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.

A correlative analysis between inflammatory cytokines and trigeminal neuralgia or hemifacial spasm.

BACKGROUND: It is necessary to understand the mechanism of trigeminal neuralgia (TN) and hemifacial spasm (HFS) in order to seek for an effective noninvasive remedy. As previous studies implied that inflammatory cytokines induced by demyelination following the nerve injury may be the initiated factor causing neuropathic pain, we attempt to analyze the correlation between cytokines and these hyperactive cranial nerve disorders. METHOD: The consecutive patients whose diagnosis were confirmed by microvascular decompression surgery as primary TN or HFS caused by vascular compression and healthy volunteers between March and May 2018 in XinHua Hospital Shanghai JiaoTong University School of Medicine were recruited. Preoperatively, venous blood was collected and the protein concentrations of IL-1ß, IL-2, IL-6, IL-8, IL-10, TNF-α and IFN-γ were determined with ELISA. Each cytokine was compared between the patients and healthy volunteers. RESULTS: Ultimately, 28 healthy volunteers as well as 44 TN and 47 HFS patients were enrolled in this investigation. The serum levels of IL-1ß, IL-6, IL-8 and TNF-α in either HFS or TN patients were significantly higher than that in healthy volunteers (p < 0.05), yet which were similar between TN and HFS patients (p > 0.05). Besides, there was a significantly correlation between IL-6 concentration and severity of HFS (r = 0.933, p < 0.05) or TN (r = 0.943, p < 0.05). DISCUSSION: Vascular compression of trigeminal or facial nerve roots may induce a rise in variety of cytokines, and IL-6 may play an important role in the signaling pathways to generate ectopic impulses from these cranial nerves.

Different Pain States of Trigeminal Neuralgia Make Significant Changes in the Plasma Proteome and Some Biochemical Parameters: a Preliminary Cohort Study.

Trigeminal neuralgia (TN) with chronic and severe neuropathic pain leads to remarkable interference in daily living activities of patients. Unknown molecular mechanisms involved in TN pathophysiology are a challenge for complete treatment of the disease. The present study was conducted to investigate changes in the plasma proteome beside biochemical parameters, including calcitonin gene-related peptide (CGRP), nitric oxide (NO), amino acids, and vitamin D (Vit D) in different pain states in TN patients. Plasma samples were obtained from the control group (#13) and patients with purely paroxysmal type of classical TN (#13) before and after microvascular decompression (MVD). We analyzed plasma proteome using two-dimensional gel electrophoresis (2-DE) and identified altered proteins by applying MALDI-TOF/TOF mass spectrometry. The plasma levels of neurotransmitters (CGRP, NO, and amino acids) and Vit D were investigated by ELISA and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pain-rating index (PRI) was specified using a McGill pain questionnaire, which indicated a significant pain reduction after MVD. Plasma proteome analysis showed upregulated expression of transthyretin (TTR), retinol-binding protein 4 (RBP4), and alpha-1-acid glycoprotein 2 (AGP2) in TN patients compared to control group; whereas, TTR and RBP expression was downregulated after surgery. Moreover, the elevated NO and CGRP and decreased Vit D concentrations were observed in patients. After surgery, NO, Arg, Cit, and Gly levels were decreased along with pain relief. Our findings support the role of altered proteins in TN pathophysiology and suggest involvement of the evaluated neurotransmitters and Vit D in pain pathway sensitization during the disease.

Effects of Sex and Stress on Trigeminal Neuropathic Pain-Like Behavior in Rats.

