Brain metastases recurrence diagnosis

Brain metastases recurrence diagnosis

It is difficult to differentiate local brain metastases recurrence from radiation induced-changes in case of suspicious contrast enhancement. New advanced MRI techniques (perfusion and spectrometry) and Amino Acid Positron Emission tomography allow to be more accurate and could avoid a stereotactic biopsy for histological assessment, the only reliable but invasive method.

Whereas positron emission tomography (PET) with the widely used 18F-2-deoxy-2-fluoro-D-glucose (18F-FDG) has low diagnostic accuracy after SRS, the use of radiolabelled amino acids or amino acid analogues such as L-methyl-11C-methionine (11C-MET) and O-(2-18F-Fluoroethyl)-L-Tyrosine (18F-FET) reaches sensitivity and specificity values in the range of 78 and 100 % rendering especially 18F-FET a highly reliable tracer in glioma imaging.


In patients with MRI-suspected tumor recurrence after focused high dose radiotherapy, 18F-FET PET has a high sensitivity and specificity for the differentiation of vital tumor tissue and radiation-induced lesions 1).


Tran et al. performed a feasibility study to prospectively evaluate 11C methionine positron emission tomography and11C PBR28 positron emission tomography in 5 patients with 7 previously SRS-treated brain metastases demonstrating regrowth to differentiate tumor regrowth (TR) from radiation necrosis (RN).

Sequential imaging with dual tracers was well-tolerated. [11C]methionine was accurate for detecting pathologically confirmed TR in 7/7 lesions, whereas [11C]PBR28 was only accurate in 3/7 lesions. Tumor PBRTSPO expression was elevated in both melanoma and lung cancer cells, contributing to lack of specificity of [11C]PBR28-PET.

Sequential use of PET tracers is safe and effective. [11C]Methionine was a reliable TR marker, but [11C]PBR28 was not a reliable marker of RN. Studies are needed to determine the causes of post-radiation inflammation and identify specific markers of RN to improve diagnostic imaging 2).

The multimodal MRI has greatly contributed to refine the differential diagnosis between tumour recurrence and radionecrosis, which remains difficult. The FDG PET is helpful, in favour of the diagnosis of local tumour recurrence when a hypermetabolic lesion is found. Others tracers (such as carbon 11 or a fluoride isotope) deserve interest but are not available in all centres. Stereotactic biopsy should be discussed if any doubt remains 3).

An increase in FLAIR signal of the fluid within the resection cavity might be a highly specific and early sign of local tumor recurrence/tumor progression also for brain metastases. 4).


1)

Romagna A, Unterrainer M, Schmid-Tannwald C, Brendel M, Tonn JC, Nachbichler SB, Muacevic A, Bartenstein P, Kreth FW, Albert NL. Suspected recurrence of brain metastases after focused high dose radiotherapy: can [18F]FET- PET overcome diagnostic uncertainties? Radiat Oncol. 2016 Oct 21;11(1):139. doi: 10.1186/s13014-016-0713-8. PMID: 27769279; PMCID: PMC5073742.
2)

Tran TT, Gallezot JD, Jilaveanu LB, Zito C, Turcu G, Lim K, Nabulsi N, Huang H, Huttner A, Kluger HM, Chiang VL, Carson R. [11C]Methionine and [11C]PBR28 as PET Imaging Tracers to Differentiate Metastatic Tumor Recurrence or Radiation Necrosis. Mol Imaging. 2020 Jan-Dec;19:1536012120968669. doi: 10.1177/1536012120968669. PMID: 33147119.
3)

Patsouris A, Augereau P, Tanguy JY, Morel O, Menei P, Rousseau A, Paumier A. [Differentiation from local tumour recurrence and radionecrosis after stereotactic radiosurgery for treatment of brain metastasis.]. Cancer Radiother. 2014 Jan 13. pii: S1278-3218(13)00444-7. doi: 10.1016/j.canrad.2013.10.013. [Epub ahead of print] French. PubMed PMID: 24433952.
4)

Bette S, Gempt J, Wiestler B, Huber T, Specht H, Meyer B, Zimmer C, Kirschke JS, Boeckh-Behrens T. Increase in FLAIR Signal of the Fluid Within the Resection Cavity as Early Recurrence Marker: Also Valid for Brain Metastases? Rofo. 2017 Jan;189(1):63-70. doi: 10.1055/s-0042-119686. PubMed PMID: 28002859.

