The pathophysiology of trigeminal neuralgia: a molecular review

J Neurosurg 139:1471–1479, 2023

The goal of this study was to provide a comprehensive overview of the current understanding of molecular and genetic mechanisms underlying the pathophysiology of trigeminal neuralgia (TN).

METHODS The authors searched PubMed systematically for primary research literature investigating specific molecular mechanisms from samples derived from patients with TN. The genes/molecules of interest from the selected literature were then cross-referenced with corresponding studies in animal models of TN.

RESULTS From approximately 345 articles, a total of 12 articles were selected and included in the review, focusing on ionotropic channel expressivity and mutations, reactive oxygen species expressivity, inflammatory marker expressivity, and microRNA expressivity. Of the 12 included articles, only 4 had studies completed in other animal models regarding the corresponding TN mechanism found in humans.

CONCLUSIONS The current literature does not suggest a conclusive disease mechanism for TN in humans. In addition to neurovascular conflict/compression of the trigeminal nerve, recent studies have indicated that TN may be linked to inflammatory and reactive oxygen species signaling as well. Recent genetic studies in patients with TN have yet to be investigated further in animal models.

Is atlantoaxial instability the cause of Chiari malformation? Outcome analysis of 65 patients treated by atlantoaxial fixation

Is atlantoaxial instability the cause of Chiari malformation?

J Neurosurg Spine 22:116–127, 2015

Understanding that atlantoaxial instability is the cause of Chiari malformation (CM), the author treated 65 patients using atlantoaxial stabilization. The results are analyzed.

Methods Cases of CM treated using atlantoaxial fixation during the period from January 2010 to November 2013 were reviewed and analyzed. Surgery was aimed at segmental arthrodesis.

Results The author treated 65 patients with CM in the defined study period. Fifty-five patients had associated syringomyelia. Forty-six patients had associated basilar invagination. Thirty-seven patients had both basilar invagination and syringomyelia. Three patients had been treated earlier using foramen magnum decompression and duraplasty. According to the extent of their functional capabilities, patients were divided into 5 clinical grades. On the basis of the type of facetal alignment and atlantoaxial instability, the patients were divided into 3 groups. Type I dislocation (17 patients) was anterior atlantoaxial instability wherein the facet of the atlas was dislocated anterior to the facet of the axis. Type II dislocation (31 patients) was posterior atlantoaxial instability wherein the facet of the atlas was dislocated posterior to the facet of the axis. Type III dislocation (17 patients) was the absence of demonstrable facetal malalignment and was labeled as “central” atlantoaxial dislocation. In 18 patients, dynamic images showed vertical, mobile and at-least partially reducible atlantoaxial dislocation. All patients were treated with atlantoaxial plate and screw fixation using techniques described in 1994 and 2004. Foramen magnum decompression or syrinx manipulation was not performed in any patient. Occipital bone and subaxial spinal elements were not included in the fixation construct. One patient died, and death occurred in the immediate postoperative phase and was related to a vertebral artery injury incurred during the operation. One patient had persistent symptoms. In the rest of the patients there was gratifying clinical improvement. More remarkably, in 7 patients, the symptoms of lower cranial nerve paresis improved. No patient worsened in their neurological function after surgery. Reductions in the size of the syrinx and regression of the CM were observed in 6 of 11 cases in which postoperative MRI was possible. During the follow-up period, there was no delayed worsening of neurological function or symptoms in any patient. Sixty-three patients improved after surgery, and the improvement was sustained during the average follow-up period of 18 months.

Conclusions On the basis of outcomes in this study, it appears that the pathogenesis of CM with or without associated basilar invagination and/or syringomyelia is primarily related to atlantoaxial instability. The data suggest that the surgical treatment in these cases should be directed toward atlantoaxial stabilization and segmental arthrodesis. Except in cases in which there is assimilation of the atlas, inclusion of the occipital bone is neither indicated nor provides optimum stability. Foramen magnum decompression is not necessary and may be counter-effective in the long run.

