Foix-Chavany-Marie Syndrome case reports

Foix-Chavany-Marie Syndrome case reports

Demaerel R, Klein S, Van Calenbergh F. Syndrome of the Trephined presenting as Foix-Chavany-Marie syndrome [published online ahead of print, 2020 Jun 30]. Clin Neurol Neurosurg. 2020;196:106058. doi:10.1016/j.clineuro.2020.106058


Digby et al.from the Division of Neurosurgery, Addenbrooke’s HospitalCambridge, describes a case of a 62-year-old man who developed Foix-Chavany-Marie syndrome subsequent to traumatic brain injury. The initial presentation of the syndrome was profound loss of voluntary control of orofacial muscles, causing a loss of speech and impairment of swallow. Over subsequent months, a remarkable recovery of these functions was observed. The natural history of FCMS in this case was favourable, with good improvement in function over months. Furthermore, the pattern of bilateral opercular injury was more readily recognised on MRI than on CT, supporting the role of MRI in cases of traumatic brain injury 1).


Nitta et al.from the Department of Neurosurgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, reported a Foix-Chavany-Marie syndrome after unilateral anterior opercular contusion 2).


Martino et al. from the Department of Neurological Surgery, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marqués de Valdecilla, Santander, reported a 25-year-old right-handed man with an incidentally diagnosed right frontotemporoinsular tumor who underwent surgery using an asleep-awake-asleep technique with direct cortical and subcortical electrical stimulation and a transopercular approach to the insula. While resecting the anterior part of the pars opercularis the patient suffered sudden anarthria and bilateral facial weakness. He was unable to speak or show his teeth on command, but he was able to voluntarily move his upper and lower limbs. This syndrome lasted for 8 days. Postoperative diffusion tensor imaging tractography revealed that connections of the pars opercularis of the right inferior frontal gyrus with the frontal aslant tract (FAT) and arcuate fasciculus (AF) were damaged. This case supplies evidence for localizing the structural substrate of FCMS. It was possible, for the first time in the literature, to accurately correlate the occurrence of FCMS to the resection of connections between the FAT and AF, and the right pars opercularis of the inferior frontal gyrus. The FAT has been recently described, but it may be an important connection to mediate supplementary motor area control of orofacial movement. The present case also contributes to our knowledge of complication avoidance in operculoinsular surgery. A transopercular approach to insuloopercular gliomas can generate FCMS, especially in cases of previous contralateral lesions. The prognosis is favorable, but the patient should be informed of this particular hazard, and the surgeon should anticipate the surgical strategy in case the syndrome occurs intraoperatively in an awake patient 3).


In 2013 Theys et al. from the Department of Neurosurgery, University Hospitals Leuven, reported a 48-year-old male patient recovering from complete anarthria after unilateral right-sided subcortical hemorrhagic stroke is described. The main outcome measures included clinical and neuroimaging data at three different time points (at the onset of symptoms, after 6 weeks and after 6 months). At 6 weeks, increased activations in the right and left frontal operculum were found and were followed by a trend towards normalization of the activation pattern at 6 months. These results suggest a role of anterior opercular regions in recovery from anarthria after subcortical stroke 4).


In 2009 Campbell et al. from the Department of Neurosurgery, Institute of Neurological Sciences, Southern General Hospital, Glasgow, presented a transient manifestation of the syndrome, in a patient who suffered two sequential traumatic brain injuries 5).


In 2006 Duffau et al. from the Department of Neurosurgery, Hôpital de la Salpêtrière, Paris reported in 42 patients a Foix-Chavany-Marie syndrome in 3 cases 6).


In 2003 they reported a 26-year-old right-handed man experienced partial seizures that were poorly controlled by antiepileptic drugs during a 2-year period as a result of a right insulo-opercular low grade glioma, leading to the proposal of surgical resection. In addition, 1 year before the operation, the patient experienced a severe brain injury that resulted in a coma. A computed tomographic scan revealed left opercular contusion. The patient recovered completely within 6 months.

