Exploring biomarkers in trigeminal neuralgia patients operated with microvascular decompression: A comparison with multiple sclerosis patients and non-neurological controls.

BACKGROUND: Trigeminal neuralgia (TN) is a severe facial pain condition often associated with a neurovascular conflict. However, neuroinflammation has also been implicated in TN, as it frequently co-occurs with multiple sclerosis (MS). METHODS: We analysed protein expression levels of TN patients compared to MS patients and controls. Proximity Extension Assay technology was used to analyse the levels of 92 proteins with the Multiplex Neuro-Exploratory panel provided by SciLifeLab, Uppsala, Sweden. Serum and CSF samples were collected from TN patients before (n = 33 and n = 27, respectively) and after (n = 28 and n = 8, respectively) microvascular decompression surgery. Additionally, we included samples from MS patients (n = 20) and controls (n = 20) for comparison. RESULTS: In both serum and CSF, several proteins were found increased in TN patients compared to either MS patients, controls, or both, including EIF4B, PTPN1, EREG, TBCB, PMVK, FKBP5, CD63, CRADD, BST2, CD302, CRIP2, CCL27, PPP3R1, WWP2, KLB, PLA2G10, TDGF1, SMOC1, RBKS, LTBP3, CLSTN1, NXPH1, SFRP1, HMOX2, and GGT5. The overall expression of the 92 proteins in postoperative TN samples seems to shift towards the levels of MS patients and controls in both serum and CSF, as compared to preoperative samples. Interestingly, there was no difference in protein levels between MS patients and controls. CONCLUSIONS: We conclude that TN patients showed increased serum and CSF levels of specific proteins and that successful surgery normalizes these protein levels, highlighting its potential as an effective treatment. However, the similarity between MS and controls challenges the idea of shared pathophysiology with TN, suggesting distinct underlying mechanisms in these conditions. SIGNIFICANCE: This study advances our understanding of trigeminal neuralgia (TN) and its association with multiple sclerosis (MS). By analysing 92 protein biomarkers, we identified distinctive molecular profiles in TN patients, shedding light on potential pathophysiological mechanisms. The observation that successful surgery normalizes many protein levels suggests a promising avenue for TN treatment. Furthermore, the contrasting protein patterns between TN and MS challenge prevailing assumptions of similarity between the two conditions and point to distinct pathophysiological mechanisms.

Increased CSF Levels of Apolipoproteins and Complement Factors in Trigeminal Neuralgia Patients-In Depth Proteomic Analysis Using Mass Spectrometry.

The main cause of trigeminal neuralgia (TN) is compression of a blood vessel at the root entry zone of the trigeminal nerve. However, a neurovascular conflict does not seem to be the only etiology and other mechanisms are implicated in the development of the disease. We hypothesized that TN patients may have distinct protein expression in the CSF. In this study, lumbar CSF from TN patients (n = 17), scheduled to undergo microvascular decompression, and from controls (n = 20) was analyzed and compared with in depth mass spectrometry TMTbased quantitative proteomics. We identified 2552 unique proteins, of which 46 were significantly altered (26 increased, and 20 decreased, q-value < .05) in TN patients compared with controls. An over-representation analysis showed proteins involved in high-density lipoprotein, such as Apolipoprotein A4, Apolipoprotein M, and Apolipoprotein A1, and the extracellular region, including proteins involved in the complement cascade to be over-represented. We conclude that TN patients have distinct protein expression in the CSF compared to controls. The pathophysiological background of the protein alterations found in this study warrants further investigation in future studies. PERSPECTIVE: In this article, cerebrospinal fluid from patients with trigeminal neuralgia was analyzed using in depth shotgun proteomics, revealing 46 differentially expressed proteins compared to controls. Among these, apolipoproteins and proteins involved in the complement system were elevated and significantly over-represented, implying an inflammatory component in the pathophysiology of the disease.

