Pain

Trigeminal nerve

Trigeminal nerve

Johann Friedrich Meckel made the first description of the subarachnoid space investing the trigeminal nerve into the middle fossa.

Possible pathways for facial pain include: trigeminal nerve (portio major as well as portio minor (motor root).

Supratentorial sensory perception, including facial pain, is subserved by the trigeminal nerve, in particular, by the branches of its ophthalmic nerve, which provide an extensive innervation of the dura mater and of the major brain blood vessels. In addition, contrary to previous assumptions, studies on awake patients during surgery have demonstrated that the mechanical stimulation of the pia mater and small cerebral vessels can also produce pain. The trigeminovascular system, located at the interface between the nervous and vascular systems, is therefore perfectly positioned to detect sensory inputs and influence blood flow regulation. Despite the fact that it remains only partially understood, the trigeminovascular system is most probably involved in several pathologies, including very frequent ones such as migraine, or other severe conditions, such as subarachnoid hemorrhage. The incomplete knowledge about the exact roles of the trigeminal system in headache, blood flow regulation, Blood-brain Barrier Permeability, and trigemino-cardiac reflex warrants for an increased investigation of the anatomy and physiology of the trigeminal system 1).

Anatomy

The trigeminal nerve complex is a very important and somewhat unique component of the nervous system. It is responsible for the sensory signals that arise from the most part of the face, mouth, nose, meninges, and facial muscles, and also for the motor commands carried to the masticatory muscles. These signals travel through a very complex set of structures: dermal receptors, trigeminal branches, Gasserian ganglion, central nuclei, and thalamus, finally reaching the cerebral cortex. Other neural structures participate, directly or indirectly, in the transmission and modulation of the signals, especially the nociceptive ones; these include vagus nerve, sphenopalatine ganglion, occipital nerves, cervical spinal cord, periaqueductal gray matter, hypothalamus, and motor cortex. But not all stimuli transmitted through the trigeminal system are perceivable. There is a constant selection and modulation of the signals, with either suppression or potentiation of the impulses. As a result, either normal sensory perceptions are elicited or erratic painful sensations are created 2).

Originating in the posterior fossa of the brain stem, it follows a long and complex course towards its distribution territory, crossing several regions with a complex anatomy and establishing important relationships with several structures.

The nerve fibers originate in the brainstem and are part of several grey matter nuclei occupying all the brainstem and even the first spinal cervical segments.

Each of these sensitive and motor nuclei represents different processing centers, and there is a true systematization of the information this nervous tract is responsible for conducting.

The sensitive nucleus is the largest, comprising 3 true sub-nuclei, each responsible for each aspect of the general sensitivity. The highest is the mesencephalic nucleus, located in the tegmentum close to the midline and to the grey matter close to the Sylvian aqueduct. The neurons that form this nucleus are in charge of the propioceptive integration in the Vth nerve territory, high level information for correct mastication. The main nucleus is in the pons, it is also situated in the depth of the tegmentum, and is responsible for the tactile integration of the territory of this nerve. Finally, the inferior nucleus occupies the tegmentum of the medulla, extending caudally to the first segments of the cervical spine, and is in charge of thermal and pain information. Its location explains the possible appearance of symptoms in the facial territory in patients with a degenerative/inflammatory disorder of the upper cervical spine. There is one single motor nucleus, located in the pons tegmentum supplying mastication muscles, and is correspondingly called mastication nucleus. The fibers related with all these nuclei gather in the pons and emerge through the lateral sector of its anterior aspect, forming a thick nervous tract with two roots: a thicker and lateral sensitive root and a thinner more medial motor root.

The only intra-axial segment of the Vth ends there and initiates its long course to its distribution territory; it is formed by different sub-segments before dividing itself into its terminal branches (the cisternal and Gasserian or transdural segments).

The point where the roots emerge in the brainstem is called “REZ” (Root Entry Zone), an anatomical landmark of great functional hierarchy.

Trigeminal nerve cisternal portion

see Trigeminal nerve cisternal portion.

Branches

The trigeminal nerve as the name indicates is composed of three large branches. They are the ophthalmic nerve (V1, sensory), maxillary nerve (V2, sensory), and mandibular nerve (V3, motor and sensory) branches. The large sensory root and smaller motor root leave the brainstem at the mid-lateral surface of pons.

Function

The trigeminal nerve (the fifth cranial nerve, or simply CN V) is a nerve responsible for sensation in the face and certain motor functions such as biting and chewing. It is the largest of the cranial nerves. Its name (“trigeminal” = tri- or three, and -geminus or twin, or thrice twinned) derives from the fact that each trigeminal nerve, one on each side of the pons, has three major branches: the ophthalmic nerve (V1), the maxillary nerve (V2), and the mandibular nerve (V3). The ophthalmic and maxillary nerves are purely sensory. The mandibular nerve has both cutaneous and motor functions.

Sensory information from the face and body is processed by parallel pathways in the central nervous system. The motor division of the trigeminal nerve is derived from the basal plate of the embryonic pons, while the sensory division originates from the cranial neural crest.

Trigeminal nerve sensory pathways

see Trigeminal nerve sensory pathways.

Trigeminal nerve-related pathology

Trigeminal nerve-related pathology.

Imaging

see Trigeminal nerve imaging.

References

1)

Terrier LM, Hadjikhani N, Velut S, Magnain C, Amelot A, Bernard F, Zöllei L, Destrieux C. The trigeminal system: The meningovascular complex- A review. J Anat. 2021 Feb 18. doi: 10.1111/joa.13413. Epub ahead of print. PMID: 33604906.
2)

Goellner E, Rocha CE. Anatomy of Trigeminal Neuromodulation Targets: From Periphery to the Brain. Prog Neurol Surg. 2020 Oct 6;35:1-17. doi: 10.1159/000511257. Epub ahead of print. PMID: 33022684.