Posterior ring apophysis separation combined with lumbar disc herniation in adults: a 10-year experience in the surgical management of 87 cases

J Neurosurg Spine 14:475–483, 2011 475. DOI: 10.3171/2010.11.SPINE10392

The association of posterior ring apophysis separation (PRAS) with lumbar disc herniation (LDH) is uncommon and represents a true subgroup of disc herniation mainly seen in the adolescent population. The objective of this study was to describe a decade of experience in the care of adult patients with PRAS with LDH, giving particular attention to its diagnosis, surgical treatment, and outcome.

Methods. This retrospective study focuses on a case series of adult patients with PRAS associated with LDH who underwent surgery for lumbar disc disease in the author’s neurosurgical department between 1999 and 2008. Posterior ring apophysis separation was diagnosed in 87 (5.35%) of 1625 patients surgically treated for LDH; these patients made up the PRAS group. During a 6-month period in 2005, LDH without PRAS was diagnosed in 89 consecutive patients at the same facility; these patients constituted the control group. Presenting symptoms, physical examination findings, and preoperative imaging results were obtained from medical records. Immediate operative results were assessed, as were complications, long-term outcome, and the need for repeat surgery.

Results. This study is the first to document the distinguishing features between adult patients with and those without PRAS. The difference in average age was statistically significant (p < 0.001) between the study group (36.22 years) and the control group (44.30 years), as was the incidence of male patients (86.20% vs 71.91%, p = 0.020), incidence of military patients (74.71% vs 57.30%, p = 0.015), average duration of symptoms (16.13 vs 8.4 months, p = 0.016), and incidence of reactive scoliosis (19.54% vs 4.49%, p = 0.002). The most common anatomical location of disc herniation in the PRAS group was L5–S1 (51.72%) versus L4–L5 (53.93%) in the control group (p = 0.017). In terms of previous injury, motor deficits, back and/or leg pain, lateral or central location of LDH, mean anteroposterior diameter of disc herniation, hard or soft discs, and surgical complications, there was no statistical difference between the 2 patient groups. Similarly, there was no difference in recurrence rates and clinical outcomes between the patients with or without PRAS.

Conclusions. Posterior ring apophysis separation with LDH is probably more common in adults than is generally recognized. It must be suspected when young male patients with persistent sciatic scoliosis and no history of injury show signs of calcified LDH. Computed tomography scanning with sagittal reconstructions is the procedure of choice for diagnosing. The L5–S1 intervertebral disc level is most commonly affected, especially the superior endplate of S-1. This condition needs more extensive surgical exposure and resection to relieve the nerve impingement. The occurrence of an apophyseal lesion was not associated with recurrent disc herniation or a fair outcome.

Mechanisms of cerebellar tonsil herniation in patients with Chiari malformations as guide to clinical management

Acta Neurochir (2010) 152:1117–1127.DOI 10.1007/s00701-010-0636-3

The pathogenesis of Chiari malformations is incompletely understood. We tested the hypothesis that different etiologies have different mechanisms of cerebellar tonsil herniation (CTH), as revealed by posterior cranial fossa (PCF) morphology.

Methods In 741 patients with Chiari malformation type I (CM-I) and 11 patients with Chiari malformation type II (CM-II), the size of the occipital enchondrium and volume of the PCF (PCFV) were measured on reconstructed 2D-CT and MR images of the skull. Measurements were compared with those in 80 age- and sex-matched healthy control individuals, and the results were correlated with clinical findings.

Results Significant reductions of PCF size and volume were present in 388 patients with classical CM-I, 11 patients with CM-II, and five patients with CM-I and craniosynostosis. Occipital bone size and PCFV were normal in 225 patients with CM-I and occipitoatlantoaxial joint instability, 55 patients with CM-I and tethered cord syndrome (TCS), 30 patients with CM-I and intracranial mass lesions, and 28 patients with CM-I and lumboperitoneal shunts. Ten patients had miscellaneous etiologies. The size and area of the foramen magnum were significantly smaller in patients with classical CM-I and CM-I occurring with craniosynostosis and significantly larger in patients with CM-II and CM-I occurring with TCS.