Cerebrospinal fluid biomarkers of inflammation in trigeminal neuralgia patients operated with microvascular decompression.

Compression of the trigeminal root entry zone by a blood vessel can cause trigeminal neuralgia (TN). However, a neurovascular conflict does not explain all cases of TN, and TN can exist without a neurovascular contact. A common observation during microvascular decompression surgery to treat TN is arachnoiditis in the region of the trigeminal nerve. Thus, aberrant inflammatory mechanisms may be involved in the pathophysiology of TN but information about the role of inflammation in TN is scarce. We used Proximity Extension Assay technology to analyse the levels of 92 protein biomarkers related to inflammation in lumbar cerebrospinal fluid from patients with TN (n = 27) before and after microvascular decompression compared to individuals without TN. We aimed to analyse the pattern of inflammation-related proteins in order to improve our understanding of the pathophysiology of TN. The main finding was that immunological protein levels in the cerebrospinal fluid from patients with TN decreased after surgery towards levels observed in healthy controls. Two proteins seemed to be of specific interest for TN: TRAIL and TNF-ß. Thus, inflammatory activity might be one important mechanism in TN.

Clinical study of cerebrospinal fluid neuropeptides in patients with primary trigeminal neuralgia.

OBJECTIVES: To investigate the expression levels of calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and ß-endorphin in the cerebrospinal fluid (CSF) and peripheral blood of patients with primary trigeminal neuralgia (TN). PATIENTS AND METHODS: We included 20 patients with primary TN who underwent percutaneous radiofrequency thermocoagulation and collected four types of samples from all of them: sample A: CSF samples; sample B: peripheral blood samples; sample C: peripheral blood samples collected one day before the operation; sample D: peripheral blood samples withdrawn one day after the operation. Another 20 CSF samples of patients with nervous system disease or gynecological disease were collected as a control (sample E). Samples A and B were obtained at the same time. We also evaluated the expression of CGRP, SP, ß-endorphin, and VIP by visual analog scale (VAS) scores one day before and one day after the operation. In addition, heart rate (HR) at baseline and at the time of sample collection, mean arterial pressure (MAP), and all side effects of the procedure were recorded. RESULTS: Significance were found concerning about CGRP, SP, ß-endorphin, and VIP in TN patients and the controls (P<0.001). The expression of CGRP, SP, and VIP in sample A was higher than that in sample E. However, the ß-endorphin level in sample A was lower than that in sample E. There was a positive correlation between sample A and B regarding the expression of CGRP, SP, ß-endorphin, and VIP (P<0. 01). There was no relationship between the time of disease onset and the expression of CGRP, SP, ß-endorphin, and VIP in sample A and sample B (P>0.05). No difference was detected between the neuropeptides levels in samples B and C (P>0.05). Notably, VAS in sample D was significantly lower than that in sample C (P<0.01). Finally, there was no difference between the intraoperative HR and MAP values in the studied samples. CONCLUSION: In primary TN patients, the blood levels of CGRP, SP, ß-endorphin, and VIP were associated with those in CSF samples. There was a significant difference between the levels of the four neuropeptides in CSF and control samples. Our results also indicated that the levels of neuropeptides in blood samples can be tested for those in CSF. The disease onset and duration exerted insignificant effects on the production and release of CGRP, SP, ß-endorphin, and VIP.

Rostrocaudal dynamics of CSF biomarkers.

The rostrocaudal gradient (RCG) of markers present in cerebrospinal fluid (CSF) has not been studied adequately due to lack of appropriate control populations and ethical restrictions. The aim of this study is to understand the rostrocaudal gradient of CSF biomarkers. We contacted a study comparing CSF levels of seven biomarkers from cisternal (rostral) and lumbar (caudal) CSF obtained from patients with trigeminal neuralgia and tension-type headache. The RCGs of CSF/serum albumin ratio, 8-isoprostane. GFAP, total tau and beta amyloid protein were higher than one. The RCGs of lactate, VEGF and the heavy chain of neurofilament protein were lower than one. The study provides new values for several commonly examined markers of cisternal CSF. Knowledge of the RCG gradient of different CSF markers is important in interpreting studies reporting ventricular CSF values.