Ziconotide

Ziconotide

Decreasing the risk of granuloma formation. with ziconotide 1) have been indeterminate, with some case reports demonstrating regression 2) and others showing persistence of inflammation 3) after substitution.

Intrathecal drug therapy has been established as an effective treatment option for patients with chronic pain of malignant or non-malignant origin, with an established safety profile and fewer adverse effects, compared to oral or parenteral pain medications. Morphine (a μ-opioid receptor agonist) and ziconotide (a non-opioid calcium channel antagonist) are the only IT agents approved by the US Food and Drug Administration for chronic pain treatment. Although both are considered first-line IT therapies, each drug has unique properties and considerations.

A review of Chalil et al. will evaluate the pivotal trials that established the use of morphine and ziconotide as first-line IT therapy for patients with chronic pain, as well as safety and efficacy data generated from various retrospective and prospective studies.

Morphine and ziconotide are effective IT therapies for patients with chronic malignant or non-malignant pain that is refractory to other interventions. IT ziconotide is recommended as first-line therapy due to its efficacy and avoidance of many adverse effects commonly associated with opioids. The use of IT morphine is also considered first-line; however, the risks of respiratory depression, withdrawal with drug discontinuation or pump malfunction, and the development of tolerance require careful patient selection and management 4).

Shao et al. showed that ziconotide intrathecal drug therapy improves pain as well as emotional components and function. The study adds prospective evidence to the literature on IDT for neuropathic pain, specifically its role in improving disability, emotional well-being, and catastrophizing 5).

Case reports

Staub et al. reported the first case describing the use of a single-shot lumbar intrathecal trial of ziconotide and subsequent placement of lumbar (as opposed to thoracic) intrathecal ziconotide pump for persistent idiopathic facial pain (PIFP). A single-injection intrathecal trial is a low-risk, viable option for patients with this debilitating and frustrating pain condition. Successful trials and subsequent intrathecal pump placement with ziconotide may supplant multimodal medication management and/or invasive orofacial surgical intervention for PIFP 6).

References

1)

Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference–2012: consensus on diagnosis, detection, and treatment of catheter-tip granulomas (inflammatory masses). Neuromodulation. 2012; 15: 483–95; discussion 496
2)

Codipietro L, Maino P. Aseptic arachnoiditis in a patient treated with intrathecal morphine infu- sion: symptom resolution on switch to ziconotide. Neuromodulation. 2015; 18:217–20; discussion 220
3)

Tomycz ND, Ortiz V, McFadden KA, et al. Management of symptomatic intrathecal catheter- associated inflammatory masses. Clin Neurol Neurosurg. 2012; 114:190–195
4)

Chalil A, Staudt MD, Harland TA, Leimer EM, Bhullar R, Argoff CE. A safety review of approved intrathecal analgesics for chronic pain management. Expert Opin Drug Saf. 2021 Feb 15. doi: 10.1080/14740338.2021.1889513. Epub ahead of print. PMID: 33583318.
5)

Shao MM, Khazen O, Hellman A, Czerwinski M, Dentinger R, DiMarzio M, Gillogly M, Hadanny A, Argoff C, Pilitsis JG. Effect of First-Line Ziconotide Intrathecal Drug Therapy for Neuropathic Pain on Disability, Emotional Well-Being, and Pain Catastrophizing. World Neurosurg. 2021 Jan;145:e340-e347. doi: 10.1016/j.wneu.2020.10.079. Epub 2020 Oct 20. PMID: 33096281.
6)

Staub BP, Casini GP, Monaco EA 3rd, Sekula RF Jr, Emerick TD. Near-resolution of persistent idiopathic facial pain with low-dose lumbar intrathecal ziconotide: a case report. J Pain Res. 2019 Mar 8;12:945-949. doi: 10.2147/JPR.S193746. PMID: 30881103; PMCID: PMC6413753.

Dorsal root ganglion

Dorsal root ganglion

A posterior root ganglion (or spinal ganglion) (also known as a dorsal root ganglion), is a cluster of nerve cell bodies (a ganglion) in a posterior root of a spinal nerve.

This structure is critical in the processing of the pain signal from the peripheral nervous system to its position in the central nervous system.

1st order neuron: small, finely myelinated afferents; soma in dorsal root ganglion (no synapse). Enter cord at dorsolateral tract (zone of Lissauer). Synapse: substantia gelatinosa (Rexed II).

The dorsal root ganglion (sensory) is also located in the foramen within the nerve root sheath.

In the “STIR” image the dorsal root ganglion may enhance on fat suppression images.

In extreme lateral lumbar disc herniation pain tends to be more severe (may be due to the fact that the dorsal root ganglion may be compressed directly) and often has more of a burning dysesthetic quality.

Compression of the dorsal root ganglion may result in a slower recovery from discectomy and overall less satisfying outcome than with the more commonplace paramedian disc herniation.

In a study, Sanz et al. identified a metalloproteinase-dependent mechanism necessary to promote growth in embryonic dorsal root ganglion cells (DRGs). Treatment of embryonic DRG neurons with pan-metalloproteinase inhibitors, tissue inhibitor of metalloproteinase-3, or an inhibitor of ADAM Metallopeptidase Domain 10 (ADAM10) reduces outgrowth from DRG neurons indicating that metalloproteinase activity is important for outgrowth.

The IgLON family members Neurotrimin (NTM) and Limbic System-Associated Membrane Protein (LSAMP) were identified as ADAM10 substrates that are shed from the cell surface of Dorsal root ganglion (DRG) neurons. Overexpression of LSAMP and NTM suppresses outgrowth from DRG neurons. Furthermore, LSAMP loss of function decreases the outgrowth sensitivity to an ADAM10 inhibitor. Together this findings support a role for ADAM-dependent shedding of cell surface LSAMP in promoting outgrowth from DRG neurons 1).

Dorsal root ganglion recording

Dorsal root ganglion (DRG) are promising sites for recording sensory activity. Current technologies for DRG recording are stiff and typically do not have sufficient site density for high-fidelity neural data techniques.