Conclusions Important clues concerning the pathogenesis of CTH were provided by morphometric measurements of the PCF. When these assessments were correlated with etiological factors, the following causal mechanisms were suggested: (1) cranial constriction; (2) cranial settling; (3) spinal cord tethering; (4) intracranial hypertension; and (5) intraspinal hypotension

Characterization of Cyclic CSF Flow in the Foramen Magnum and Upper Cervical Spinal Canal with MR Flow Imaging and Computational Fluid Dynamics

AJNR Am J Neuroradiol 31:997–1002.DOI 10.3174/ajnr.A1995

CSF flow has been shown to exhibit complex patterns in MR images in both healthy subjects and in patients with Chiari I. Abnormal CSF flow oscillations, according to prevailing opinion, cause syringomyelia and other clinical manifestations that affect some patients with the Chiari I malformation.

For this article, we reviewed the literature on PC MR of CSF flow, collected the published CFD studies relevant to CSF flow, and performed flow simulations. PC MR creates cine and still images of CSF flow and measurements of flow velocities. CFD, a technique used to compute flow and pressure in liquid systems, simulates the CSF flow patterns that occur in a specific geometry or anatomy of the SAS and a specific volume of flow.

Published PC MR studies show greater peak CSF velocities and more complex flow patterns in patients with Chiari I than in healthy subjects, with synchronous bidirectional flow one of the characteristic markers of pathologic flow. In mathematic models of the SAS created from high-resolution MR images, CFD displays complex CSF flow patterns similar to those shown in PC MR in patients. CFD shows that the pressure and flow patterns vary from level to level in the upper spinal canal and differ between patients with Chiari and healthy volunteers. In models in which elasticity and motion are incorporated, CFD displays CSF pressure waves in the SAS.

PC MR and CFD studies to date demonstrate significant alterations of CSF flow and pressure patterns in patients with Chiari I. CSF flow has nonlaminar complex spatial and temporal variations and associated pressure waves and pressure gradients. Additional simulations of CSF flow supplemented by PC MR will lead to better measures for distinguishing pathologic flow abnormalities that cause syringomyelia, headaches, and other clinical manifestations in Chiari I malformations.

CFD  computational fluid dynamics; PC MR  phase-contrast cardiac-gated MR studies; SAS  subarachnoid space

Pathogenesis of syringomyelia associated with Chiari type 1 malformation: review of evidences and proposal of a new hypothesis

Neurosurg Rev (2010) 33:271–285. DOI 10.1007/s10143-010-0266-5

The exact pathogenesis of syringomyelia associated with Chiari type 1 malformation is unknown, although a number of authors have reported their theories of syrinx formation. The purpose of this review is to understand evidences based on the known theories and to create a new hypothesis of the pathogenesis. We critically review the literatures on clinicopathological, radiological, and clinical features of this disorder.

The previously proposed theories mainly focused on the driven mechanisms of the cerebrospinal fluid (CSF) into the spinal cord. They did not fully explain radiological features or effects of surgical treatment such as shunting procedures.

Common findings of the syrinx in clinicopathological studies were the communication with the central canal and extracanalicular extension to the posterior gray matter. Most of the magnetic resonance imaging studies demonstrated blockade and alternated CSF dynamics at the foramen magnum, but failed to show direct communication of the syrinx with the CSF spaces.

Pressure studies revealed almost identical intrasyrinx pressure to the subarachnoid space and decreased compliance of the spinal CSF space.

Recent imaging studies suggest that the extracellular fluid accumulation may play an important role. The review of evidences promotes a new hypothesis of syrinx formation. Decreased absorption mechanisms of the extracellular fluid may underlie the pathogenesis of syringomyelia. Reduced compliance of the posterior spinal veins associated with the decreased compliance of the spinal subarachnoid space will result in disturbed absorption of the extracellular fluid through the intramedullary venous channels and formation of syringomyelia.