Nerve Axons Research Articles

In vivo imaging of axonal transport in peripheral nerves of rodent forelimbs.

Axonal transport is the essential process by which neurons actively traffic a variety of cargoes between the cell soma and axon terminals. Accordingly, dysfunctional axonal transport is linked to many nervous system conditions. Therefore, being able to image and quantify this dynamic process in live neurons of animal disease models is beneficial for understanding neuropathology and testing new therapies at the preclinical level. As such, intravital approaches have been developed to assess cargo movement in the hindlimb sciatic nerves of live, anaesthetised mice. Here, we describe an adapted method for in vivo imaging of axonal transport in intact median and ulnar nerves of the rodent forelimb. Injection of a fluorescently labelled and non-toxic fragment of tetanus neurotoxin (HCT) into the mouse forepaw permits the identification of signalling endosomes in intact axons of median and ulnar nerves. Through immunofluorescent analysis of forelimb lumbrical muscles and median/ulnar nerves, we confirmed that HCT is taken up at motor nerve terminals and predominantly locates to motor axons. We then showed that the baseline trafficking of signalling endosomes is similar between the median/ulnar nerves and the sciatic nerve in adult wild-type mice. Importantly, this adapted method can be readily tailored for assessment of additional cargoes, such as mitochondria. By measuring transport in forelimb and hindlimb nerves, comparative anatomical and functional analyses can be performed in rodent disease models to aid our understanding of peripheral nerve disease pathogenesis and response to injury.

Safety and efficacy of intravesical instillation of resiniferatoxin in healthy cats: A preliminary study.

To evaluate the safety of intravesical application of resiniferatoxin (RTX) in healthy cats and its effects on calcitonin gene-related peptide (CGRP) and substance P (SP) produced by C-fibers. Seven adult female cats received either 25 mL of saline (control; n = 1), or intravesical RTX at 5, 25, or 50 μg in 25 mL of saline to a final concentration of 0.2 μg/mL (318 nM), 1 μg/mL (1,591 nM), and 2 μg/mL (3,181 nM) (n = 2 per group). The treatment was instilled into the urinary bladder for 20 min. Plasma concentrations of RTX were measured at 0, 0.5, 1, and 4 h. Physical exam, complete blood count, and serum biochemical analysis were performed on day 0, 7, and 14. After 14 days, the sacral dorsal root ganglia (DRG) and the urinary bladder were harvested for histological and immunofluorescence analysis. Intravesical RTX was well tolerated and plasma concentrations were below the quantifiable limits except for one cat receiving 1 μg/mL. Mild to moderate histopathological changes, including epithelial changes, edema, and blood vessel proliferation, were observed at lower doses (0.2 and 1 μg/mL), and were more severe at the higher dose (2 μg/mL). C-fiber ablation was observed in the urinary bladder tissue at all doses, as shown by an apparent reduction of both CGRP and SP immunoreactive axons. A dose of 25 μg (1 μg/mL) of RTX instilled in the urinary bladder of healthy cats appeared to decrease the density of SP and CGRP nerve axons innervating bladder and induced moderate changes in the bladder tissue.

Guillain-Barre Syndrome in a Patient Posted for Elective Caesarean Delivery: An Anaesthetic Dilemma

Guillain-Barre syndrome (GBS) is an acute polyneuropathy most commonly associated with acute flaccid paralysis which may be associated with sensory and autonomic neuropathy. Antecedent infection may trigger an immune response which may cause a cross reaction leading to demyelination and degeneration of axons in nerves. Here we present a case of a 28 year old female, G2P1 at 37 weeks of gestation with a history of previous lower segment caesarean section (LSCS) and oligohydramnios with suspected Guillain-Barre syndrome posted for elective LSCS. She presented with dribbling of saliva from angle of mouth and inability to close both eyes with slurring of speech since 2 days. MRI brain was advised which showed no specific changes. Neurology evaluation was done and Guillain-Barre syndrome with isolated facial diplegia was suspected. Due to risks associated with general anaesthesia and succinylcholine in this patient, a decision was made to proceed with a low dose spinal anaesthesia. Once administered, the level of subarachnoid block was noted to be at T6. The caesarean section proceeded uneventfully with no major hemodynamic changes. A healthy baby girl was delivered and patient was noted to have full motor and sensory recovery in the post-operative period. Providing anaesthesia to patients with Guillain-Barre syndrome can be very challenging. Meticulous pre-anaesthetic planning is needed. A thorough pre-anaesthetic evaluation considering risks and benefits of each modality of anaesthesia is crucial before anaesthetizing these patients.