In acute experiments, Sperry et al. demonstrated single-unit neural recordings in sacral DRG of anesthetized felines using a 4.5 µm-thick, high-density flexible polyimide microelectrode array with 60 sites and 30-40 µm site spacing. They delivered arrays into DRG with ultrananocrystalline diamond shuttles designed for high stiffness affording a smaller footprint. They recorded neural activity during sensory activation, including cutaneous brushing and bladder filling, as well as during electrical stimulation of the pudendal nerve and anal sphincter. They used a specialized neural signal analysis software to sort densely-packed neural signals.

They successfully delivered arrays in five of six experiments and recorded single-unit sensory activity in four experiments. The median neural signal amplitude was 55 μV peak-to-peak and the maximum unique units recorded at one array position was 260, with 157 driven by sensory or electrical stimulation. In one experiment, they used the neural analysis software to track eight sorted single units as the array was retracted ~500 μm.

This study is the first demonstration of ultrathin, flexible, high-density electronics delivered into DRG, with capabilities for recording and tracking sensory information that is a significant improvement over conventional DRG interfaces 2).

C2 root ganglion

C2 root ganglion.

Sacral dorsal root ganglion

Sacral dorsal root ganglion.

Dorsal root ganglion stimulation

Dorsal root ganglion stimulation.

References

1)

Sanz RL, Ferraro GB, Girouard MP, Fournier AE. Ectodomain shedding of Limbic System-Associated Membrane Protein (LSAMP) by ADAM Metallopeptidases promotes neurite outgrowth in DRG neurons. Sci Rep. 2017 Aug 11;7(1):7961. doi: 10.1038/s41598-017-08315-0. PubMed PMID: 28801670.
2)

Sperry ZJ, Na K, Jun J, Madden LR, Socha A, Yoon E, Seymour J, Bruns TM. High-density neural recordings from feline sacral dorsal root ganglia with thin-film array. J Neural Eng. 2021 Feb 5. doi: 10.1088/1741-2552/abe398. Epub ahead of print. PMID: 33545709.

Diffusion tensor imaging for trigeminal neuralgia

Diffusion tensor imaging for trigeminal neuralgia

A total of 22 patients with classic trigeminal neuralgia and 22 healthy controls (HC) with matching age, gender, and education were selected. All subjects underwent 3.0 T magnetic resonance diffusion tensor imaging and high resolution T1-weighted imaging. The corpus callosum (CC) was reconstructed by DTI technology, which was divided into three substructure regions: genu, body, and splenium. Group differences in multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD), were compared between CTN patients and HC, and correlations between the white matter change and disease duration and VAS in CTN patients were assessed.

Compared with HC group, CTN patients had extensive damage to the CC white matter. The FA of the genu (P = 0.04) and body (P = 001) parts decreased, while RD (P = 0.003; P = 0.02) and MD (P = 0.002; P = 0.04) increased. In addition, the authors observed that the disease duration and VAS of CTN patients were negatively correlated with FA.

The corpus callosum substructure region has extensive damage in chronic pain, and the selective microstructural integrity damage was particularly manifested by changes in axons and myelin sheath in the genu and body of corpus callosum 1).

Diffusion tensor imaging (DTI) has revealed microstructural changes in the symptomatic trigeminal root and root entry zone of patients with unilateral TN.

Noninvasive DTI analysis of patients with TN may lead to improved trigeminal neuralgia diagnosis of TN subtypes (e.g., TN1 and TN2) and improve patient selection for surgical intervention. DTI measurements may also provide insights into prognosis after intervention, as TN1 patients are known to have better surgical outcomes than TN2 patients 2).

As diffusion tensor imaging (DTI) is able to assess tissue integrity, Leal et al., used diffusion to detect abnormalities in trigeminal nerves (TGN) in patients with trigeminal neuralgia (TN) caused by neurovascular compression (NVC) who had undergone microvascular decompression (MVD).

Using DTI sequencing on a 3-T MRI scanner, we measured the fraction of anisotropy (FA) and apparent diffusion coefficient (ADC) of the TGN in 10 patients who had undergone MVD for TN and in 6 normal subjects. We compared data between affected and unaffected nerves in patients and both nerves in normal subjects (controls). We then correlated these data with CSA and V. Data from the affected side and the unaffected side before and 4 years after MVD were compared.

RESULTS: Before MVD, the FA of the affected side (0.37 ± 0.03) was significantly lower (p < 0.05) compared to the unaffected side in patients (0.48 ± 0.03) and controls (0.52 ± 0.02), and the ADC in the affected side (5.6 ± 0.34 mm2/s) was significantly higher (p < 0.05) compared to the unaffected side in patients (4.26 ± 0.25 mm2/s) and controls (3.84 ± 0.18 mm2/s). Affected nerves had smaller V and CSA compared to unaffected nerves and controls (p < 0.05). After MVD, the FA in the affected side (0.41 ± 0.02) remained significantly lower (p < 0.05) compared to the unaffected side (0.51 ± 0.02), but the ADC in the affected side (4.24 ± 0.34 mm2/s) had become similar (p > 0.05) to the unaffected side (4.01 ± 0.33 mm2/s).

CONCLUSIONS: DTI revealed a loss of anisotropy and an increase in diffusivity in affected nerves before surgery. Diffusion alterations correlated with atrophic changes in patients with TN caused by NVC. After removal of the compression, the loss of FA remained, but ADC normalized in the affected nerves, suggesting improvement in the diffusion of the trigeminal root 3).

Herveh et al. studied the trigeminal nerve in seven healthy volunteers and six patients with trigeminal neuralgia using the diffusion tensor imaging derived parameter fractional anisotropy (FA). While controls did not show a difference between both sides, there was a reduction of FA in the affected nerve in three of six patients with accompanying nerve-vessel conflict and atrophy. Reversibility of abnormally low FA values was demonstrated in one patient successfully treated with microvascular decompression 4).