Severe traumatic brain injury outcome

Severe traumatic brain injury outcome

Younger age, modified Fisher scale (mFS) score, and Intracerebral hemorrhage volume are associated with Intracranial pressure elevation in patients with a severe traumatic brain injury. Imaging features may stratify patients by their risk of subsequent ICP elevation 1).


There has been a secular trend towards reduced incidence of severe traumatic brain injury in the first world, driven by public health interventions such as seatbelt legislation, helmet use, and workplace health and safety regulations. This has paralleled improved outcomes following TBI delivered in a large part by the widespread establishment of specialised neurointensive care 2).

The impact of a moderate to severe brain injury depends on the following:

Severity of initial injury

Rate/completeness of physiological recovery

Functions affected

Meaning of dysfunction to the individual

Resources available to aid recovery

Areas of function not affected by TBI

see Effect of trauma center designation in severe traumatic brain injury outcome


Mortality or severe disability affects the majority of patients after severe traumatic brain injury (TBI). Adherence to the brain trauma foundation severe traumatic brain injury guidelines has overall improved outcomes; however, traditional as well as novel interventions towards intracranial hypertension and secondary brain injury have come under scrutiny after series of negative randomized controlled trials. In fact, it would not be unfair to say there has been no single major breakthrough in the management of severe TBI in the last two decades. One plausible hypothesis for the aforementioned failures is that by the time treatment is initiated for neuroprotection, or physiologic optimization, irreversible brain injury has already set in. Lazaridis et al., and others, have developed predictive models based on machine learning from continuous time series of intracranial pressure and partial pressure of brain tissue oxygen. These models provide accurate predictions of physiologic crises events in a timely fashion, offering the opportunity for an earlier application of targeted interventions. In a article, Lazaridis et al., review the rationale for prediction, discuss available predictive models with examples, and offer suggestions for their future prospective testing in conjunction with preventive clinical algorithms 3).


Determining the prognostic significance of clinical factors for patients with severe head injury can lead to an improved understanding of the pathophysiology of head injury and to improvement in therapy. A technique known as the sequential Bayes method has been used previously for the purpose of prognosis. The application of this method assumes that prognostic factors are statistically independent. It is now known that they are not. Violation of the assumption of independence may produce errors in determining prognosis. As an alternative technique for predicting the outcome of patients with severe head injury, a logistic regression model is proposed. A preliminary evaluation of the method using data from 115 patients with head injury shows the feasibility of using early data to predict outcome accurately and of being able to rank input variables in order of their prognostc significance. 4).


A prospective and consecutive series of 225 patients with severe head injuries who were managed in a uniform way was analyzed to relate outcome to several clinical variables. Good recovery or moderate disability were achieved by 56% of the patients, 10% remained severely disabled or vegetative, and 34% died. Factors important in predicting a poor outcome included the presence of intracranial hematoma, increasing age, motor impairment, impaired or absent eye movements or pupillary light reflexes, early hypotension, hypoxemia or hypercarbia, and raised intracranial pressure over 20 mm Hg despite artificial ventilation. Most of these predictive factors were assessed on admission, but a subset of 158 patients was identified in whom coma was present on admission and was known to have persisted at least until the following day. Although the mortality in this subset (40%) was higher than in the total series, it was lower than in several comparable reported series of patients with severe head injury. Predictive correlations were equally strong in the entire series and in the subset of 158 patients with coma. A plea is made for inclusion in the definition of “severe head injury” of all patients who do not obey commands or utter recognizable words on admission to the hospital after early resuscitation 5).


