[Advancements in corneal sensory reconstruction for the treatment of neurotrophic keratopathy].

Neurotrophic corneal disease is a degenerative eye condition that occurs due to damage to the trigeminal nerve. This condition presents as a persistent corneal epithelial defect, corneal ulceration, or even perforation, and the main cause is a loss of corneal nerve function. While traditional treatments mainly focus on supportive measures to repair corneal damage, they cannot cure the condition completely. A new surgical treatment option called corneal sensory reconstruction surgery can rebuild the corneal nerve, slow down the progression of the corneal disease, promote corneal epithelial repair, and improve vision. This article reviews the surgical techniques used in corneal sensory reconstruction, including direct nerve repositioning and indirect nerve transplantation, and discusses their treatment outcomes and future prospects.

[Modern capabilities in diagnosis and treatment of neurotrophic keratopathy]. / Sovremennye vozmozhnosti diagnostiki i lecheniya neirotroficheskoi keratopatii.

In recent years, the problem of diagnosing and treating neurotrophic keratopathy (NK) has become relevant in view of its prevalence reaching 1.6-11.0 per 10000 people. While previously it was associated only with neuroparalytic keratitis, at present the violation of sensitive and trophic innervation of the cornea with the development of characteristic keratopathy is observed in many diseases and injuries of the organ of vision. Diagnosis of NK is based on anamnestic information and assessment of clinical and functional parameters: determination of the stability of the tear film, tear production and assessment of staining of the ocular surface with vital dyes. The main role in the diagnosis of NK belongs to corneal sensitivity determined with the Cochet-Bonnet esthesiometer. Treatment of NK is designed to restore or increase corneal sensitivity and involves tear replacement therapy, instillations of preparations derived from patient's own blood, anti-inflammatory, metabolic and antibacterial therapy. However, instillations of human erve growth factor (NGF) - the drug Cenegermin (registered in Europe in 2017 at a dose of 20 µg/ml under the name Oxervate), a recombinant form of human rhNGF from Escherichia coli bacteria - exhibit the highest pathogenetic orientation. Its «target¼ is the affected nerve fibers (specific receptors for their growth factor), which makes it possible to eliminate the violation of reparative processes in neural and epithelial cells. A high and long-term clinical efficacy of a course of six (with an interval of 2 hours) instillations of the drug for 8 weeks in the treatment of children and adults with NK has been established. Among the pathogenetically justified methods of surgical treatment, there is the so-called surgical neurotization of the cornea involving the contralateral supraorbital, supratrochlear, great auricular and other nerves, which has a long-term clinical effect.

[Recognition, classification and treatment of trigeminal neuropathy].

Trigeminal neuropathy (TNO) manifests with unilateral or bilateral facio-oral sensory disturbances accompanied by pain and trigeminal nerve dysfunction. Although TNO may be posttraumatic or idiopathic, a thorough history and examination including magnetic resonance imaging is needed to exclude the multitude of secondary TNO causes. TNO-related pain necessitates multimodal treatment which in severe cases may encompass neurosurgical neuromodulation.

Trigeminal neuropathy: Two case reports of gasserian ganglion stimulation.

This report describes the successful treatment of two patients with trigeminal neuropathy by using gasserian ganglion stimulation. Case reports: The first case report deals with a 53-year-old woman suffering from right-sided facial pain after a gamma knife lesion for schwannoma of the right inner ear. For 9 years, several interventions with the aim of relieving the pain were unsuccessful; in fact, they had aggravated the symptoms. A trial with a neurostimulator at the level of the Gasser ganglion had an immediately positive effect on her score for facial pain, which decreased from 7.3 to 0 on a visual analog scale, assessed during a period of 2 months. Additionally, the patient had weaned off all her medication by the end of the period. The second case report describes a 64-year-old man suffering from trigeminal neuropathy, which mainly manifested itself as an itch. For a period of 15 years, neither medication nor several interventions were effective. A trial with an electrode at the level of the Gasser ganglion reduced his pain score from 7.0 to 1.5 on a visual analog scale, assessed during a period of three months. His medication could be limited to pregabalin 150 mg bidaily. In contrast, prior to the implantation, his oral medication consisted of pregabalin 75 mg up to five times a day. Conclusion: These case reports show that stimulation of the gasserian ganglion is a successful, minimally invasive, and non-destructive treatment in refractory trigeminal neuropathy and should be considered earlier in the treatment algorithm of trigeminal neuropathy.

Expert consensus on the identification, diagnosis, and treatment of neurotrophic keratopathy.