3T MR diffusion weighted, T1, T2 and FLAIR sequences were acquired for Multiple sclerosis related trigeminal neuralgia MS-TN, TN, and controls. Multi-tensor tractography was used to delineate CN V across cisternal, root entry zone (REZ), pontine and peri-lesional segments. Diffusion metrics including fractional anisotropy (FA), and radial (RD), axial (AD), and mean diffusivities (MD) were measured from each segment.

CN V segments showed distinctive diffusivity patterns. The TN group showed higher FA in the cisternal segment ipsilateral to the side of pain, and lower FA in the ipsilateral REZ segment. The MS-TN group showed lower FA in the ipsilateral peri-lesional segments, suggesting differential microstructural changes along CN V in these conditions.

The study demonstrates objective differences in CN V microstrucuture in TN and MS-TN using non-invasive neuroimaging. This represents a significant improvement in the methods currently available to study pain in MS 5).

The aim of a study was to evaluate the microstructural tissue abnormalities in the trigeminal nerve in symptomatic trigeminal neuralgia not related to neurovascular compression using diffusion tensor imaging. Mean values of the quantitative diffusion parameters of trigeminal nerve, fractional anisotropy and apparent diffusion coefficient, were measured in a group of four symptomatic trigeminal neuralgia patients without neurovascular compression who showed focal non-enhancing T2-hyperintense lesions in the pontine trigeminal pathway. These diffusion parameters were compared between the affected and unaffected sides in the same patient and with four age-matched healthy controls. Cranial magnetic resonance imaging revealed hyperintense lesions in the dorsolateral part of the pons along the central trigeminal pathway on T2-fluid-attenuated inversion recovery sequences. The mean fractional anisotropy value on the affected side was significantly decreased (P = 0.001) compared to the unaffected side and healthy controls. Similarly, the mean apparent diffusion coefficient value was significantly higher (P = 0.001) on the affected side compared to the unaffected side and healthy controls. The cause of trigeminal neuralgia in our patients was abnormal pontine lesions affecting the central trigeminal pathway. The diffusion tensor imaging results suggest that microstructural tissue abnormalities of the trigeminal nerve also exist even in non-neurovascular compression-related trigeminal neuralgia 6).

DTI analysis allows the quantification of structural alterations, even in those patients without any discernible neurovascular contact on MRI. Moreover, our findings support the hypothesis that both the arteries and veins can cause structural alterations that lead to TN. These aspects can be useful for making treatment decisions 7).

The mean diameter of compression arteries (DCA) in NVC patients with TN (1.58 ± 0.34 mm) was larger than that without TN (0.89 ± 0.29 mm). Compared with NVC without TN and HC, the mean values of RD at the site of NVC with TN were significantly increased; however, no significant changes of AD were found between the groups. Correlation analysis showed that DCA positively correlated with radial diffusivity (RD) in NVC patients with and without TN (r = 0.830, p = 0.000). No significant correlation was found between DCA and axial diffusivity (AD) (r = 0.178, p = 0.077).

Larger-diameter compression arteries may increase the chances of TN, and may be a possible facilitating factor for TN 8).

Fractional anisotropy (FA) value quantitatively showed the alteration of trigeminal nerve (TGN) caused by Neurovascular compression (NVC). It provided direct evidence about the effect of NVC which facilitated the diagnosis and surgical decision of Type 2 trigeminal neuralgia (TN) . Besides, significant reduction of FA value may predict an optimistic outcome of microvascular decompression (MVD) 9).

Sophisticated structural MRI techniques including diffusion tensor imaging provide new opportunities to assess the trigeminal nerves and CNS to provide insight into TN etiology and pathogenesis. Specifically, studies have used high-resolution structural MRI methods to visualize patterns of trigeminal nerve-vessel relationships and to detect subtle pathological features at the trigeminal REZ. Structural MRI has also identified CNS abnormalities in cortical and subcortical gray matter and white matter and demonstrated that effective neurosurgical treatment for TN is associated with a reversal of specific nerve and brain abnormalities 10).

Forty-three patients with trigeminal neuralgia were recruited, and diffusion tensor imaging was performed before radiofrequency rhizotomy. By selecting the cisternal segment of the trigeminal nerve manually, they measured the volume of trigeminal nerve, fractional anisotropy, apparent diffusion coefficient, axial diffusivity, and radial diffusivity. The apparent diffusion coefficient and mean value of fractional anisotropy, axial diffusivity, and radial diffusivity were compared between the affected and normal side in the same patient, and were correlated with pre-rhizotomy and post-rhizotomy visual analogue scale pain scores. The results showed the affected side had significantly decreased fractional anisotropy, increased apparent diffusion coefficient and radial diffusivity, and no significant change of axial diffusivity. The volume of the trigeminal nerve on affected side was also significantly smaller. There was a trend of fractional anisotropy reduction and visual analogue scale pain score reduction (P = 0.072). The results suggest that demyelination without axonal injury, and decreased size of the trigeminal nerve, are the microstructural abnormalities of the trigeminal nerve in patients with trigeminal neuralgia caused by neurovascular compression. The application of diffusion tensor imaging in understanding the pathophysiology of trigeminal neuralgia, and predicting the treatment effect has potential and warrants further study 11).