AIMS: To investigate the effects and interactions of sex and stress (provoked by chronic restraint [RS]) on pain-like behavior in a rat model of trigeminal neuropathic pain. METHODS: The effects of sex and RS (carried out for 14 days as a model for stress) on somatosensory measures (reaction to pinprick, von Frey threshold) in a rat model of trigeminal neuropathic pain were examined. The study design was 2 × 4, with surgery (pain) and sham surgery (no pain) interacting with male restrained (RS) and unrestrained (nRS) rats and female RS and nRS rats. A total of 64 Sprague Dawley rats (32 males and 32 females) were used. Half of the animals in each sex group underwent RS, and the remaining half were left unstressed. Following the RS period, trigeminal neuropathic pain was induced by unilateral infraorbital nerve chronic constriction injury (IOCCI). Half of the animals in the RS group and half in the nRS group (both males and females) were exposed to IOCCI, and the remaining halves to sham surgery. Elevated plus maze (EPM) assessment and plasma interferon gamma (IFN-γ) levels were used to measure the effects of RS. Analysis of variance (ANOVA) was used to assess the effects of stress, sex, and their interactions on plasma IFN-γ levels, changes in body weight, EPM parameters, tactile allodynia, and mechanohyperalgesia. Pairwise comparisons were performed by using Tukey post hoc test corrected for multiple comparisons. RESULTS: Both male and female RS rats showed significantly altered exploratory behavior (as measured by EPM) and had significantly lower plasma IFN-γ levels than nRS rats. Rats exposed to RS gained weight significantly slower than the nRS rats, irrespective of sex. Following RS but before surgery, RS rats showed significant bilateral reductions in von Frey thresholds and significantly increased pinprick response difference scores compared to nRS rats, irrespective of sex. From 17 days postsurgery, RSIOCCI rats showed significantly reduced von Frey thresholds and significantly increased pinprick response difference scores compared to nRS-IOCCI rats, and the von Frey thresholds were significantly lower in females than in males. RS-sham females-but not RS-sham males-developed persistently reduced thresholds and increased pinprick response difference scores. CONCLUSION: RS produced an increased bilateral sensitivity to stimuli applied to the vibrissal pad following infraorbital nerve injury, irrespective of sex. This observed sensitivity subsequently persisted in RS-sham female rats but not in RS-sham male rats. Stress induced a significant but moderate increase in pain-like behavior in female rats compared to male rats. RS had no significant sex effects on IFN-γ levels, EPM parameters, or body weight gain. This suggests that stress may have a selective effect on pain-like behavior in both sexes, but the possible mechanisms are unclear.

The Study of Calcium, Phosphonium, Magnesium, and Ferrum Concentration in Serum of Patients With Primary Trigeminal Neuralgia.

OBJECTIVE: To measure the concentration of 4 essential elements (Ca, P, Mg, Fe) in serum of patients with primary trigeminal neuralgia. And evaluate the role of the 4 elements in serum on the pathogenesis of trigeminal neuralgia (TN), and the relevance of etiology. METHODS: From June 2013 to June 2014, a number of 80 patients with primary trigeminal neuralgia were collected. We present a retrospective review of the concentration of 4 essential elements with those of control group of 80 patients without TN. The concentrations of 4 elements were measured with Olympus AU 400 automatic biochemistry analyzer. RESULTS: In primary TN patients, the concentration of Ca, P, Mg in serum is lower than the control group obviously (P <0.05), but the concentration of Fe in serum is higher than the control group obviously (P <0.05). Along with level of the VOS improved, the concentration of Ca, P, and Mg in serum becomes lower and lower. However, along with level of the VOS improved, the concentration of Fe in serum becomes higher and higher. CONCLUSION: Patients with primary TN, the change of 4 elements concentration in serum is connected with biochemical material change. The change of the microelement may play an important role in the development of Trigeminal neuralgia, possibly demyelinating lesions.

Withdrawal reaction of carbamazepine after neurovascular decompression for trigeminal neuralgia: a preliminary study.

OBJECTIVE: To evaluate the representations and the relevant factors of carbamazepine-associated withdrawal reaction (CAWR) after microvascular decompression (MVD) to treat trigeminal neuralgia (TN). METHODS: The present series included 90 patients who were referred from September 2010 to January 2013 and diagnosed with classical TN. The carbamazepine (CBZ) serum level was tested twice at 24h pre- and 24h post-operation by using HPLC analysis. The analysis of correlating selected factors and CAWR was performed. RESULTS: Among 90 patients, 26 (28.9%) suffered from post-operative CAWR for 3 days after MVD. The symptoms of CAWR include overexcitement, e.g. insomnia, dysphoria, hand fremitus, hallucination and severe headache. The history of CBZ therapy before MVD, pre-operative dosage of CBZ, and the D-value of CBZ blood concentrations demonstrated statistic differences between the patients with CAWR and those without CAWR. Patient characteristics such as gender, age, and duration of neuralgia, neuralgia-related factors including neuralgia extent and neurovascular compression severity, and operation conditions including duration of MVD procedure, effect of MVD and complication of MVD had no influence on the occurrence of CAWR. CONCLUSION: It is strongly suggested that CAWR is dependent on the pre-operative dosage and the changing rate of pre- and post-operative CBZ blood concentrations.

Clues for previously undiagnosed connective tissue disease in patients with trigeminal neuralgia.