BACKGROUND: Neurotrophic keratopathy (NK) is a relatively uncommon, underdiagnosed degenerative corneal disease that is caused by damage to the ophthalmic branch of the trigeminal nerve by conditions such as herpes simplex or zoster keratitis, intracranial space-occupying lesions, diabetes, or neurosurgical procedures. Over time, epithelial breakdown, corneal ulceration, corneal melting (thinning), perforation, and loss of vision may occur. The best opportunity to reverse ocular surface damage is in the earliest stage of NK. However, patients typically experience few symptoms and diagnosis is often delayed. Increased awareness of the causes of NK, consensus on when and how to screen for NK, and recommendations for how to treat NK are needed. METHODS: An 11-member expert panel used a validated methodology (a RAND/UCLA modified Delphi panel) to develop consensus on when to screen for and how best to diagnose and treat NK. Clinicians reviewed literature on the diagnosis and management of NK then rated a detailed set of 735 scenarios. In 646 scenarios, panelists rated whether a test of corneal sensitivity was warranted; in 20 scenarios, they considered the adequacy of specific tests and examinations to diagnose and stage NK; and in 69 scenarios, they rated the appropriateness of treatments for NK. Panelist ratings were used to develop clinical recommendations. RESULTS: There was agreement on 94% of scenarios. Based on this consensus, we present distinct circumstances when we strongly recommend or may consider a test for corneal sensitivity. We also present recommendations on the diagnostic tests to be performed in patients in whom NK is suspected and treatment options for NK. CONCLUSIONS: These expert recommendations should be validated with clinical data. The recommendations represent the consensus of experts, are informed by published literature and experience, and may improve outcomes by helping improve diagnosis and treatment of patients with NK.

Effectiveness of high-frequency cervical spinal cord stimulation in the treatment of refractory trigeminal neuropathy: A case report.

RATIONALE: Treatment of chronic neuropathic pain in the head and face regions presents a challenge for pain specialists due to the lack of reliable medical and surgical approaches. PATIENT CONCERNS: A 62-year-old patient came to our attention for an intense facial pain secondary to a lesion of the right trigeminal nerve (all branches) due to a petroclival meningioma. DIAGNOSES: The patient also presented with gait impairment as well as a deficit of the right facial, auditory, trochlear and abducens cranial nerves. INTERVENTIONS: Conventional medical management (CMM) as well as tonic SCS were already adopted but they all dramatically failed. We intervened with the use of high-frequency (10 kHz) spinal cord stimulation (HFSCS) at the cervicomedullary junction (CMJ). The patient was thus provided with HFSCS at the CMJ. Pain and quality of life (QoL) were assessed 1 and 3 months after implantation. We also tested the trigeminal-facial reflex responses. OUTCOMES: HFSCS led to a full relief from the debilitating electric shocks like pain in the right hemiface, even though a background dull pain appeared. The gradual addition of pregabalin helped in fully relieving the painful symptomatology, with a significant improvement in QoL. Moreover, sensitivity amelioration on the inner portion of the mouth allowed the patient to start feeding again also using that side of the mouth. These findings were paralleled by a significant reshape of trigeminal-facial reflex responses suggesting an inhibition of nociceptive sensory inputs at brainstem level following HFSCS. LESSONS: This is the first report suggesting the usefulness of HFSCS at the CMJ in neuropathic pain due to trigeminal nerve neuropathy non-responsive to tonic SCS and CMM.

Effects of stellate ganglion block on postoperative trigeminal neuropathy after dental surgery: a propensity score matching analysis.

This study aimed to evaluate the effects of stellate ganglion block (SGB) on postoperative trigeminal neuropathy (TNP) after dental surgery. This was a retrospective study based on the medical records of all patients with postoperative TNP at Kyushu Dental University Hospital from 2014 to 2019. Patients were divided into the SGB group (received SGB) and non-SGB group (did not receive SGB). We evaluated the severity of TNP at 3 months after surgery and the incidence rate of abnormal sensations. Abnormal sensations were counted using patients' reports of uncomfortable symptoms during the treatment, including dysaesthesia, allodynia, and hyperalgesia. A propensity score (PS) matching analysis was performed to evaluate these data. After PS matching, amongst others, the force equivalent values of the Semmes-Weinstein test at 3-months post-treatment were significantly lower in the SGB group than in the non-SGB group (2.00 ± 0.44 vs 2.30 ± 0.48; p < 0.05). In addition, after PS matching, the incidence rate of abnormal sensations during the treatment was significantly lower in the SGB group than in the non-SGB group (10 cases [4.7%] vs 22 cases [10.3%]; p < 0.05). Collectively, the findings support that SGB may improve the recovery from postoperative TNP and reduce the incidence rate of abnormal sensations after dental surgery.