References

1)

Li R, Chang N, Liu Y, Zhang Y, Luo Y, Zhang T, Zhao Q, Qi X. The Integrity of the Substructure of the Corpus Callosum in Patients with Right Classic Trigeminal Neuralgia-A Diffusion Tensor Imaging Study. J Craniofac Surg. 2020 Sep 22. doi: 10.1097/SCS.0000000000007082. Epub ahead of print. PMID: 32969923.
2)

Willsey MS, Collins KL, Conrad EC, Chubb HA, Patil PG. Diffusion tensor imaging reveals microstructural differences between subtypes of trigeminal neuralgia. J Neurosurg. 2019 Jul 19:1-7. doi: 10.3171/2019.4.JNS19299. [Epub ahead of print] PubMed PMID: 31323635.
3)

Leal PRL, Roch J, Hermier M, Berthezene Y, Sindou M. Diffusion tensor imaging abnormalities of the trigeminal nerve root in patients with classical trigeminal neuralgia: a pre- and postoperative comparative study 4 years after microvascular decompression. Acta Neurochir (Wien). 2019 May 2. doi: 10.1007/s00701-019-03913-5. [Epub ahead of print] PubMed PMID: 31049710.
4)

Herweh C, Kress B, Rasche D, Tronnier V, Tröger J, Sartor K, Stippich C. Loss of anisotropy in trigeminal neuralgia revealed by diffusion tensor imaging. Neurology. 2007 Mar 6;68(10):776-8. PubMed PMID: 17339587.
5)

Chen DQ, DeSouza DD, Hayes DJ, Davis KD, O’Connor P, Hodaie M. Diffusivity signatures characterize trigeminal neuralgia associated with multiple sclerosis. Mult Scler. 2016 Jan;22(1):51-63. doi: 10.1177/1352458515579440. PubMed PMID: 25921052.
6)

Neetu S, Sunil K, Ashish A, Jayantee K, Usha Kant M. Microstructural abnormalities of the trigeminal nerve by diffusion-tensor imaging in trigeminal neuralgia without neurovascular compression. Neuroradiol J. 2016 Feb;29(1):13-8. doi: 10.1177/1971400915620439. PubMed PMID: 26678753; PubMed Central PMCID: PMC4978338.
7)

Lutz J, Thon N, Stahl R, Lummel N, Tonn JC, Linn J, Mehrkens JH. Microstructural alterations in trigeminal neuralgia determined by diffusion tensor imaging are independent of symptom duration, severity, and type of neurovascular conflict. J Neurosurg. 2016 Mar;124(3):823-30. doi: 10.3171/2015.2.JNS142587. PubMed PMID: 26406792.
8)

Lin W, Zhu WP, Chen YL, Han GC, Rong Y, Zhou YR, Zhang QW. Large-diameter compression arteries as a possible facilitating factor for trigeminal neuralgia: analysis of axial and radial diffusivity. Acta Neurochir (Wien). 2016 Mar;158(3):521-6. doi: 10.1007/s00701-015-2673-4. PubMed PMID: 26733127; PubMed Central PMCID: PMC4752583.
9)

Chen F, Chen L, Li W, Li L, Xu X, Li W, Le W, Xie W, He H, Li P. Pre-operative declining proportion of fractional anisotropy of trigeminal nerve is correlated with the outcome of micro-vascular decompression surgery. BMC Neurol. 2016 Jul 16;16:106. doi: 10.1186/s12883-016-0620-5. PubMed PMID: 27422267; PubMed Central PMCID: PMC4947245.
10)

DeSouza DD, Hodaie M, Davis KD. Structural Magnetic Resonance Imaging Can Identify Trigeminal System Abnormalities in Classical Trigeminal Neuralgia. Front Neuroanat. 2016 Oct 19;10:95. Review. PubMed PMID: 27807409; PubMed Central PMCID: PMC5070392.
11)

Chen ST, Yang JT, Yeh MY, Weng HH, Chen CF, Tsai YH. Using Diffusion Tensor Imaging to Evaluate Microstructural Changes and Outcomes after Radiofrequency Rhizotomy of Trigeminal Nerves in Patients with Trigeminal Neuralgia. PLoS One. 2016 Dec 20;11(12):e0167584. doi: 10.1371/journal.pone.0167584. PubMed PMID: 27997548.

Occipital nerve stimulation for cluster headache

Occipital nerve stimulation for cluster headache

Occipital nerve stimulation (ONS) has been proposed chronic cluster headache treatment (rCCH) but its efficacy has only been showed in small short-term series.

Leplus et al. evaluated 105 patients with rCCH, treated by ONS within a multicenter ONS prospective registry. Efficacy was evaluated by frequency, intensity of pain attacks, quality of life (QoL) EuroQol 5 dimensions (EQ5D), functional (Headache Impact Test-6, Migraine Disability Assessment) and emotional (Hospital Anxiety Depression Scale [HAD]) impacts, and medication consumption.

At last follow-up (mean 43.8 mo), attack frequency was reduced >50% in 69% of the patients. Mean weekly attack frequency decreased from 22.5 at baseline to 9.9 (P < .001) after ONS. Preventive and abortive medications were significantly decreased. Functional impact, anxiety, and QoL significantly improved after ONS. In excellent responders (59% of the patients), attack frequency decreased by 80% and QoL (EQ5D visual analog scale) dramatically improved from 37.8/100 to 73.2/100. When comparing baseline and 1-yr and last follow-up outcomes, efficacy was sustained over time. In multivariable analysis, low preoperative HAD-depression score was correlated to a higher risk of ONS failure. During the follow-up, 67 patients experienced at least one complication, 29 requiring an additional surgery: infection (6%), lead migration (12%) or fracture (4.5%), hardware dysfunction (8.2%), and local pain (20%).

The results showed that long–term efficacy of ONS in CCH was maintained over time. In responders, ONS induced a major reduction of functional and emotional headache-related impacts and a dramatic improvement of QoL. These results obtained in real-life conditions support its use and dissemination in rCCH patients 1).

33 patients, of whom 16 had chronic migraine (CM), nine had chronic cluster headache (CCH), and six had secondary headache disorders. PENS was given using Algotec® disposable 21 gauge PENS therapy probes (8 cm) to the occipital nerve ipsilateral to the pain (or bilaterally in cases of bilateral pain). Stimulation was delivered at 2 Hz/100 Hz, at 3 cycles/s, between 1.2 and 2.5 V depending on patient tolerability, for 25-28 min.