The Development of Transcranial Magnetic Stimulation

This review describes the development of transcranial magnetic stimulation in 1985 and the research related to this technique over the following 10 years. It not only focuses on work done at the National Institutes of Health but provides a survey of other related research as well. Key topics are the calculation of the electric field produced during magnetic stimulation, the interaction of this electric field with a long nerve axon, coil design, the time course of the magnetic stimulation pulse, and the safety of magnetic stimulation.

Disease-associated oligodendrocyte signatures in neurodegenerative disease: the known and unknown.

Disease-associated oligodendrocyte signatures in neurodegenerative disease: the known and unknown.

Srgap2 suppression ameliorates retinal ganglion cell degeneration in mice.

Slit-Robo GTPase-activating protein 2 (SRGAP2) plays important roles in axon guidance, neuronal migration, synapse formation, and nerve regeneration. However, the role of SRGAP2 in neuroretinal degenerative disease remains unclear. In this study, we found that SRGAP2 protein was first expressed in the retina of normal mice at the embryonic stage and was mainly located in the mature retinal ganglion cell layer and the inner nuclear layer. SRGAP2 protein in the retina and optic nerve increased after optic nerve crush. Then, we established a heterozygous knockout (Srgap2+/-) mouse model of optic nerve crush and found that Srgap2 suppression increased retinal ganglion cell survival, lowered intraocular pressure, inhibited glial cell activation, and partially restored retinal function. In vitro experiments showed that Srgap2 suppression activated the mammalian target of rapamycin signaling pathway. RNA sequencing results showed that the expression of small heat shock protein genes (Cryaa, Cryba4, and Crygs) related to optic nerve injury were upregulated in the retina of Srgap2+/- mice. These results suggest that Srgap2 suppression reduced the robust activation of glial cells, activated the mammalian target of rapamycin signaling pathway related to nerve protein, increased the expression of small heat shock protein genes, inhibited the degeneration of retinal ganglion cells, and partially restored optic nerve function.

A hyaluronic acid granular hydrogel nerve guidance conduit promotes regeneration and functional recovery of injured sciatic nerves in rats.

A hyaluronic acid granular hydrogel can promote neuronal and astrocyte colony formation and axonal extension in vitro, suggesting that the hydrogel can simulate an extracellular matrix structure to promote neural regeneration. However, in vivo experiments have not been conducted. In this study, we transplanted a hyaluronic acid granular hydrogel nerve guidance conduit to repair a 10-mm long sciatic nerve gap. The Basso, Beattie, and Bresnahan locomotor rating scale, sciatic nerve compound muscle action potential recording, Fluoro-Gold retrograde tracing, growth related protein 43/S100 immunofluorescence staining, transmission electron microscopy, gastrocnemius muscle dry/wet weight ratio, and Masson's trichrome staining results showed that the nerve guidance conduit exhibited similar regeneration of sciatic nerve axons and myelin sheath, and recovery of the electrophysiological function and motor function as autologous nerve transplantation. The conduit results were superior to those of a bulk hydrogel or silicone tube transplant. These findings suggest that tissue-engineered nerve conduits containing hyaluronic acid granular hydrogels effectively promote the morphological and functional recovery of the injured sciatic nerve. The nerve conduits have the potential as a material for repairing peripheral nerve defects.

Гормональная и бактериальная регуляция фенотипических изменений врожденных лимфоидных клеток (ILC) у больных рассеянным склерозом и здоровых доноров

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease in which the immune system attacks myelin basic protein of nerve axons. Recently, there has been growing interest in studying the role of a newly described population of innate immunity cells – innate lymphoid cells (ILCs) in the pathogenesis of the disease. At the same time, it was found that during pregnancy there is a weakening of Th1-mediated autoimmune pathologies manifestations, including MS. In this work, we studied phenotypic characteristics of ILC cells in MS patients in comparison with healthy donors after 48 h incubation with pregnancy hormone estriol (E3) and commensal microflora cells. To activate ILC, strains of Ecsherichia coli K12 and Lactobacillus plantarum 8R-A3 were used. ILC phenotype was assessed by flow cytometry using monoclonal antibody staining. It has been established that E3 and bacterial factors are able to regulate the maturation of ILC subtypes in different ways. In particular, MS patients’ cells are more susceptible to hormonal modulation, while those of healthy donors are more susceptible to bacterial modulation. In general, the studied factors influence the phenotypic changes in ILC cells, leading to the transition from one type to another, both in healthy donors and in MS.