Survival rate of isolated severe TBI patients who required an emergent neurosurgical intervention could be time dependent. These patients might benefit from expedited process (computed tomographic scan, neurosurgical consultation, etc.) to shorten the time to surgical intervention 6).

The impact of a moderate to severe brain injury can include:

Cognitive deficits including difficulties with:

Attention Concentration Distractibility Memory Speed of Processing Confusion Perseveration Impulsiveness Language Processing “Executive functions” Speech and Language

not understanding the spoken word (receptive aphasia) difficulty speaking and being understood (expressive aphasia) slurred speech speaking very fast or very slow problems reading problems writing Sensory

difficulties with interpretation of touch, temperature, movement, limb position and fine discrimination Perceptual

the integration or patterning of sensory impressions into psychologically meaningful data Vision

partial or total loss of vision weakness of eye muscles and double vision (diplopia) blurred vision problems judging distance involuntary eye movements (nystagmus) intolerance of light (photophobia) Hearing

decrease or loss of hearing ringing in the ears (tinnitus) increased sensitivity to sounds Smell

loss or diminished sense of smell (anosmia) Taste

loss or diminished sense of taste Seizures

the convulsions associated with epilepsy that can be several types and can involve disruption in consciousness, sensory perception, or motor movements Physical Changes

Physical paralysis/spasticity Chronic pain Control of bowel and bladder Sleep disorders Loss of stamina Appetite changes Regulation of body temperature Menstrual difficulties Social-Emotional

Dependent behaviors Emotional ability Lack of motivation Irritability Aggression Depression Disinhibition Denial/lack of awareness


Both single predictors from early clinical examination and multiple hospitalization variables/parameters can be used to determine the long-term prognosis of TBI. Predictive models like the IMPACT or CRASH prognosis calculator (based on large sample sizes) can predict mortality and unfavorable outcomes. Moreover, imaging techniques like MRI (Magnetic Resonance Imaging) can also predict consciousness recovery and mental recovery in severe TBI, while biomarkers associated with stress correlate with, and hence can be used to predict, severity and mortality. All predictors have limitations in clinical application. Further studies comparing different predictors and models are required to resolve limitations of current predictors 7).


1)

Murray NM, Wolman DN, Mlynash M, Threlkeld ZD, Christensen S, Heit JJ, Harris OA, Hirsch KG. Early Head Computed Tomography Abnormalities Associated with Elevated Intracranial Pressure in Severe Traumatic Brain Injury. J Neuroimaging. 2020 Nov 4. doi: 10.1111/jon.12799. Epub ahead of print. PMID: 33146933.
2)

Khellaf A, Khan DZ, Helmy A. Recent advances in traumatic brain injury. J Neurol. 2019 Sep 28. doi: 10.1007/s00415-019-09541-4. [Epub ahead of print] PubMed PMID: 31563989.
3)

Lazaridis C, Rusin CG, Robertson CS. Secondary Brain Injury: Predicting and Preventing Insults. Neuropharmacology. 2018 Jun 6. pii: S0028-3908(18)30279-X. doi: 10.1016/j.neuropharm.2018.06.005. [Epub ahead of print] Review. PubMed PMID: 29885419.
4)

Stablein DM, Miller JD, Choi SC, Becker DP. Statistical methods for determining prognosis in severe head injury. Neurosurgery. 1980 Mar;6(3):243-8. PubMed PMID: 6770283.
5)

Miller JD, Butterworth JF, Gudeman SK, Faulkner JE, Choi SC, Selhorst JB, Harbison JW, Lutz HA, Young HF, Becker DP. Further experience in the management of severe head injury. J Neurosurg. 1981 Mar;54(3):289-99. PubMed PMID: 7463128.
6)

Matsushima K, Inaba K, Siboni S, Skiada D, Strumwasser AM, Magee GA, Sung GY, Benjaminm ER, Lam L, Demetriades D. Emergent operation for isolated severe traumatic brain injury: Does time matter? J Trauma Acute Care Surg. 2015 Aug 28. [Epub ahead of print] PubMed PMID: 26317818.
7)

Gao L, Wu X. Prediction of clinical outcome in severe traumatic brain injury. Front Biosci (Landmark Ed). 2015 Jan 1;20:763-771. PubMed PMID: 25553477.