Six of nine patients with CCH improved significantly after the first session. In all patients with CCH, PENS therapy was well tolerated, with no significant adverse events reported. One patient with CCH reverted to an episodic cluster. Only four patients with CM experienced any benefit.

PENS therapy shows potential as a relatively non-invasive, low-risk, and inexpensive component of the treatment options for refractory primary headache disorders, particularly CCH 2).

Seventeen patients (12 CM and 5 CCH) were treated with bilateral burst pattern ONS, including 4 who had previously had tonic ONS. Results were assessed in terms of the frequency of headaches (number of headache days per month for CM, and number of attacks per day for CCH) and their intensity on the numeric pain rating scale.

Burst ONS produced a statistically significant mean reduction of 10.2 headache days per month in CM. In CCH, there were significant mean reductions in headache frequency (92%) and intensity (42%).

Paraesthesia is not necessary for good quality analgesia in ONS. Larger studies will be required to determine whether the efficacies of the two stimulation modes differ. Burst ONS is imperceptible and therefore potentially amenable to robustly blinded clinical trials 3).

Eight patients with medically intractable chronic cluster headache were implanted in the suboccipital region with electrodes for occipital nerve stimulation. Other than the first patient, who was initially stimulated unilaterally before being stimulated bilaterally, all patients were stimulated bilaterally during treatment.

At a median follow-up of 20 months (range 6-27 months for bilateral stimulation), six of eight patients reported responses that were sufficiently meaningful for them to recommend the treatment to similarly affected patients with chronic cluster headache. Two patients noticed a substantial improvement (90% and 95%) in their attacks; three patients noticed a moderate improvement (40%, 60%, and 20-80%) and one reported mild improvement (25%). Improvements occurred in both frequency and severity of attacks. These changes took place over weeks or months, although attacks returned in days when the device malfunctioned (eg, with battery depletion). Adverse events of concern were lead migrations in one patient and battery depletion requiring replacement in four.

Occipital nerve stimulation in cluster headache seems to offer a safe, effective treatment option that could begin a new era of neurostimulation therapy for primary headache syndromes 4).

References

1)

Leplus A, Fontaine D, Donnet A, Regis J, Lucas C, Buisset N, Blond S, Raoul S, Guegan-Massardier E, Derrey S, Jarraya B, Dang-Vu B, Bourdain F, Valade D, Roos C, Creach C, Chabardes S, Giraud P, Voirin J, Bloch J, Colnat-Coulbois S, Caire F, Rigoard P, Tran L, Cruzel C, Lantéri-Minet M; French ONS registry group. Long–Term Efficacy of Occipital Nerve Stimulation for Medically Intractable Cluster Headache. Neurosurgery. 2020 Sep 28:nyaa373. doi: 10.1093/neuros/nyaa373. Epub ahead of print. PMID: 32985662.
2)

Weatherall MW, Nandi D. Percutaneous electrical nerve stimulation (PENS) therapy for refractory primary headache disorders: a pilot study. Br J Neurosurg. 2019 Oct 3:1-5. doi: 10.1080/02688697.2019.1671951. [Epub ahead of print] PubMed PMID: 31578882.
3)

Garcia-Ortega R, Edwards T, Moir L, Aziz TZ, Green AL, FitzGerald JJ. Burst Occipital Nerve Stimulation for Chronic Migraine and Chronic Cluster Headache. Neuromodulation. 2019 Jul;22(5):638-644. doi: 10.1111/ner.12977. Epub 2019 Jun 14. PubMed PMID: 31199547.
4)

Burns B, Watkins L, Goadsby PJ. Treatment of medically intractable cluster headache by occipital nerve stimulation: long–term follow-up of 8 patients. Lancet. 2007; 369:1099–1106

Postoperative pain

Postoperative pain

Perioperative pain assessment and management in neurosurgical patients varies widely across the globe. There is lack of data from developing world regarding practices of pain assessment and management in neurosurgical population.

A survey aimed to capture practices and perceptions regarding perioperative pain assessment and management in neurosurgical patients among anesthesiologists who are members of the Indian Society of Neuroanaesthesiology and Critical Care (ISNACC) and evaluated if hospital and pain characteristics predicted the use of structured pain assessment protocol and use of opioids for postoperative pain management.

A 26-item English language questionnaire was administered to members of ISNACC using Kwiksurveys platform after ethics committee approval. This outcome measures were adoption of structured protocol for pain assessment and opioid usage for postoperative pain management.

The response rate for this survey was 55.15% (289/524). One hundred eighteen (41%) responders informed that their hospital setup had a structured pain protocol while 43 (15%) responders reported using opioids for postoperative pain management. Predictors of the use of structured pain protocol were private setup (odds ratio [OR] 2.64; 95% confidence interval [CI] 1.52-4.59; p=0.001), higher pain intensity (OR 0.37; 95% CI 0.21-0.64; p<0.001) and use of pain scale (OR 7.94; 95% CI 3.99-15.81; p<0.001) while availability of structured pain protocol (OR 2.04; 95% CI 1.02-4.05; p=0.043) was the only significant variable for postoperative opioid use.

Less than half of the Indian neuroanesthesiologists who are members of ISNACC use structured protocol for pain assessment and very few use opioids for postoperative pain management in neurosurgical patients 1).

Studying the characteristics of postoperative pain at such an early stage allows for improved management. It helps to predict, according to the type of surgery and the anaesthesia used, those patients in which higher VAS values may be seen and to better adapt analgesic therapy 2).

Despite advances in surgical and anesthesiology techniques, many patients continue to experience postoperative pain after lumbar disc operations

The administration of tramadol with paracetamol was more effective than tramadol alone for early acute postoperative pain therapy following lumbar discectomy. Therefore while adding paracetamol in early pain management is recommended, continuing paracetamol for the late postoperative period is not advised 3).