Targeting the cranial nerve: microradiosurgery for trigeminal neuralgia with CISS and 3D-flash MR imaging sequences.

OBJECT: The authors undertook a study to identify magnetic resonance (MR) imaging techniques that can be used reliably during gamma knife surgery (GKS) to identify the trigeminal nerve, surrounding vasculature, and areas of compression. METHODS: Preoperative visualization of the trigeminal nerve and surrounding vasculature as well as targeting the area of vascular compression may increase the effectiveness of GKS for trigeminal neuralgia. During the past years our gamma knife centers have researched different MR imaging sequences with regard to their ability to visualize cranial nerves and vascular structures. Constructive interference in steady-state (CISS) fusion imaging with three-dimensional gradient echo sequences (3D-Flash) was found to be of greatest value in the authors' 25 most recent patients. In 24 (96%) out of the 25 patients, the fifth cranial nerve, surrounding vessels, and areas of compression could be reliably identified using CISS/3D-Flash. The MR images were acceptable despite patients' history of microvascular decompression, radiofrequency (RF) ablation, or concomitant disease. In one of 25 patients with a history of multiple RF lesions, the visualization was inadequate due to severe trigeminal nerve atrophy. CONCLUSIONS: The CISS/3D-Flash fusion imaging has become the preferred imaging method at the authors' institutions during GKS for trigeminal neuralgia. It affords the best visualization of the trigeminal nerve, surrounding vasculature, and the precise location of vascular compression.

Effect of cerebrospinal fluid return on success rate of percutaneous retrogasserian glycerol rhizotomy.

BACKGROUND AND OBJECTIVE: Trigeminal neuralgia is a painful syndrome, which has been commonly treated with percutaneous retrogasserian glycerol rhizotomy (PRGR). This study was performed to evaluate the effect of cerebrospinal fluid (CSF) return on the success rate of PRGR. METHODS: In this retrospective, nonrandomized, observational case series, 100 cases underwent 140 PRGRs under fluoroscopic guidance and were followed up for 6 to 36 months. The results were compared in the presence or absence of CSF return before PRGR. RESULTS: The PRGR was successful in 115 procedures (82.1%). CSF return was present in 84 procedures (60%) and, among these, 76 PRGRs (90.5%) produced pain relief. More than 1 year of pain relief without medications was present in 60 of 84 procedures (71.4%). CSF return before PRGR was absent in 56 procedures (40%) and success resulted in 39 procedures (69.6%). Pain relief for more than 1 year without medications was present in 19 procedures (33.9%). The success rate and duration of pain relief was greater in the presence of CSF return compared with absence of CSF return (P < .005). The incidence of complications such as facial dysesthesia (40%), corneal anesthesia (2.8%), herpes simplex (3.5%), and nonbacterial meningitis (0.7%) was not significantly different in 2 groups ( P > .05). CONCLUSION: The presence of CSF is an important factor in determining the success rate and duration of pain relief of PRGR.

Nitric oxide metabolites in the cisternal cerebral spinal fluid of patients with subarachnoid hemorrhage.