BACKGROUND: Connective tissue diseases (CTD) may be associated with idiopathic trigeminal neuralgia (TN). The prevalence and diagnostic implications of this association are, however, not well established. OBJECTIVES: The objective of this study was to evaluate, in TN patients, if rheumatologic clinical and laboratory findings could contribute to the early diagnosis of rheumatic diseases. METHODS: Forty-six consecutive TN patients, 67% female, mean disease duration 8.78 +/- 7.25 years, and 47 controls were initially interviewed using a standard questionnaire based on common signs/symptoms of systemic lupus erythematosus, Sjögren syndrome, mixed CTD, and systemic sclerosis. Autoantibodies were detected by standard techniques. Those with rheumatologic complaints or positive autoantibodies were referred to the Rheumatology Outpatient Clinic for a more detailed evaluation. Secondary causes of TN were excluded. RESULTS: The frequency of Raynaud phenomenon (P = 0.026) and ANA reactivity (P = 0.04) were significantly higher in TN patients compared with controls. Fourteen TN patients were ANA positive. Seven of them reported concomitant rheumatic complaints, and interestingly, diffuse CTD was diagnosed in 4 (57%) of these patients: 1 systemic lupus erythematosus; 2 Sjögren syndrome; and 1 undifferentiated disease with scleritis and positive parotid scintigraphy. In all cases, TN preceded by at least 10 months the rheumatologic signs/symptoms. Moreover, these 4 TN patients with CTD had a higher frequency of sicca symptoms (P = 0.001) and higher titers of ANA (>or=1:320) (P = 0.006) than the remaining 42 TN patients without CTD diagnoses. Sixteen patients had isolated laboratory or clinical abnormalities, and none of them had CTD diagnoses. CONCLUSIONS: The concomitant presence of sicca symptoms and high titer ANA are clues for the early investigation of rheumatic diseases in TN patients.

[Unexpected loss of therapeutic effect of oxcarbazepine]. / Ungewöhlicher Wirkungsverlust von Oxcarbazepin.

After months of successful analgesic therapy with oxcarbazepine, a 52-year old woman with trigeminal neuralgia suddenly experienced episodes of heavy trigeminal attacks regularly in the evening at about the same time. Asked about changes in daily life or eating habits, she reported the ingestion of healing earth daily in the morning. After stopping the ingestion of healing earth, analgesic control of trigeminal neuralgia was restored without any changes of the initial pharmacotherapy. In daily practice, interactions which significantly influence the absorption of drugs are often overlooked. The documentation of these interactions in drug interaction databases, in the prescribing information, and in the literature is sparse though clinically relevant. Separating the ingestion of interacting substances by a time interval may not sufficiently avoid the interaction in every case. Particular caution is warranted when slow-release cation containing drugs or substances with entero-hepatic circulation are used.

[Observation of vasoactive intestinal polypeptide in patients with trigeminal neuralgia: a 16-cases report].

OBJECTIVE: The aim of this study was to observe whether vasoactive intestinal polypeptide (VIP) participated in the attack of trigeminal neuralgia, and to understand further its pathogenetic mechanism. METHODS: Sixteen patients were studied. During the attacks the venous blood was sampled from both the external jugular vein and cubital fossa vein ipsilateral to the pain, and after operations the venous blood from the external jugular vein was sampled again, the external jugular vein blood of eleven normal volunteers was collected as the control. Plasma levels of VIP were determined using sensitive radioimmunoassays. RESULTS: During the attacks of trigeminal neuralgia the levels of VIP in the external jugular vein blood were significantly higher than that in the cubital fossa vein blood, postoperative external jugular vein blood and the external jugular vein blood of normal volunteers. CONCLUSION: VIP indeed participates in the attack of trigeminal neuralgia in the local region, the role of VIP may be relating to enhancing the effects of substance P in local neurogenic inflammation.

Carbamazepine-induced sinus node dysfunction and atrioventricular block in elderly women.