Management of nerve injuries by utilization of nutraceuticals

Nerve injuries leads to loss of function from different organs of patient. It is caused due to dysfunction of neural cell. This dysfunction can occur by different ways like of genetics, protein accumulation in neural cell or any of the sudden accident. The nerve consist of various parts and one axon. The same nerve divides as CNS part and PNS part. The regeneration of nerve axon in PNS can be possible to function but the CNS part of axon cannot be regenerated. This regeneration takes place takes place with injured cell. This injury leads to pain referred as neuropathic pain. The nerve cell injury can be putted into three categories as of Neuropraxia, Axonotmesis and Neurotmesis. The injured neural cell leads to neurodegeneration. There are several treatments available on the basis of nutrients and constituents taken from herbal medicinal plants. Nutraceuticals is a branch known by its food supplements and nutrients of any herbal plant which have positive effect towards patient health and management of related disease. Nutraceuticals have less side and adverse effect towards patient. There are some medications which is derived from herbal medicinal plant such as Ginseng, Ashwagandha, Bacopa monnieri, Ginkgo biloba, Centella asiatica. Some compounds belong to as class of flavonoids, celastrol, trehalose, lycopene, sesamol, resveratrol and curcumin are showing high positive impression. The present scenario demands for the herbal medicinal treatment and for the fulfilment of this need the approach towards nutraceutical are raising high. Neuroprotection mechanism also shown by these nutrients. Apart from neuro regeneration, neuroprotective effect the nutraceutical also show antioxidant, anti-inflammatory effect. Polyphenol compound help to increase neural function.

Multiple Penile and Pelvic Schwannomas in an Adult Male: A Case Report

Schwannomas are relatively common benign tumours that gradually increase in size and develop in the peripheral nerve sheaths of adults. However, they are exceptionally rare in the penile and pelvic regions. Hereby, the authors present a case report of an extremely rare case of concomitant multiple schwannomas in the penis and pelvis. A 32-year-old adult male presented with complaints of multiple small swellings on the penile shaft, which were associated with episodes of severe pain. Clinically, there were multiple small, firm to hard, tender nodular swellings on the penile shaft. Ultrasound and Magnetic Resonance Imaging (MRI) revealed six well-marginated lesions in the penile areolar tissue and two lesions along the course of the left sciatic nerve in the left hemipelvis. Surgical excision followed by histopathological evaluation confirmed the diagnosis of multiple schwannomas. Due to their rarity and non specific presentation, most of these lesions are not diagnosed clinically. Therefore, presurgical imaging is necessary to evaluate their anatomical and morphological features. Although imaging findings in schwannomas are not always precise, Histopathological Examination is required for a definitive diagnosis. Histopathology typically shows the mixed presence of Antoni A and Antoni B bodies containing spindle cells arranged tightly and loosely, respectively, in a collagenous matrix. Immunohistochemistry (IHC) typically shows positivity for S-100 protein, which is characteristic of schwannomas. They are also positive for neuron-specific enolase and vimentin, but negative for Cluster of Differentiation(CD) 117 and Smooth Muscle Actin (SMA). Schwannomas are treated by complete surgical excision with preservation of the nerve axon, and they have a good prognosis with a low chance of recurrence.

Human parvovirus B19 infection in hospitalized patients suspected of infection with pathogenic microorganism.