Etiology

Epidural fibrosis and epidural adhesion after laminectomy are developed from adjacent dense scar tissue, which is a natural wound healing process 4) 5) 6) 7) , and ranked as the major contributor for postoperative pain recurrence after laminectomy or discectomy.

Treatment

The goal of postoperative pain management is to relieve pain while keeping side effects to a minimum. After hundreds of years of advances, the mainstay of pain therapy is still the opioids. While they are very effective analgesics, opioids also carry with them many undesirable side effects: sedation, respiratory depression, nausea and vomiting, hypotension and bradycardia, pruritus, and inhibition of bowel function. The treatment of complications such as nausea and pruritus may include the administration of antihistamines, which have an additive effect on sedation and respiratory depression.

References

1)

Sriganesh K, Bidkar PU, Krishnakumar M, Singh GP, Hrishi AP, Jangra K. Perioperative Analgesia In Neurosurgery (PAIN): A national survey of pain assessment and management among neuroanesthesiologists of India. Int J Clin Pract. 2020 Sep 23:e13718. doi: 10.1111/ijcp.13718. Epub ahead of print. PMID: 32966673.
2)

Cabedo N, Valero R, Alcón A, Gomar C. Prevalence and characterization of postoperative pain in the Postanaesthesia Care Unit. Rev Esp Anestesiol Reanim. 2017 Mar 28. pii: S0034-9356(16)30211-0. doi: 10.1016/j.redar.2016.11.006. [Epub ahead of print] English, Spanish. PubMed PMID: 28363327.
3)

Uztüre N, Türe H, Keskin Ö, Atalay B, Köner Ö. Comparison of Tramadol versus Tramadol with Paracetamol for efficacy of postoperative pain management in lumbar discectomy: a randomized controlled study. Int J Clin Pract. 2019 Sep 11. doi: 10.1111/ijcp.13414. [Epub ahead of print] PubMed PMID: 31508863.
4)

Alkalay RN, Kim DH, Urry DW, Xu J, Parker TM, Glazer PA. Prevention of postlaminectomy epidural fibrosis using bioelastic materials. Spine (Phila Pa 1976) 2003;28:1659–1665.
5)

Hsu CJ, Chou WY, Teng HP, Chang WN, Chou YJ. Coralline hydroxyapatite and laminectomy-derived bone as adjuvant graft material for lumbar posterolateral fusion. J Neurosurg Spine. 2005;3:271–275.
6)

Temel SG, Ozturk C, Temiz A, Ersozlu S, Aydinli U. A new material for prevention of epidural fibrosis after laminectomy: oxidized regenerated cellulose (interceed), an absorbable barrier. J Spinal Disord Tech. 2006;19:270–275.
7)

Yu CH, Lee JH, Baek HR, Nam H. The effectiveness of poloxamer 407-based new anti-adhesive material in a laminectomy model in rats. Eur Spine J. 2012;21:971–979.

Sphenopalatine ganglion stimulation

Sphenopalatine ganglion stimulation

see also Sphenopalatine ganglion radiofrequency.

Sphenopalatine ganglion stimulation seems efficacious and is well tolerated, and potentially offers an alternative approach to the treatment of chronic cluster headache 1).

A randomized, sham-controlled study of 32 patients was performed to evaluate further the use of SPG stimulation for the acute treatment of chronic cluster headache. Of the 32 patients, 28 completed the randomized experimental period. Overall, 68% of patients experienced an acute response, a frequency response, or both. In this study the majority of adverse events were related to the implantation procedure, which typically resolved or remained mild in nature at 3 months following the implant procedure. This and other studies highlight the promise of using SPG stimulation to treat the pain-associated cluster headache. SPG stimulation could be a safe and effective option for chronic cluster headache 2).

The lead location does play a crucial role in SPG stimulation for cluster headache 3).

Pathway CH 1 study

see Pathway CH 1 study

Case series

SPG stimulation was performed in 13 patients between 2015 and 2018 in a single center. Lead location was determined by intraoperative computed tomography scan and correlated with the planned lead position as well as clinical data and stimulation parameters. Patients with a reduction of 50% or more in pain intensity or frequency were considered responsive.

Eleven patients (84.6%) responded to SPG stimulation with eight being frequency responders (61.5%). In seven cases, there were less than two electrodes between vidian canal and foramen rotundum, there was no significant correlation with negative stimulation results (p = 0.91). The mean distance of lead location between pre- and postoperative images did not correlate with clinical outcomes (p = 0.84) and was even bigger in responders (4.91 mm vs. 4.53 mm). The closest electrode contact to the vidian canal was in the stimulation area in all but one patient, regardless of its overall distance to canal. The distance of the closest electrode to the vidian canal was, however, not significantly correlated to the percentage of frequency (p = 0.68) or intensity reduction (p = 0.61).

There was no significant correlation regarding aberrations of lead position from the planned position with clinical outcome. However, this study might be underpowered to detect such a correlation. The closest electrode contact to the vidian canal was in the stimulation area in all but one patient in the final programming. This indicates that, overall, the lead location does play a crucial role in SPG stimulation for cluster headache 4).

Thirty-two patients were enrolled and 28 completed the randomized experimental period. Pain relief was achieved in 67.1% of full stimulation-treated attacks compared to 7.4% of sham-treated and 7.3% of sub-perception-treated attacks ( P  < 0.0001). Nineteen of 28 (68%) patients experienced a clinically significant improvement: seven (25%) achieved pain relief in ≥50% of treated attacks, 10 (36%), a ≥50% reduction in attack frequency, and two (7%), both. Five SAEs occurred and most patients (81%) experienced transient, mild/moderate loss of sensation within distinct maxillary nerve regions; 65% of events resolved within three months.

On-demand SPG stimulation using the ATI Neurostimulation System is an effective novel therapy for CCH sufferers, with dual beneficial effects, acute pain relief and observed attack prevention, and has an acceptable safety profile compared to similar surgical procedures 5).

