5-Aminolevulinic Acid-Induced Fluorescence in Focal Cortical Dysplasia: Report of 3 Cases

Abstract

Background: Three patients enrolled in a clinical trial of 5-aminolevulinic-acid (5-ALA)-induced fluorescence-guidance, which has been demonstrated to facilitate intracranial tumor resection, were found on neuropathological examination to have focal cortical dysplasia (FCD).

Objective: To evaluate in this case series visible fluorescence and quantitative levels of protoporphyrin IX (PpIX) during surgery and correlate these findings with preoperative magnetic resonance imaging (MRI) and histopathology.

Methods: Patients were administered 5-ALA (20 mg/kg) approximately 3 h prior to surgery and underwent image-guided, microsurgical resection of their MRI- and electrophysiologically identified lesions. Intraoperative visible fluorescence was evaluated using an operating microscope adapted with a commercially available blue light module. Quantitative PpIX levels were assessed using a handheld fiber-optic probe and a wide-field imaging spectrometer. Sites of fluorescence measurements were co-registered with both preoperative MRI and histopathological analysis.

Results: Three patients with a pathologically confirmed diagnosis of FCD (Types 1b, 2a, and 2b) underwent surgery. All patients demonstrated some degree of visible fluorescence (faint or moderate), and all patients had quantitatively elevated concentrations of PpIX. No evidence of neoplasia was identified on histopathology, and in 1 patient, the highest concentrations of PpIX were found at a tissue site with marked gliosis but no typical histological features of FCD.

Conclusion: FCD has been found to be associated with intraoperative 5-ALA-induced visible fluorescence and quantitatively confirmed elevated concentrations of the fluorophore PpIX in 3 patients. This finding suggests that there may be a role for fluorescence-guidance during surgical intervention for epilepsy-associated FCD.

Keywords: 5-Aminolevulinic acid; Epilepsy; Fluorescence guided surgery; Focal cortical dysplasia; Optical spectroscopy; Protoporphyrin IX.

FIGURE 1.

Case 1. The preoperative magnetic resonance imaging (MRI) shows a nonenhancing, multicystic, T2-hyperintense mass in the region of the left anterior hippocampus and amygdala. A, Fast inversion-recovery-prepared 3-dimensional gradient echo with gadolinium contrast-enhancement, axial plane. B, Axial T2W.

FIGURE 2.

Case 1. A, White light image through the operating microscope of the surgical field during resection. B, Blue light image of the same surgical field demonstrating visible fluorescence of the lesion. C, Axial reformatted MRI corresponding to the intraoperative location of operating microscope.

FIGURE 3.

Case 1. Micrograph of representative H & E—stained slide of surgical specimen with abnormal tangential cortical lamination, mild gliosis, and corpora amylacea. No balloon cells or huge neurons were present. The pathological diagnosis was focal cortical dysplasia (FCD) Type 1b.

FIGURE 4.

Case 2. Preoperative MRI. A, Axial T1W spin echo postgadolinium MRI showing thickening of the left frontal cortex and blurring of the gray–white junction. There is no contrast enhancement. B, Axial T2W Fluid Attenuation Inversion Recovery (FLAIR) with increased signal intensity demonstrating the left frontal lesion.

FIGURE 5.

Case 2. Intraoperative probe spectroscopy. A, A blue-light image of the surgical field through the operating microscope during lesion resection shows the hand-held probe at the point of highest measured protoporphyrin IX (PpIX) concentration in this case. The white arrow points to the tissue being interrogated by the tip of the probe (a hand-held suction coming in from the bottom left is seen below). B, Spectra from the same site. The continuous, red line spectrum represents the actual measured data; the dashed line is the fit calculated by a light transport model.

FIGURE 6.

Case 2. H & E histology of the specimen taken at the site of faint visible fluorescence and the highest level of PpIX concentration revealed expected atypical enlarged neuronal cells that were mis-spaced and mis-oriented on a background of mild gliosis. Scale bar, 100 μm.

FIGURE 7.

Case 3. Preoperative MRI. A, Oblique coronal T2W image shows indistinct cortex in the left frontal region with T2 prolongation extending deep into the white matter. B, Coronal T2W FLAIR demonstrates the same left frontal abnormality. C, Three-dimension magnetization-prepared rapid gradient echo T1W axial image with gadolinium.

FIGURE 8.

Case 3. A, Intraoperative white-light image through the operating microscope during lesion resection. B, Blue-light image of the same surgical field. C, White-light image with superimposed color wash showing quantitative levels of PpIX. The white circle region of interest has a PpIX concentration of 0.22 μg/ml. The color bar is a log scale in μg/ml. D, Spectrum for region of interest shown in 8C. The blue circles are measured values (by the wide-field imaging system) of emission at wavelengths represented on the abscissa. The total model fit (highest continuous line spectrum) and the modeled components for the fluorescence are shown; the modeled spectrum for PpIX is the second highest line spectrum. E, Co-registered, contrast-enhanced axial T1W MR image of this location. F, Corresponding contrast-enhanced coronal T1W MR image.

FIGURE 9.

Case 3. H & E histology of specimen from the site depicted in Figure 8. No atypical neuronal forms of FCD are seen, but marked astro- and microgliosis is present. Scale bar, 100 μm.

FIGURE 10.

Concentration of ALA-induced PpIX for presumed normal cortex and for specimens histologically demonstrating FCD, gliosis, or both. Open circles represent measurement sites without associated visible fluorescence; filled circles were measurement sites that demonstrated visible fluorescence. No normal cortex sites were visibly fluorescent. The Y-axis is logarithmic. The nonspecific histology findings in one specimen were calcified vessels focally.