.

Surgical procedures were well tolerated, with no related complications. At the follow-up of 12 months, 20 patients (95.2%) experienced a >90% decrease in seizure frequency and 16 patients (76.2%) were free of disabling seizures (Engel class I). Among them, eight (38.1%) were classified as Engel class Ia and the other eight (38.1%) as Engel class Ib. Four others (19%) had rare disabling seizures (Engel class II). Only one (4.8%) experienced an Engel class III outcome.

Optimized SEEG-guided RF-TC is a promising complementary option for the treatment of MTLE-HS 3).

References

1) , 3)

Fan X, Shan Y, Lu C, An Y, Wang Y, Du J, Wang D, Wei P, Fisher RS, Wang Y, Ren L, Zhao G. Optimized SEEG-guided radiofrequency thermocoagulation for mesial temporal lobe epilepsy with hippocampal sclerosis. Seizure. 2019 Aug 30;71:304-311. doi: 10.1016/j.seizure.2019.08.011. [Epub ahead of print] PubMed PMID: 31521052.
2)

Bourdillon P, Cucherat M, Isnard J, Ostrowsky-Coste K, Catenoix H, Guénot M, Rheims S. Stereo-electroencephalography-guided radiofrequency thermocoagulation in patients with focal epilepsy: A systematic review and meta-analysis. Epilepsia. 2018 Dec;59(12):2296-2304. doi: 10.1111/epi.14584. Epub 2018 Oct 21. PubMed PMID: 30345535.

Magnetic resonance guided focused ultrasound thalamotomy for essential tremor

Magnetic resonance guided focused ultrasound thalamotomy for essential tremor

Magnetic resonance guided focused ultrasound is a minimally invasive surgical procedure for symptomatic treatment of Parkinson Disease. With this technology, the ventral intermediate nucleusSTN, and internal globus pallidus have been targeted for therapeutic cerebral ablation, while also minimizing the risk of hemorrhage and infection from more invasive neurosurgical procedures.

In a pilot study published in 2013, essential tremor improved in 15 patients treated with magnetic resonance guided focused ultrasound thalamotomy1).

Clinical trials have confirmed the efficacy of focused ultrasound (FUS) thalamotomy in essential tremor, but its effectiveness and safety for managing tremor-dominant Parkinson disease (TDPD) is unknown.

It might change the way that patients with essential tremor and potentially other disorders are treated 2).

Effectiveness

The post-treatment effectiveness was evaluated using the clinical rating scale for tremors. Thalamic MRgHIFU had substantial therapeutic effects on patients, based on MRgHIFU-mediated improvements in movement control and significant changes in brain mu rhythms. Ultrasonic thalamotomy may reduce hyper-excitable activity in the motor cortex, resulting in normalized behavioral activity after sonication treatment. Thus, non-invasive and spatially accurate MRgHIFU technology can serve as a potent therapeutic tool with broad clinical applications 3).

Safety

Magnetic resonance guided focused ultrasound (MRgFUS) for thalamotomy is a safe, effective and less-invasive surgical method for treating medication-refractory essential tremor (ET). However, several issues must be resolved before clinical application of MRgFUS, including optimal patient selection and management of patients during treatment 4).

Jung et al. found different MRI pattern evolution after MRgFUS for white matter and gray matter. Their results suggest that skull characteristics, such as low skull density, should be evaluated prior to MRgFUS to successfully achieve thermal rise 5).

Nursing management

In a large academic medical center in the mid-Atlantic region, the Department of Neurosurgery conducted a continued access study, recently approved by the Food and Drug Administration, to evaluate the effectiveness of transcranial FUS thalamotomy for the treatment of medication-refractory ET.

One patient’s experience will be introduced, including discussion of evidence-based treatment options for ET and information on the nursing management of the patient undergoing FUS thalamotomy 6).