Case reports

A 59-year-old chronic cluster headache (CCH) patient who had side shifts of attacks and was treated with bilateral continuous SPG stimulation. The patient suffered from CCH for 9 years, and the intensity of pain and the frequency of attacks had gradually increased over time. At the time of admission, he experienced daily attacks. Medical therapy and SPG blocks were offered, but he only achieved transient pain relief. After a careful preoperative examination and discussion with the patient, we provided bilateral SPG stimulation. The electrode was implanted under C-arm fluoroscopic guidance. After continuous stimulation, the patient experienced significant reductions in headache severity. The frequency of attacks was reduced from daily to less than once per week. He also discontinued all of the related drugs that he was taking. This is the first report of bilateral continuous SPG stimulation for CCH. This report indicates that continuous SPG stimulation is a feasible therapeutic option for CCH. However, large-scale and long-term studies are required to elucidate the efficacy of SPG stimulation 6).

References

1)

Goadsby PJ, Sahai-Srivastava S, Kezirian EJ, et al. Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial. Lancet Neurol. 2019;18(12):1081-1090. doi:10.1016/S1474-4422(19)30322-9
2)

Láinez MJ, Puche M, Garcia A, Gascón F. Sphenopalatine ganglion stimulation for the treatment of cluster headache. Ther Adv Neurol Disord. 2014;7(3):162-168. doi:10.1177/1756285613510961
3) , 4)

Piedade GS, Vesper J, Hoyer R, Klenzner T, Slotty PJ. Accuracy of Electrode Position in Sphenopalatine Ganglion Stimulation in Correlation With Clinical Efficacy [published online ahead of print, 2020 Sep 8]. Neuromodulation. 2020;10.1111/ner.13261. doi:10.1111/ner.13261
5)

Schoenen J, Jensen RH, Lantéri-Minet M, Láinez MJ, Gaul C, Goodman AM, Caparso A, May A. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013 Jul;33(10):816-30. doi: 10.1177/0333102412473667. Epub 2013 Jan 11. PubMed PMID: 23314784; PubMed Central PMCID: PMC3724276.
6)

Meng DW, Zhang JG, Zheng Z, Wang X, Luo F, Zhang K. Chronic Bilateral Sphenopalatine Ganglion Stimulation for Intractable Bilateral Chronic Cluster Headache: A Case Report. Pain Physician. 2016 May;19(4):E637-E642. PubMed PMID: 27228531

Multiple sclerosis related trigeminal neuralgia treatment

Multiple sclerosis related trigeminal neuralgia treatment

The optimal treatment for medically refractory trigeminal neuralgia in multiple sclerosis (MS-TN) patients is unknown.

Surgical interventions are less effective for the treatment of MS-related TN compared with classic TN, and higher recurrence rates are observed and is more difficult to manage pharmacologically.

Treatment failure occurs in most of the MS-related TN patients independently of the type of treatment.

Lee et al. compared treatment outcomes between stereotactic radiosurgery (SRS) and radiofrequency ablation (RFA).

They performed a retrospective study of MS-TN patients treated with SRS or RFA between 2002 and 2019. Outcomes included degree of pain relief, pain recurrence, and sensory changes, segregated based on initial treatment, final treatment following retreatment with the same modality, and crossover patients.

Sixty surgical cases for 42 MS-TN patients were reviewed. Initial pain freedom outcomes and rates of retreatment were similar (SRS: 30%; RFA: 42%). RFA resulted in faster onset of pain freedom (RFA: <1 week; SRS: 15 weeks; p < 0.001). SRS patients with pain relief had longer intervals to pain recurrence at 2 years (p = 0.044). Final treatment outcomes favored RFA for pain freedom/off-medication outcomes (RFA: 44%; SRS: 11%; p = 0.031), though RFA resulted in more paresthesia (RFA: 81%; SRS: 39%; p = 0.012). Both provided at least 80% of adequate pain relief. Crossover patients did not have improved pain relief.

SRS and RFA are both valid surgical options for MS-TN. Discussion with providers will need to balance patient preference with their unique treatment characteristics 1).

Microvascular decompression

see Microvascular decompression for trigeminal neuralgia and multiple sclerosis.

Gamma Knife surgery

Between July 1992 and November 2010, 43 cases with more than 1 year of follow-up were operated with GKS for TN related to MS and prospectively evaluated in the Timone University Hospital, Marseille, France. Radiosurgery using the Gamma Knife (model B or C or Perfexion) was performed. A single 4-mm isocenter was positioned at a median distance of 8 mm (range 5.7-14.7) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range 75-90) was delivered. Results: The median follow-up period was 53.8 months (12-157.1). Thirty-nine patients (90.7%) were initially pain free. Their actuarial probability of remaining pain free without medication at 6 months, 1, 3, 5 and 10 years was 87.2, 71.8, 43.1, 38.3 and 20.5%, respectively, and remained stable till 12 years. The hypoesthesia actuarial rate at 6 months, 1 and 2 years was 11.5, 11.5 and 16%, and remained stable till 12 years. GKS proved safe and effective in this special group of patients 2).

Balloon compression

see Percutaneous balloon compression trigeminal rhizotomy for multiple sclerosis related trigeminal neuralgia.

References

1)

Lee AT, Raygor KP, Elefant F, et al. Comparison of Stereotactic Radiosurgery and Radiofrequency Ablation for Trigeminal Neuralgia in Multiple Sclerosis Patients [published online ahead of print, 2020 Sep 3]. Stereotact Funct Neurosurg. 2020;1-8. doi:10.1159/000509315
2)

Tuleasca C, Carron R, Resseguier N, Donnet A, Roussel P, Gaudart J, Levivier M, Régis J. Multiple Sclerosis-Related Trigeminal Neuralgia: A Prospective Series of 43 Patients Treated with Gamma Knife Surgery with More than One Year of Follow-Up. Stereotact Funct Neurosurg. 2014 Jul 8;92(4):203-210. [Epub ahead of print] PubMed PMID: 25011487.

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