OBJECTIVE: To investigate nitric oxide (NO) metabolism after subarachnoid hemorrhage (SAH). METHODS: We measured the concentrations of the NO metabolites, nitrite and nitrate, in cerebrospinal fluid (CSF) obtained from the cisternal drainage of patients with SAH. Studies were performed for 31 patients who had undergone surgical obliteration of bleeding aneurysms within 3 days of their hemorrhage. The concentrations of nitrite and nitrate in the CSF were measured for 14 days using a nitrate/nitrite kit and samples that were obtained on a daily basis from the cisternal drainage. RESULTS: Compared with the control values in the CSF (2.6 +/- 0.4 mumol/L, n = 14) obtained from patients with hemifacial spasm, trigeminal neuralgia, or nonruptured aneurysms, the concentrations of nitrite and nitrate in the CSF were significantly elevated in the acute stage of SAH and remained elevated. The concentration of NO metabolites may correlate with the amount of bleeding, inasmuch as the values in patients in Fisher Group 3 (n = 25) were higher than those in patients in Fisher Group 2 (n = 6). The concentration of nitrate was higher than that of nitrite, suggesting that NO in the subarachnoid space is mainly absorbed by hemoglobin and degraded to nitrate. No differences were demonstrated in patients treated with high doses of methylprednisolone (n = 17) compared with those treated with usual-dose steroids (n = 14). Steroids are known to prevent the formation of inducible NO synthase mediated by inflammatory cytokines. CONCLUSION: NO metabolism in the brain is stimulated after SAH. Nitrate is the dominant NO metabolite in CSF after SAH. The involvement of inducible NO synthase in the pathophysiology of NO metabolism after SAH was not clearly suggested based on the present data.

Carbonic anhydrase II in the cerebrospinal fluid: its value as a disease marker.

Carbonic anhydrase (CA) II is the predominant CA isoenzyme in the brain of mammals. We have recently developed a dual-label time-resolved immunofluorometric assay to quantify minute amounts of CA I and II in the cerebrospinal fluid (CSF). The present study was aimed at elucidating the clinical value of such measurements in the case of neurological disorders. Lumbar CSF samples were obtained from 111 patients suffering from various neurological diseases and from 97 control patients with no specific signs of central nervous system diseases. The highest CA II concentrations were found in patients with brain infarction (median 66.5 micrograms L-1, n = 20), whereas the control patients had markedly lower values (median 7.8 micrograms L-1, n = 97). Relative to a reference range calculated from the control material (10.2 +/- 17.2 micrograms L-1), the sensitivity of CA II measurement in differentiating brain infarction was 100%. Patients with transient ischaemic attack (median 11.2 micrograms L-1, n = 9), multiple sclerosis (median 14.7 micrograms L-1, n = 18) or epilepsy (median 20.3 micrograms L-1, n = 17) usually had CA II concentrations within the normal range, but those with central nervous system infection (n = 14), dementia (n = 19) or trigeminal neuralgia (n = 6) tended to have higher CA II levels in their CSF, the median values being 39.1 micrograms L-1, 45.5 micrograms L-1 and 44.0 micrograms L-1 respectively. The findings indicate that the concentration of CA II in the CSF marks disease activity in patients with brain damage. This finding could provide a basis for further studies estimating the value of CA II measurement as a new laboratory marker of diseases affecting the brain.

Cerebrospinal fluid neuropeptides and monoaminergic transmitters in patients with trigeminal neuralgia.

The pathogenesis of trigeminal neuralgia remains largely unknown. "Peripheral" as well as "central" causes have been suggested. To investigate the role of serotonergic, noradrenergic, dopaminergic, and peptidergic systems, we determined the concentrations of epinephrine, norepinephrine, and their breakdown product, vanillylmandelic acid, in the cerebrospinal fluid of 16 patients (55.3 +/- 8.3 years) with trigeminal neuralgia. As a marker for the dopaminergic system, we determined cerebrospinal fluid concentrations of dopamine and its metabolite, homovanillic acid. As a marker for the serotonergic system, we measured cerebrospinal fluid levels of the serotonin metabolite, 5-hydroxyindoleacetic acid. In addition, levels of the neuropeptides, substance P and somatostatin, were determined. The concentration of norepinephrine (P < 0.01) and its metabolite, vanillylmandelic acid, (P < 0.05) were significantly decreased in our patients. The level of the dopamine metabolite, homovanillic acid, was also significantly reduced (P < 0.01). Also significantly decreased was 5-hydroxyindoleacetic acid (P < 0.01). Substance P was significantly elevated (P < 0.05). Somatostatin was significantly decreased (P < 0.05). We hypothesize that the sum of complex neurochemical changes plays a role in the pathogenesis of trigeminal neuralgia. The elevated substance P could support the concept of a neurogenic inflammation in the trigeminovascular system, whereas changes in the monoaminergic transmitters and their metabolites seem to reflect a more central dysfunction possibly due to a longer duration of the disease and an accompanying depression.