Prospective randomized clinical trials

In a double-blinded, prospective, sham-controlled randomized controlled trial of MR-guided focused ultrasound thalamotomy for treatment of tremor-dominant PD, 62% of treated patients demonstrated improvement in tremor scores from baseline to 3 months postoperatively, as compared to 22% in the sham group. There has been only one open-label trial of MR-guided focused ultrasound subthalamotomy for patients with PD, demonstrating improvements of 71% for rigidity, 36% for akinesia, and 77% for tremor 6 months after treatment. Among the two open-label trials of MR-guided focused ultrasound pallidotomy for patients with PD, dyskinesia and overall motor scores improved up to 52% and 45% at 6 months postoperatively. Although MR-guided focused ultrasound thalamotomy is now approved by the U.S. Food and Drug Administration for treatment of parkinsonian tremor, additional high-quality randomized controlled trials are warranted and are underway to determine the safety and efficacy of MR-guided focused ultrasound subthalamotomy and pallidotomy for treatment of the cardinal features of PD. These studies will be paramount to aid clinicians to determine the ideal ablative target for individual patients. Additional work will be required to assess the durability of MR-guided focused ultrasound lesions, ideal timing of MR-guided focused ultrasound ablation in the course of PD, and the safety of performing bilateral lesions 7).

Case series

References

1)

Elias WJ, Huss D, Voss T, Loomba J, Khaled M, Zadicario E, Frysinger RC, Sperling SA, Wylie S, Monteith SJ, Druzgal J, Shah BB, Harrison M, Wintermark M. A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med. 2013 Aug 15;369(7):640-8. doi: 10.1056/NEJMoa1300962. PubMed PMID: 23944301.
2)

Lipsman N, Schwartz ML, Huang Y, Lee L, Sankar T, Chapman M, Hynynen K, Lozano AM. MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study. Lancet Neurol. 2013 May;12(5):462-8. doi: 10.1016/S1474-4422(13)70048-6. Epub 2013 Mar 21. PubMed PMID: 23523144.
3)

Chang JW, Min BK, Kim BS, Chang WS, Lee YH. Neurophysiologic correlates of sonication treatment in patients with essential tremor. Ultrasound Med Biol. 2015 Jan;41(1):124-31. doi: 10.1016/j.ultrasmedbio.2014.08.008. Epub 2014 Oct 22. PubMed PMID: 25438838.
4)

Chang WS, Jung HH, Kweon EJ, Zadicario E, Rachmilevitch I, Chang JW. Unilateral magnetic resonance guided focused ultrasound thalamotomy for essential tremor: practices and clinicoradiological outcomes. J Neurol Neurosurg Psychiatry. 2015 Mar;86(3):257-64. doi: 10.1136/jnnp-2014-307642. Epub 2014 May 29. PubMed PMID: 24876191.
5)

Jung HH, Chang WS, Rachmilevitch I, Tlusty T, Zadicario E, Chang JW. Different magnetic resonance imaging patterns after transcranial magnetic resonance-guided focused ultrasound of the ventral intermediate nucleus of the thalamus and anterior limb of the internal capsule in patients with essential tremor or obsessive-compulsive disorder. J Neurosurg. 2015 Jan;122(1):162-8. doi: 10.3171/2014.8.JNS132603. PubMed PMID: 25343176.
6)

Shaw KD, Johnston AS, Rush-Evans S, Prather S, Maynard K. Nursing Management of the Patient Undergoing Focused Ultrasound: A New Treatment Option for Essential Tremor. J Neurosci Nurs. 2017 Aug 16. doi: 10.1097/JNN.0000000000000301. [Epub ahead of print] PubMed PMID: 28817495.
7)

Moosa S, Martínez-Fernández R, Elias WJ, Del Alamo M, Eisenberg HM, Fishman PS. The role of high-intensity focused ultrasound as a symptomatic treatment for Parkinson’s disease. Mov Disord. 2019 Jul 10. doi: 10.1002/mds.27779. [Epub ahead of print] Review. PubMed PMID: 31291491.
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