Trigeminal-Targeted Treatments in Migraine: Is 60% the Magic Number?

Trigeminal-targeted treatments (TTTs), the most specific and selective therapeutic migraine approach to date, are effective in approximately 60% of patients regardless of treatment type or mechanism, at least if used alone. Sixty percent is also the proportion of migraineurs who develop migraine-like episodes following experimental intravenous administration of trigeminal neuropeptides and roughly 60% is the percentage of patients with a unilateral migraine tracing the area of cutaneous distribution of the trigeminal ophthalmic branch. Hence, mechanisms other than the trigeminovascular activation are probably involved in the 40% of migraineurs who do not respond to TTTs. A closer cooperation between clinical and basic neuroscientists is needed to explore migraine models because only a careful appraisal of migraine endophenotypes may help to unravel their underlying multifaceted pathophysiological machinery.

Update on corneal neurotisation.

Corneal neurotisation describes surgical restoration of nerve growth into the cornea to restore corneal sensation and trophic function. It represents an exciting and effective emerging treatment for neurotrophic keratopathy. Techniques described to date involve either direct nerve transfer or an interpositional nerve graft coapted to a healthy donor nerve. We review the experience to date with particular emphasis on a detailed review of techniques, outcomes and current thoughts.

Dopamine receptor D2, but not D1, mediates descending dopaminergic pathway-produced analgesic effect in a trigeminal neuropathic pain mouse model.

Neuropathic pain represents a challenge to clinicians because it is resistant to commonly prescribed analgesics due to its largely unknown mechanisms. Here, we investigated a descending dopaminergic pathway-mediated modulation of trigeminal neuropathic pain. We performed chronic constriction injury of the infraorbital nerve from the maxillary branch of trigeminal nerve to induce trigeminal neuropathic pain in mice. Our retrograde tracing showed that the descending dopaminergic projection from hypothalamic A11 nucleus to spinal trigeminal nucleus caudalis is bilateral. Optogenetic/chemogenetic manipulation of dopamine receptors D1 and D2 in the spinal trigeminal nucleus caudalis produced opposite effects on the nerve injury-induced trigeminal neuropathic pain. Specific excitation of dopaminergic neurons in the A11 nucleus attenuated the trigeminal neuropathic pain through the activation of D2 receptors in the spinal trigeminal nucleus caudalis. Conversely, specific ablation of the A11 dopaminergic neurons exacerbated such pain. Our results suggest that the descending A11-spinal trigeminal nucleus caudalis dopaminergic projection is critical for the modulation of trigeminal neuropathic pain and could be manipulated to treat such pain.

Molecular basis of trigeminal nerve disorders and healing.

OBJECTIVE: This review aims to describe trigeminal neuralgia and the molecular basis contributing to the pathophysiology of this condition by focusing on the state of the art. PATIENTS AND METHODS: An electronic search of PubMed was performed using the following keywords: "trigeminal neuralgia" AND "classification", "pathophysiology," "molecular basis" and "mitochondrial role." RESULTS: Mitochondrial abnormality, whether functional or morphological, can contribute to neurological disorders. Additionally, one recent finding showed that gain-of-function mutation in the voltage-gated sodium channel NaV1.6 contributes to the pathophysiology of trigeminal neuralgia by increasing the excitability of trigeminal nerve ganglion neurons. It also exacerbates the pathophysiology of vascular compression. Healing of the trigeminal nerve is controlled by many molecular signaling pathways, including extracellular-signal-regulated kinase, c-Jun, p38, Notch, and mitogen-activated protein kinases. CONCLUSIONS: More investigations regarding the gain-of-function mutation of NaV1.6 sodium channels are essential for the diagnosis and treatment of trigeminal nerve disorders, regardless of whether these are associated with vascular compression or not.

Case Series: Management of Neurotrophic Keratitis from Familial Dysautonomia.