Infectious retrovirus is inactivated by serum but not by cerebrospinal fluid or fluid from tumor bed in patients with malignant glioma.

Intravenous gene transfer using recombinant retroviruses tends to suffer from a low infectious viral titer when conducted in vivo. This is, in part, caused by complement-mediated proteolytic inactivation of the retrovirus in human serum. However, if the retroviruses were directly injected into the brain, they might not be inactivated. Supernatant from amphotropic retrovirus-producing cells harboring the BAG vectors was incubated with sera or cerebrospinal fluid (CSF) of patients with gliomas or unrelated disorders. The retroviruses were severely inactivated in sera. However, no such inactivation was noted in CSF or fluid from the tumor bed of glioma patients. These data suggest that gene transfer using recombinant retroviruses could be done into the cavity after removal of the tumor in glioma patients.

Trigeminal facial pain: a model of peptides and monoamines in intracerebral cerebrospinal fluid.

A biochemical model of chronic trigeminal facial pain with elevated substance P (SP) and co-dysfunctional dopamine (DA), norepinephrine (NE) and purinergic systems is proposed. The serotonergic system is hypoactive as judged by low 5 hydroxyindoleacetic acid (5HIM). In distinction, intracerebral opioids may not be dysfunctional in facial pain as measured by normal levels of beta endorphin (BE). The neuropeptides somatostatin (SOM), cholecystokinin (CCK), met and leu-enkephalin (MENK, LENK) have very small picogram concentrations in these pain patients, but no definite conclusion can be reached on their role in trigeminal pain, alone or with monoamines, because of the small numbers, both sample size and concentrations. Interpretive obstacles to such human neurochemical studies suggest that future work might move to human clinical trials comodulating SP down, inhibitory peptides (SOM, CCK) up, and enhancing monoamine systems.

Increased concentrations of aspartic acid in the cerebrospinal fluid of patients with epilepsy and trigeminal neuralgia: an effect of medication?

The concentrations of free amino acids in the cerebrospinal fluid (CSF) were quantitated in 14 patients with epilepsy, 7 patients with trigeminal neuralgia, 10 patients with various neurological diseases and in 30 apparently healthy individuals. In the CSF of patients with epilepsy, the mean concentrations of aspartic acid (Asp), glutamine (Gln), histidine and phosphoserine were significantly higher than in the healthy individuals. The mean concentration of aspartic acid was higher in the patients on antiepileptic drug (AED) therapy than in the patients without AED therapy. The patients with trigeminal neuralgia had significantly increased CSF-concentrations of aspartic acid, glutamine and phosphoserine as compared to healthy individuals. Some patients receiving AED showed increased concentration of gamma-amino-butyric-acid (GABA).

Evaluation of endorphin content in the CSF of patients with trigeminal neuralgia before and after Gasserian ganglion thermocoagulation.

The beta-endorphin content in cerebrospinal fluid (CSF) was evaluated in 10 patients with idiopathic trigeminal neuralgia during medical treatment (with or without carbamazepine) and after selective thermocoagulation of the Gasserian ganglion. These values were compared with those obtained in a control group of seven patients without pain problems. No statistically significant difference was found between patients suffering from trigeminal neuralgia and those without pain. Furthermore, neither pharmacological treatment nor surgery changed CSF endorphin values. It is concluded that there is no pathogenetic relationship between trigeminal neuralgia and endorphins.