Intraoperative corticosubcortical electrical functional mapping was performed along the resection, allowing the identification and preservation of the facial and upper limb motor structures. A subtotal removal of the glioma was achieved. The patient had postoperative anarthria, with loss of voluntary muscular functions of the face and tongue, and he had trouble chewing and swallowing. All of these symptoms resolved within 3 months.

These findings provide insight into the use of surgery to treat a right insulo-opercular tumor. First, surgeons must be particularly cautious in cases with a potential contralateral lesion (e.g., history of head injury), even if such a lesion is not visible on magnetic resonance imaging scans; preoperative metabolic imaging and electrophysiological investigations should be considered before an operative decision is made. Second, surgeons must perform intraoperative functional mapping to identify and to attempt to preserve the corticosubcortical facial motor structures. A procedure performed while the patient is awake should be discussed to detect the structures involved in chewing and swallowing in cases of suspected bilateral lesions. Third, the patient must be informed of this particular risk before surgery is performed 7).


A 10-year-old boy was brain injured in a traffic accident in August 1996. He was found comatous (initial GCS = 6) without any focal neurological deficit. The hemodynamic situation was stable even though he presented two wounds of the scalp and a hemoperitoneum that required intensive perfusions. The initial CT scan elicited a frontal fracture, ischemo hemorrhagic lesions of the right frontopolar and anterior temporal cortex. On the second day, he developed on the left side a subdural collection and a extradural hematoma which was surgically withdrawn. The comatous state ended on the ninth day. On examination, The child was awake and alert, able to understand spoken and written language but unable to speak. There was masticatory diplegia: the mouth was half open, the patient was drooling, chewing was impossible. The most striking feature was the automatic voluntary dissociation which might be observed on laughing, crying and yawning. The patient was unable to initiate swallowing but reflex swallowing was preserved once food was placed into the pharynx. The child had a deficit of voluntary control of muscles supplied by nerves V, VI, IX, X, XI. These clinical features are the hallmarks of SFMC. The first case was reported in 1837 by Magnus. The syndrome was described by Foix Chavany et Marie in 1926, and called SFMC by Weller (1993). His literature review of 62 SFMC allowed the differentiation of five clinical types: the classical and most common form associated with cerebrovascular disease, a subacute form caused by central nervous system infections, a developmental form, a reversible form in children with epilepsy and a rare type associated with neurodegenerative disorders. Bilateral opercular lesions was confirmed in 31 of 41 patients who had CT or MRI performed, and by necropsy in 7 of 10 patients. As previously reported, the outcome was poor for this boy who recovered very limited orofacial motor abilities. The medical functional readaptation was long et tedious and took in consideration the fact that the speech disturbance was anarthria and not an aphasic or an apraxic one and the age of onset of this acute acquired syndrome 8).

References

1)

Digby R, Wells A, Menon D, Helmy A. Foix-Chavany-Marie syndrome secondary to bilateral traumatic operculum injury. Acta Neurochir (Wien). 2018 Oct 17. doi: 10.1007/s00701-018-3702-x. [Epub ahead of print] PubMed PMID: 30328523.
2)

Nitta N, Shiino A, Sakaue Y, Nozaki K. Foix-Chavany-Marie syndrome after unilateral anterior opercular contusion: a case report. Clin Neurol Neurosurg. 2013 Aug;115(8):1539-41. doi: 10.1016/j.clineuro.2012.12.036. Epub 2013 Jan 28. PubMed PMID: 23369402.
3)

Martino J, de Lucas EM, Ibáñez-Plágaro FJ, Valle-Folgueral JM, Vázquez-Barquero A. Foix-Chavany-Marie syndrome caused by a disconnection between the right pars opercularis of the inferior frontal gyrus and the supplementary motor area. J Neurosurg. 2012 Nov;117(5):844-50. doi: 10.3171/2012.7.JNS12404. Epub 2012 Sep 7. PubMed PMID: 22957529.
4)