We report on four elderly women in whom carbamazepine was suspected of inducing sinus node dysfunction (3 patients) and atrioventricular block (1 patient). Patients were treated with carbamazepine, 200 to 600 mg a day, for trigeminal neuralgia (n = 3) or epilepsy (n = 1). After 1 to 16 months of carbamazepine therapy, these patients were admitted to our emergency room because of bradyarrhythmia. Their conduction disturbances on electrocardiographic monitoring disappeared immediately after the cessation of carbamazepine intake. Provocation tests were performed on three patients. Because of renal insufficiency, one patient could not undergo the provocation test. Her carbamazepine clearance was markedly decreased. Carbamazepine induced sinus arrest in two patients within 48 hours after intake, but did not induce atrioventricular block in the remaining patient. In two patients, computer simulation of carbamazepine pharmacokinetics was performed and disclosed a clear-cut relationship between the plasma concentration of carbamazepine and the frequency of sinus arrest. During the test, the maximum plasma carbamazepine concentration in these two patients did not exceed the therapeutic range. However, it did exceed the range in the one with a negative test. Our results suggest that careful monitoring of ECG and plasma drug concentration is required with carbamazepine therapy, especially in elderly women.

Autonomic nervous system and neuroendocrine changes in patients with idiopathic trigeminal neuralgia.

To investigate sympathetic nervous system and neuroendocrine changes in idiopathic trigeminal neuralgia, we determined the plasma level of the catecholamines norepinephrine and epinephrine, as well as cortisol and ACTH in 16 patients (55.3 +/- 8.3 years) with trigeminal neuralgia at four different times during the day (7.00, 13.00, 17.00 and 23.00). Morning and evening values of plasma norepinephrine as well as the daily mean value (dmv) were significantly higher (p < 0.01) in patients with trigeminal neuralgia than in an age- and gender-matched control group. Moreover, morning, afternoon and dmv epinephrine values were also significantly elevated. The dmv norepinephrine levels correlated with the intensity of the attacks (r = 0.68, p < 0.01), the frequency of the attacks (r = 0.75, p < 0.01) and the duration of the disease (r = 0.78, p < 0.01). In addition to elevated catecholamines, trigeminal neuralgia patients also demonstrated significantly increased morning, evening and daily mean values of plasma cortisol. Thus, patients with trigeminal pain have an increased sympathetic nervous system activity for an extended period of time without a direct link to pain attacks, which suggests that the sympathetic nervous system itself is at least co-activated in trigeminal neuralgia and perhaps plays a role in the induction and maintenance of trigeminal pain. The neuroendocrine changes are similar to cluster headache and point to a central dysregulation of the hypothalamic-pituitary-adrenal axis, possibly due to the cyclic phenomena in idiopathic trigeminal neuralgia.

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.

[Carbamazepine-fluvoxamine interaction. Consequences for the carbamazepine plasma level]. / Interaction carbamazépine-fluvoxamine. Conséquences sur le taux plasmatique de carbamazépine.

The current practices concerning psychotropic drugs use plasma levels for the therapeutic adaptation and for the prevention of overdose and side effects. We observed, among two patients treated with constant dosages of carbamazepine (CBZ), that the addition of fluvoxamine (FLV) has increased significantly plasma levels of CBZ. The first patient, suffering of an affective bipolar trouble (ICD-10), was hospitalized for major depression. His admission treatment was CBZ (800 mg/day) and cyamemazine (75 mg/day). The introduction of the FLV (200 mg/day) was justified by the symptomatology. Then, plasma levels of CBZ increased progressively. No clinic or biological side effect was observed. Rapidly, CBZ oral dosages were decreased, but the plasma levels of CBZ reached the therapeutic window only when the FLV prescription was definitively stopped. The other patient was hospitalized for an acute exacerbation of a paranoiac disorder. He was treated with haloperidol for this episode. For five years, he received CBZ for neuralgia of the Trigeminus. The emergence of a depressive disorder justified a FLV treatment. From the introduction of FLV, plasma levels of CBZ were significantly increased. The reduction, then the stop of the FLV treatment, has allowed the standardization of plasma concentrations of CBZ. Three similar studies were found in the literature. The danger of this interaction was notified in two studies (one case each). Furthermore, in the third study (three cases) was put forward the hypothesis of a new therapeutic pathway. this hypothesis was suggested by the fact that these two medications were proposed independently to treat impulsive behaviors.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hormonal disorders in women with prosopalgia in osteochondrosis of the cervical spine and the possible means for their correction]. / Gormonal'nye narusheniia u zhenshchin s prozopalgiiami pri osteokhondroze sheinogo otdela pozvonochnika i vozmozhnye puti ikh korrektsii.

Radioimmunoassay was employed to determine basal levels of LH, FSH, prolactin, total testosterone and 17 beta-estradiol in plasma from 52 pre- or postmenopausal women with prosopalgia consequent to cervical osteochondrosis. The measurements were made before and after laser treatment. Different from the control, basal levels of the hormones and the trends in their changes due to laser therapy depended on the patients' age and the disease stage.