Asleep subthalamic deep brain stimulation for Parkinson’s disease

Asleep subthalamic deep brain stimulation for Parkinson’s disease

Recent advances in methods used for deep brain stimulation (DBS) include subthalamic nucleus electrode implantation in the “asleep” patient without the traditional use of microelectrode recordings or intraoperative test stimulation.

Meta-Analysis

2019

Liu et al. systematically reviewed the literature to compare the efficacy and safety of awake and asleep deep brain stimulation surgery. They identified cohort studies from the Cochrane libraryMEDLINE, and EMBASE (January 1970 to August 2019) by using Review Manager 5.3 software to conduct a meta-analysis following the PRISMA guidelines. Fourteen cohort studies involving 1,523 patients were included. The meta-analysis results showed that there were no significant differences between the GA and LA groups in UPDRSIII score improvement (standard mean difference [SMD] 0.06; 95% CI -0.16 to 0.28; p = 0.60), postoperative LEDD requirement (SMD -0.17; 95% CI -0.44 to 0.12; p = 0.23), or operation time (SMD 0.18; 95% CI -0.31 to 0.67; p = 0.47). Additionally, there was no significant difference in the incidence of adverse events (OR 0.98; 95% CI 0.53-1.80; p = 0.94), including postoperative speech disturbance and intracranial hemorrhage. However, the volume of intracranial air was significantly lower in the GA group than that in the LA group. In a subgroup analysis, there was no significant difference in clinical efficacy between the microelectrode recording (MER) and non-MER groups. We demonstrated equivalent clinical outcomes of DBS surgery between GA and LA in terms of improvement of symptoms and the incidence of adverse events. Key Messages: MER might not be necessary for DBS implantation. For patients who cannot tolerate DBS surgery while being awake, GA should be an appropriate alternative 1).

Case series

A retrospective review of clinical outcomes of 152 consecutive patients. Their outcomes at 1 yr postimplantation are reported; these include Unified Parkinson’s Disease Rating Scale (UPDRS) assessment, Mobility Tinetti TestPDQ-39 quality of life assessment, Mattis Dementia Rating ScaleBeck Depression Inventory, and Beck Anxiety Inventory. They also report on a new parietal trajectory for electrode implantation.

UPDRS III improved from 39 to 20.5 (47%, P < .001). The total UPDRS score improved from 67.6 to 36.4 (46%, P < .001). UPDRS II scores improved from 18.9 to 10.5 (44%, P < .001) and UPDRS IV scores improved from 7.1 to 3.6 (49%, P < .001). There was a significant reduction in levodopa equivalent daily dose after surgery (mean: 35%, P < .001). PDQ-39 summary index improved by a mean of 7.1 points. There was no significant difference found in clinical outcomes between the frontal and parietal approaches.

“Asleep” robot-assisted DBS of the subthalamic nucleus demonstrates comparable outcomes with traditional techniques in the treatment of Parkinson’s disease. 2).


The objective of a study of Senemmar et al. was to investigate whether asleep deep brain stimulation surgery of the subthalamic nucleus (STN) improves therapeutic window (TW) for both directional (dDBS) and omnidirectional (oDBS) stimulation in a large single-center population.

A total of 104 consecutive patients with Parkinson’s disease (PD) undergoing STN-DBS surgery (80 asleep and 24 awake) were compared regarding TW, therapeutic thresholdside effect threshold, improvement of Unified PD Rating Scale motor score (UPDRS-III) and degree of levodopa equivalent daily dose (LEDD) reduction.