Theys T, Van Cauter S, Kho KH, Vijverman AC, Peeters RR, Sunaert S, van Loon J. Neural correlates of recovery from Foix-Chavany-Marie syndrome. J Neurol. 2013 Feb;260(2):415-20. doi: 10.1007/s00415-012-6641-0. Epub 2012 Aug 15. PubMed PMID: 22893305.
5)

Campbell E, St George EJ, Livingston A, Littlechild P. Case report of transient acquired Foix-Chavany-Marie syndrome following sequential trauma. Br J Neurosurg. 2009 Dec;23(6):625-7. doi: 10.3109/02688690902818841. PubMed PMID: 19922277.
6)

Duffau H, Taillandier L, Gatignol P, Capelle L. The insular lobe and brain plasticity: Lessons from tumor surgery. Clin Neurol Neurosurg. 2006 Sep;108(6):543-8. Epub 2005 Oct 6. PubMed PMID: 16213653.
7)

Duffau H, Karachi C, Gatignol P, Capelle L. Transient Foix-Chavany-Marie syndrome after surgical resection of a right insulo-opercular low-grade glioma: case report. Neurosurgery. 2003 Aug;53(2):426-31; discussion 431. PubMed PMID: 12925262.
8)

Laurent-Vannier A, Fadda G, Laigle P, Dusser A, Leroy-Malherbe V. [Foix-Chavany-Marie syndrome in a child caused by a head trauma]. Rev Neurol (Paris). 1999 May;155(5):387-90. Review. French. PubMed PMID: 10427603.

NRF2

NRF2

see Nrf2 signaling pathway.

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor that in humans is encoded by the NFE2L2 gene, which protect cells from the oxidative damage caused by reactive oxygen species and, on the other hand, are associated with resistance to cancer treatments.

Several drugs that stimulate the NFE2L2 pathway are being studied for the treatment of diseases that are caused by oxidative stress.

Inhibition of Nrf2 expression might enhance the effect of TMZ on the treatment of GBM and might be a new therapeutic strategy 1).


Protective Role of NRF2 in Macrovascular Complications of Diabetes

Macrovascular complications develop in over a half of the diabetic individuals, resulting in high morbidity and mortality. This poses a severe threat to public health and a heavy burden to social economy. It is therefore important to develop effective approaches to prevent or slow down the pathogenesis and progression of macrovascular complications of diabetes (MCD). Oxidative stress is a major contributor to MCD. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) governs cellular antioxidant defence system by activating the transcription of various antioxidant genes, combating diabetes-induced oxidative stress. Accumulating experimental evidence has demonstrated that NRF2 activation protects against MCD. Structural inhibition of Kelch-like ECH-associated protein 1 (KEAP1) is a canonical way to activate NRF2. More recently, novel approaches, such as activation of the Nfe2l2 gene transcription, decreasing KEAP1 protein level by microRNA-induced degradation of Keap1 mRNA, prevention of proteasomal degradation of NRF2 protein and modulation of other upstream regulators of NRF2, have emerged in prevention of MCD. This review provides a brief introduction of the pathophysiology of MCD and the role of oxidative stress in the pathogenesis of MCD. By reviewing previous work on the activation of NRF2 in MCD, we summarize strategies to activate NRF2, providing clues for future intervention of MCD. Controversies over NRF2 activation and future perspectives are also provided in this review 2).


Accumulating evidence suggests that nuclear factor erythroid 2-related factor 2 (Nrf2) could play a neuroprotective role in experimental TBI models by regulating the expression of numerous antioxidant, anti-inflammatory, and neuroprotective proteins. However, whether Nrf2 is activated in patients following TBI is still unknown.

In a study, human brain tissues were obtained during surgery from patients suffering from TBI. The purpose of this study was to investigate the expression of Nrf2 and Nrf2-regulated gene products, NAD(P)H quinine oxidoreductase 1, and glutathione S-transferase in human injured brain tissue after TBI.

The results revealed that the nuclear level of Nrf2 was significantly increased in injured brain tissues, whereas the cytoplasmic level of Nrf2 was markedly decreased. In addition, the expression of NAD(P)H quinine oxidoreductase 1 and glutathione S-transferase was significantly upregulated. Nrf2 may be activated and confer neuroprotection against secondary brain injury following TBI. Therefore, Nrf2 could serve as a promising molecular target for the treatment of TBI 3).