SIGNIFICANCE: Familial dysautonomia is a rare genetic disorder that affects the sensory and autonomic nervous systems. Affected individuals have decreased corneal sensation and can develop serious complications from neurotrophic keratitis. Scleral devices are an excellent option for the long-term management of patients with familial dysautonomia and neurotrophic keratitis. PURPOSE: In this series, we describe three patients with familial dysautonomia and classic ocular complications fit with scleral devices. No identifiable health information is included in this case report. CASE REPORTS: Case 1: A 35-year-old white male presented with blurred vision without complaint of pain or dryness. He had moderate punctate corneal staining and central stromal corneal scarring in both eyes despite use of artificial tears, punctal plugs, and therapeutic soft lenses. He was fit with 18.2-mm commercial scleral devices, which improved vision and protected the ocular surface. Case 2: A 20-year-old cognitively impaired white female presented with history of frequent eye rubbing and self-mutilation. She had recurrent corneal abrasions with corneal scarring in both eyes and was fit with 16-mm gas-permeable prosthetic replacement of the ocular surface ecosystem devices. Case 3: An 18-year-old white male with history of frequent corneal abrasions and blurred vision was referred by his medical doctor. He and his mother were trained in the safe handling of 16- and 16.5-mm gas-permeable prosthetic replacement of the ocular surface ecosystem devices in the right and left eyes. Corneal epithelial defects healed and vision improved with daily use. CONCLUSIONS: Individuals with familial dysautonomia present unique clinical challenges owing to severe ocular surface disease and inability to perceive pain. Initial therapy for neurotrophic keratitis includes lubrication, punctal occlusion, and therapeutic lenses. Additional therapies include autologous serum tears, amniotic membrane treatment, scleral devices, and tarsorrhaphy. In this series, scleral devices are an excellent option to protect the ocular surface and prevent common ocular complications.

Posttraumatic Trigeminal-Cavernous Fistula.

INTRODUCTION: Persistent trigeminal artery is the most frequent embryonic communication between the vertebrobasilar and carotid systems. To the best of our knowledge, posttraumatic trigeminal-cavernous fistula is rarely reported in the literature. CASE PRESENTATION: We present a 47-year-old man with posttraumatic trigeminal-cavernous fistula, which we treated using Onyx embolization. CONCLUSION: Even though preservation of the parent artery is generally considered a desirable goal in fistula treatment, in special cases such as Salzmann type 2 anatomy plus a unique fistulous orifice accompanied by external carotid-cavernous fistula, it is required to embolize the persistent trigeminal artery and cavernous sinus.

Upper Cervical Spinal Cord Stimulation as an Alternative Treatment in Trigeminal Neuropathy.

OBJECTIVE: To describe the indications and outcomes of upper cervical cord stimulation in trigeminal neuropathy. METHODS: A consecutive single-center series of patients was retrospectively reviewed. It included 12 patients with trigeminal neuropathy treated with upper cervical spinal cord stimulation. Clinical features, complications, and outcomes were reviewed. RESULTS: All patients had a successful trial before the definitive implantation of a spinal cord stimulator at the level of the craniocervical junction. The mean follow-up period was 4.4 years (range, 0.3-21.1 years). The average coverage in the pain zone was 72% and the median baseline, trial, and postoperative numeric rating scale (NRS) was 7, 3, and 3, respectively. When compared with the baseline, the mean reduction achieved in the postoperative average numeric rating scale was 4 points, accounting for a 57.1% pain reduction. The long-term failure rate was 25%. CONCLUSIONS: Despite there being enough evidence to consider upper cervical spinal cord stimulation as an effective treatment for patients with neuropathic trigeminal pain, a randomized controlled trial is needed to fully assess its indications and outcomes and compare it with other therapeutic approaches.

Malignant triton tumor of trigeminal nerve-case report.

INTRODUCTION: Here we are presenting a unique case of malignant triton tumor of the trigeminal nerve in a 4-year-old boy who presented with diplopia and ptosis. INTERVENTION: Near total excision of the tumor was performed, and adjuvant chemotherapy and radiotherapy were administered. RESULTS: The patient is in good health and has no evidence of clinical and radiological tumor recurrence for 22  months.

Periocular manifestations of trigeminal trophic syndrome: A case series and literature review.

Trigeminal trophic syndrome (TTS) is a condition whereby persistent facial ulceration presents consequent to central or peripheral insult to the trigeminal nerve. Lesions are created by repetitive self-inflicted manipulation and trauma of dysaesthetic skin within the trigeminal dermatome. We discuss four cases with aetiologies varied from presumed microvascular compromise to resection of cerebral meningioma, cerebrovascular accident, and herpes zoster ophthalmicus. We discuss the management of the under-recognised associated periocular skin ulcerations that result from physical manipulation of dysesthic skin and prove to be persistent and challenging to treat. Patient education and counselling are crucial in understanding and preventing the detrimental effect of physical manipulation of the skin. Occlusive dressings can reduce recurrent trauma. Topical lubricants, antibiotics, or autologous serum may be needed in cases with corneal involvement or exposure. Surgical interventions may be used, but frequently fail if the underlying neurological pathology and skin manipulation has not been adequately addressed. TTS should be suspected in persistent or recurrent facial ulceration with concomitant anaesthesia and paraesthesia in the trigeminal distribution, with alar nasi involvement being a key feature.

Stimulation of the Gasserian ganglion in the treatment of refractory trigeminal neuropathy.