Effects of dextropropoxyphene on the steady-state kinetics of oxcarbazepine and its metabolites.

The effects of dextropropoxyphene on the steady-state kinetics of oxcarbazepine and its metabolites were investigated in eight patients with epilepsy or trigeminal neuralgia. One patient dropped out of the study, presumably due to side-effects of dextropropoxyphene. Dextropropoxyphene did not affect the plasma levels of the principal active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine. Since dextropropoxyphene is known to increase the plasma levels of carbamazepine, leading to toxicity, the findings of this study suggest that oxcarbazepine is a useful alternative to carbamazepine when concomitant dextropropoxyphene therapy is required.

Carbamazepine and folic acid in trigeminal neuralgia patients.

The effect of carbamazepine monotherapy on the red cell folate level of 133 patients with trigeminal neuralgia was evaluated. The patient group had a significantly lower mean value of red cell folate levels compared with 110 controls. No significant correlation was found between the red cell folate levels and the mean cell volume or haemoglobin values in either the carbamazepine or control group. In addition no significant correlation was found between the red cell folate levels and drug dosage. Administration of folic acid supplements raised the mean value of red cell folate significantly. Dietary folate intake was assessed in 43 trigeminal neuralgia patients and 33 matched control patients and there was no significant difference between the groups. Patients taking carbamazepine should be advised on a well-balanced diet rich in folate as opposed to being given a routine prescription of folic acid.

[Effect of neurosurgical interventions on serum levels of the essential trace elements zinc and copper--a perioperative study]. / Einfluss neurochirurgischer Eingriffe auf die Serumspiegel der essentiellen Spurenelemente Zink und Kupfer--eine perioperative Studie.

The serum-concentrations of the trace-elements zinc and copper were assessed before and after neurosurgical interventions in 60 patients. On the day of surgery the mean values of zinc and copper showed a significant decrease, but had reached their preoperative level one week later. While a influence of dexamethasone on the serum zinc levels could not be deducted, the serum copper concentrations seem to be influenced by dexamethasone. These changes seem to be connected with the activation of the hypothalamus-pituitary-adrenal axis during surgical stress.

[Electroconvulsive therapy of trigeminal neuralgia]. / Elektrosudorozhnaia terapiia v lechenii bol'nykh nevralgiiami troinichnogo nerva.

The authors describe a new method of the treatment of patients with trigeminal neuralgias using electroconvulsive therapy. The method is based on the increase of beta-endorphin concentration as a result of electroconvulsive treatment. The treatment of 12 patients in accordance with the suggested method provided beneficial results and significant enhancement of the efficacy of therapy as compared to patients undergoing conventional treatment.

Oxcarbazepine: a new drug in the management of intractable trigeminal neuralgia.

The efficacy and tolerability of oxcarbazepine, a keto derivative of carbamazepine, has been assessed in six patients (two males, four females; mean age 61 years, range 42-77), with trigeminal neuralgia refractory to carbamazepine therapy, over a period of 6 months. An excellent therapeutic response to oxcarbazepine was seen in all patients with pain control correlating well with serum drug concentrations of oxcarbazepine and its primary active metabolite 10-OH-carbazepine. Onset of the effect was observed within 24 hours in all cases. An overall serum therapeutic concentration range, in the six patients, of 50-110 mumol/l of 10-OH-carbazepine corresponding to a daily effective dose range of 1200-2400 mg (14.6-35.6 mg/kg body weight) oxcarbazepine, was observed. There was a significant correlation between oxcarbazepine dose and serum oxcarbazepine (r = 0.695, p less than 0.05) and 10-OH-carbazepine (r = 0.957, p less than 0.001) concentrations. Oxcarbazepine was well tolerated and no significant side effects were identified, though a mild hyponatraemia was observed during high doses (greater than 28 and greater than 35 mg/kg/day) in two patients. It is concluded that oxcarbazepine has potent antineuralgic properties in the absence of significant side effects and therefore may be useful in the management of intractable trigeminal neuralgia.

[The level of serotonin in the blood of patients with trigeminal neuralgia]. / Uroven' serotonina v krovi bol'nykh nevralgiiami troinichnogo nerva.

Serotonin levels in patients with trigeminal neuralgia were studied according to the pain syndrome. The results evidence normalization of the blood serotonin concentration, possibly due to a favourable effect of therapy on serotonin metabolism, which reflects activation and optimization of the gate system for pain control.