The cytoplasmic NRF2 expression was higher in tumors with a higher malignancy grade, whereas the nuclear and cytoplasmic DJ1 expression was associated with a lower grade. The presence of the isocitrate dehyrdogenase 1 mutation (IDH1) was associated with an increasing cytoplasmic and nuclear expression of NRF2 and a nuclear DJ1 expression. When primary grade IV astrocytomas were compared to secondary glioblastomas, nuclear DJ1 was associated with secondary tumors. In grade II-IV tumors, the cytoplasmic NRF2 expression was associated with a poor prognosis, whereas nuclear NRF2 and both cytoplasmic and nuclear DJ1 were associated with a better patient prognosis. Recurrent homozygous deletions of DJ1 were observed, especially in the IDH wild-type samples. When only the glioblastomas were evaluated, nuclear NRF2 and SRNX1 predicted better survival. As a conclusion, NRF2, DJ1 and SNXR1 can be used as prognosticators in gliomas 4).


Nrf2 is a basic leucine zipper (bZIP) protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation and is a key regulator in these redox-dependent events and operates in cytoprotection, drug metabolism and malignant progression in cancer cells.

Fan et al. show that patients with primary malignant brain tumors (glioblastomas, WHO °IV gliomas, GBM) have a devastating outcome and overall reduced survival when Nrf2 levels are upregulated. Nrf2 overexpression or Keap1 knockdown in glioma cells accelerate proliferation and oncogenic transformation. Further, activation of the Nrf2-Keap1 signaling upregulates xCT (aka SLC7A11 or system Xc-) and amplifies glutamate secretion thereby impacting on the tumor microenvironment. Moreover, both fostered Nrf2 expression and conversely Keap1 inhibition promote resistance to ferroptosis. Altogether, the Nrf2-Keap1 pathway operates as a switch for malignancy in gliomas promoting cell proliferation and resistance to cell death processes such as ferroptosis. Our data demonstrate that the Nrf2-Keap1 pathway is critical for cancer cell growth and operates on xCT. Nrf2 presents the Achilles’ heel of cancer cells and thus provides a valid therapeutic target for sensitizing cancer for chemotherapeutics 5).

1)

Sun W, Zhang W, Yu J, Lu Z, Yu J. Inhibition of Nrf2 might enhance the anti-tumor effect of temozolomide in glioma cells via inhibition of Ras/Raf/MEK signaling pathway [published online ahead of print, 2020 May 26]. Int J Neurosci. 2020;1-9. doi:10.1080/00207454.2020.1766458
2)

Wu J, Sun X, Jiang Z, et al. Protective role of NRF2 in macrovascular complications of diabetes [published online ahead of print, 2020 Jul 6]. J Cell Mol Med. 2020;10.1111/jcmm.15583. doi:10.1111/jcmm.15583
3)

He Y, Yan H, Ni H, Liang W, Jin W. Expression of nuclear factor erythroid 2-related factor 2 following traumatic brain injury in the human brain. Neuroreport. 2019 Feb 4. doi: 10.1097/WNR.0000000000001205. [Epub ahead of print] PubMed PMID: 30724850.
4)

Haapasalo J, Nordfors K, Granberg KJ, Kivioja T, Nykter M, Haapasalo H, Soini Y. NRF2, DJ1 and SNRX1 and their prognostic impact in astrocytic gliomas. Histol Histopathol. 2018 Feb 14:11973. doi: 10.14670/HH-11-973. [Epub ahead of print] PubMed PMID: 29441509.
5)

Fan Z, Wirth AK, Chen D, Wruck CJ, Rauh M, Buchfelder M, Savaskan N. Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis. 2017 Aug 14;6(8):e371. doi: 10.1038/oncsis.2017.65. PubMed PMID: 28805788.

CD24

CD24

Signal transducer CD24 also known as cluster of differentiation 24 or heat-stable antigen CD24 (HSA) is a protein that in humans is encoded by the CD24 gene.