OBJECTIVES: We evaluated the effectiveness of a custom-made neurostimulator with which to treat patients for refractory trigeminal neuropathic pain (TNP) at the level of the Gasserian ganglion. MATERIALS AND METHODS: A retrospective analysis of 22 patients referred to our pain clinic, AZ Sint-Nikolaas, between 2010 and 2015, was conducted using the McGill Pain and EuroQoL questionnaire before, two weeks after, and at the final follow-up after neurostimulator treatment. RESULTS: Successful test stimulations were achieved for 77.3% of patients, with satisfactory long-term pain relief reported by 44% at 24 months. The predictive value of the trial stimulation was 80%, with 82.4% of patients reporting one or more complication, the most common being neck discomfort due to fibrosis. A small cohort size (22) limited our statistical analyses. However younger patients presented with a higher incidence of negative results after 24 months or physical complications. Cut-off ages were set at the age of 62 and 58 years respectively. CONCLUSION: Stimulation of the Gasserian ganglion is a promising technique for the treatment of refractory TNP and should be considered ahead of more invasive techniques such as motor cortex or deep brain stimulation. The referral of refractory TNP patients should also be accomplished as early as possible to improve outcome.

Chronic orofacial pain.

The issues specific to trigeminal pain include the complexity of the region, the problematic impact on daily function and significant psychological impact (J Dent, 43, 2015, 1203). By nature of the geography of the pain (affecting the face, eyes, scalp, nose, mouth), it may interfere with just about every social function we take for granted and enjoy (J Orofac Pain, 25, 2011, 333). The trigeminal nerve is the largest sensory nerve in the body, protecting the essential organs that underpin our very existence (brain, eyes, nose, mouth). It is no wonder that pain within the trigeminal system in the face is often overwhelming and inescapable for the affected individual.

Úlcera neurotrófica secundaria a aplasia de nervio trigémino en paciente con síndrome de Goldenhar / Neurotrophic keratopathy secondary to trigeminal nerve aplasia in patient with Goldenhar syndrome

CASO CLÍNICO: Varón de 4 años de edad diagnosticado de síndrome de Goldenhar, sin antecedentes oftalmológicos relevantes, desarrolla una úlcera neurotrófica secundaria a aplasia de nervio trigémino que es tratada con trasplante de membrana amniótica multilaminar. DISCUSIÓN: En el síndrome de Goldenhar no suele estar descrita la aplasia de nervio trigémino como manifestación oftalmológica típica. Por tanto, parece necesario realizar controles oftalmológicos rutinarios y desde una edad temprana, para evitar la aparición de complicaciones graves asociadas a la anestesia corneal

CASE REPORT: A 4-year-old male diagnosed with Goldenhar syndrome, with an unremarkable ophthalmic history, develops a neurotrophic ulcer secondary to trigeminal nerve aplasia. It was treated with multilaminar amniotic membrane transplantation. DISCUSSION: Trigeminal nerve aplasia is not usually reported in Goldenhar syndrome. Therefore, it seems necessary to perform routine eye examinations, from an early age, to prevent serious complications associated with corneal anaesthesia

Peripheral nerve field stimulation for trigeminal neuralgia, trigeminal neuropathic pain, and persistent idiopathic facial pain.

OBJECTIVE: Peripheral nerve field stimulation (PNFS) is a promising modality for treatment of intractable facial pain. However, evidence is sparse. We are therefore presenting our experience with this technique in a small patient cohort. METHODS: Records of 10 patients (five men, five women) with intractable facial pain who underwent implantation of one or several subcutaneous electrodes for trigeminal nerve field stimulation were retrospectively analyzed. Patients' data, including pain location, etiology, duration, previous treatments, long-term effects and complications, were evaluated. RESULTS: Four patients suffered from recurrent classical trigeminal neuralgia, one had classical trigeminal neuralgia and was medically unfit for microvascular decompression. Two patients suffered from trigeminal neuropathy attributed to multiple sclerosis, one from post-herpetic neuropathy, one from trigeminal neuropathy following radiation therapy and one from persistent idiopathic facial pain. Average patient age was 74.2 years (range 57-87), and average symptom duration was 10.6 years (range 2-17). Eight patients proceeded to implantation after successful trial. Average follow-up after implantation was 11.3 months (range 5-28). Using the visual analog scale, average pain intensity was 9.3 (range 7-10) preoperatively and 0.75 (range 0-3) postoperatively. Six patients reported absence of pain with stimulation; two had only slight constant pain without attacks. CONCLUSION: PNFS may be an effective treatment for refractory facial pain and yields high patient satisfaction.