Asleep DBS surgery led to significantly wider TW compared to awake surgery for both dDBS and oDBS. However, dDBS further increased TW compared to oDBS in the asleep group only and not in the awake group. Clinical efficacy in terms of UPDRS-III improvement and LEDD reduction did not differ between groups.

The study provides first evidence for improvement of therapeutic window by asleep surgery compared to awake surgery, which can be strengthened further by dDBS. These results support the notion of preferring asleep over awake surgery but needs to be confirmed by prospective trial3).


Clinical outcome studies have shown that “asleep” DBS lead placement, performed using intraoperative imaging with stereotactic accuracy as the surgical endpoint, has motor outcomes comparable to traditional “awake” DBS using microelectrode recording (MER), but with shorter case times and improved speech fluency 4).


Ninety-six patients were retrospectively matched pairwise (48 asleep and 48 awake) and compared regarding improvement of Unified PD Rating Scale Motor Score (UPDRS-III), cognitive function, Levodopa-equivalent-daily-dose (LEDD), stimulation amplitudes, side effects, surgery duration, and complication rates. Routine testing took place at three months and one year postoperatively.

Results: Chronic DBS effects (UPDRS-III without medication and with stimulation on [OFF/ON]) significantly improved UPDRS-III only after awake surgery at three months and in both groups one year postoperatively. Acute effects (percentage UPDRS-III reduction after activation of stimulation) were also significantly better after awake surgery at three months but not at one year compared to asleep surgery. UPDRS-III subitems “freezing” and “speech” were significantly worse after asleep surgery at three months and one year, respectively. LEDD was significantly lower after awake surgery only one week postoperatively. The other measures did not differ between groups.

Overall motor function improved faster in the awake surgery group, but the difference ceased after one year. However, axial subitems were worse in the asleep surgery group suggesting that worsening of axial symptoms was risked improving overall motor function. Awake surgery still seems advantageous for STN-DBS in PD, although asleep surgery may be considered with lower threshold in patients not suitable for awake surgery 5).

References

1)

Liu Z, He S, Li L. General Anesthesia versus Local Anesthesia for Deep Brain Stimulation in Parkinson’s Disease: A Meta-Analysis. Stereotact Funct Neurosurg. 2019;97(5-6):381-390. doi:10.1159/000505079
2)

Moran CH, Pietrzyk M, Sarangmat N, Gerard CS, Barua N, Ashida R, Whone A, Szewczyk-Krolikowski K, Mooney L, Gill SS. Clinical Outcome of “Asleep” Deep Brain Stimulation for Parkinson Disease Using Robot-Assisted Delivery and Anatomic Targeting of the Subthalamic Nucleus: A Series of 152 Patients. Neurosurgery. 2020 Sep 28:nyaa367. doi: 10.1093/neuros/nyaa367. Epub ahead of print. PMID: 32985669.
3)

Senemmar F, Hartmann CJ, Slotty PJ, Vesper J, Schnitzler A, Groiss SJ. Asleep Surgery May Improve the Therapeutic Window for Deep Brain Stimulation of the Subthalamic Nucleus [published online ahead of print, 2020 Jul 13]. Neuromodulation. 2020;10.1111/ner.13237. doi:10.1111/ner.13237
4)

Mirzadeh Z, Chen T, Chapple KM, Lambert M, Karis JP, Dhall R, Ponce FA. Procedural Variables Influencing Stereotactic Accuracy and Efficiency in Deep Brain Stimulation Surgery. Oper Neurosurg (Hagerstown). 2018 Oct 18. doi: 10.1093/ons/opy291. [Epub ahead of print] PubMed PMID: 30339204.
5)

Blasberg F, Wojtecki L, Elben S, Slotty PJ, Vesper J, Schnitzler A, Groiss SJ. Comparison of Awake vs. Asleep Surgery for Subthalamic Deep Brain Stimulation in Parkinson’s Disease. Neuromodulation. 2018 Aug;21(6):541-547. doi: 10.1111/ner.12766. Epub 2018 Mar 13. PubMed PMID: 29532
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