CD24 is a cell adhesion molecule.

CD24 is a sialoglycoprotein expressed at the surface of most B lymphocytes and differentiating neuroblasts. It is also expressed on neutrophils and neutrophil precursors from the myelocyte stage onwards. The encoded protein is anchored via a glycosylphosphatidylinositol (GPI) link to the cell surface. The protein also contributes to a wide range of downstream signaling networks and is crucial for neural development. Cross-linking of CD24 on the surface of neutrophils induces apoptosis, and this appears to be defective in sepsis. CD24 gene is found on chromosome 6 (6q21) An alignment of this gene’s sequence finds genomic locations with similarity on chromosomes 1p36, 3p26, 15q21.3, 20q11.2, and Yq11.222. Whether transcription and corresponding translation, occurs at each of these other genomic locations needs to be experimentally determined 1).


CD24 is specifically upregulated and apparently associated with better survival. CD24 and Nestin expression respond differently to alteration of D-2-Hydroxyglutarate levels. CD24 upregulation is associated with histone and DNA demethylation as opposed to hypermethylation in the downregulated genes.

The Neural Stem Cell Marker CD24 has specifically upregulation in IDH-mutant Glioma 2).


On human medulloblastoma, CD24 was found to be highly expressed on Group 3, Group 4 and SHH subgroups compared with the WNT subgroup, which was predominantly positive for CD15, suggesting CD24 is an important marker of non-WNT medulloblastoma initiating cells and a potential therapeutic target in human medulloblastoma.

A study reports the use of CD24 and CD15 to isolate a GCP-like TIC population in Ptch1 deleted medulloblastoma and suggests CD24 expression as a marker to help stratify human WNT tumours from other medulloblastoma subgroups 3).


In the adult rodents’ brain, CD24 expression is restricted to immature neurons located in the neurogenesis areas.

Previous studies have confirmed that CD24 expression could be markedly elevated in the cerebral cortex after traumatic brain injury (TBI) both in humans and in mice. Although there is a close relationship between CD24 and neurogenesis, it remains unknown about the specific role of CD24 in neurogenesis areas after TBI. Here, the expression of CD24 was detected in the ipsilateral hippocampus by the Western blotting and real-time quantitative polymerase chain reaction. RNA interference was applied to investigate the effects of CD24 on post-traumatic neurogenesis. Brain sections were labeled with CD24 and doublecortin (DCX) via immunofluorescence. The Morris water maze test was used to assess cognitive functions. The results indicated that both mRNA and protein levels of CD24 were markedly elevated in the hippocampus after TBI. Meanwhile, TBI could cause a decrease of DCX-positive cells in the dentate gyrus of the hippocampus. Downregulation of CD24 significantly inhibited the phosphorylation of Src homology region 2-containing protein tyrosine phosphatase 2 in the ipsilateral hippocampus. Meanwhile, inhibition of CD24 could reduce the number of DCX-positive cells in the dentate gyrus area and impair cognitive functions of the TBI mice. These data suggested that hippocampal expression of CD24 might positively regulate neurogenesis and improve cognitive functions after TBI 4).

References

2)

Tiburcio PDB, Locke MC, Bhaskara S, Chandrasekharan MB, Huang LE. The neural stem-cell marker CD24 is specifically upregulated in IDH-mutant glioma [published online ahead of print, 2020 Jul 1]. Transl Oncol. 2020;13(10):100819. doi:10.1016/j.tranon.2020.100819
3)

Robson JP, Remke M, Kool M, et al. Identification of CD24 as a marker of Patched1 deleted medulloblastoma-initiating neural progenitor cells. PLoS One. 2019;14(1):e0210665. Published 2019 Jan 18. doi:10.1371/journal.pone.0210665
4)

Wang H, Zhou XM, Xu WD, et al. Inhibition of Elevated Hippocampal CD24 Reduces Neurogenesis in Mice With Traumatic Brain Injury. J Surg Res. 2020;245:321-329. doi:10.1016/j.jss.2019.07.082
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