Human parvovirus B19 (HPV B19) is a single-stranded DNA virus. The detection rate of HPV B19 in the blood of healthy blood donors using PCR technology was reported to be 6.323/100000. However, that among hospitalized patients suspected of being infected with a pathogenic microorganism is unknown. A retrospective analysis was conducted on 2,182 high-throughput NGS results for 1,484 inpatients admitted to the First Affiliated Hospital of Zhengzhou University from January 2020 to October 2021 who were suspected of being infected with a pathogenic microorganism, as well as on clinical data of some HPV B19-positive patients. Human parvovirus B19 was detected in 39 samples from 33 patients. The positivity rate was 2.22% among patients and 1.78% among samples. HPV B19 was detected in 20 cerebrospinal fluid samples, 13 blood samples, 3 alveolar lavage fluid samples, 2 tissue samples, and 1 throat swab. Based on clinical symptoms and NGS results, 16 patients were diagnosed with HPV B19 infection. The number of HPV B19 sequences in these patients was greater than 6, and the patients showed common symptoms such as fever (14 cases), anemia (11 cases), and severe nervous system symptoms such as meningoencephalitis (9 cases) and Guillain-Barré syndrome with peripheral motor and sensory nerve axon damage (4 cases). All 16 patients had experienced events likely to lead to decreased immunity (11 had a history of trauma/surgery/major disease, 4 had a history of precursor infection, and 3 had used immunosuppressants) and 7 had a history of blood transfusion during hospitalization. After treatment with antiviral drugs (12 cases) and intravenous human immunoglobulin (3 cases), of the 16 patients, 14 patients improved. The HPV B19 infection rate in hospitalized patients suspected of microbial infection was 2.22%. Most patients with HPV B19 infection had a history of low immunity and blood transfusion. HPV B19 could be detected in various bodily fluids and tissues (especially cerebrospinal fluid) using NGS. Patients with severe HPV B19 infection may have nervous system damage such as Guillain-Barré syndrome and meningoencephalitis. Early diagnosis using NGS and treatment with antiviral drugs and immunoglobulin can improve prognosis.

Changes in signalling from faecal neuroactive metabolites following dietary modulation of IBS pain

ObjectiveDietary therapies for irritable bowel syndrome (IBS) have received increasing interest but predicting which patients will benefit remains a challenge due to a lack of mechanistic insight. We recently found...

Schwann cell stimulation induces functional and structural changes in peripheral nerves.

Signal propagation is the essential function of nerves. Lysophosphatidic acid 18:1 (LPA) allows the selective stimulation of calcium signaling in Schwann cells but not neurons. Here, the time course of slowing and amplitude reduction on compound action potentials due to LPA exposure was observed in myelinated and unmyelinated fibers of the mouse, indicating a clear change of axonal function. Teased nerve fiber imaging showed that Schwann cell activation is also present in axon-attached Schwann cells in freshly isolated peripheral rat nerves. The LPA receptor 1 was primarily localized at the cell extensions in isolated rat Schwann cells, suggesting a role in cell migration. Structural investigation of rat C-fibers demonstrated that LPA leads to an evagination of the axons from their Schwann cells. In A-fibers, the nodes of Ranvier appeared unchanged, but the Schmidt-Lanterman incisures were shortened and myelination reduced. The latter might increase leak current, reducing the potential spread to the next node of Ranvier and explain the changes in conduction velocity. The observed structural changes provide a plausible explanation for the functional changes in myelinated and unmyelinated axons of peripheral nerves and the reported sensory sensations such as itch and pain.

Electrophysiological profile of serum vitamin B12 levels, correlation with serum methylmalonic acid levels, and determination of subclinical peripheral nerve involvement

Background/Aim: Vitamin B12 is essential for normal neural conduction in peripheral nerves. This study aimed to investigate the electrophysiological profile for varying degrees of serum B12 levels and to determine whether a correlation existed between electrophysiological profiles and serum methylmalonic acid (MMA) levels. Also, determination of subclinical peripheral nerve involvement with cold administration was planned in serum B12 levels. Methods: A total of 101 (63 females, 38 males) subjects with known serum vitamin B12 levels were selected randomly from the neurology outpatient clinic for this study. The subjects were divided into three groups based on the serum total Vitamin B12 levels: (1) B12 deficiency (<126 pg/mL), (2) low B12 (126-250 pg/mL), and (3) normal B12 (250–500 pg/mL). Serum MMA and nerve conduction studies (NCS) were assessed and compared between the three groups. After the cooling procedure was applied to the ulnar and sural nerves, NCS was repeated. Results: There were 13 subjects in the B12 deficiency group, 44 subjects in the low B12 group, and 44 subjects in the normal group. We found that ulnar sensory nerve action potential amplitudes were significantly decreased (P = 0.009), ulnar F latency (P = 0.003; P < 0.001)) was prolonged, and peroneal combined muscle action potential amplitudes decreased (P = 0.026) in the B12 deficiency when compared with the low and normal B12 groups. Sural nerve amplitude and conduction velocities were found to be significantly abnormal after the cold application in all groups (P < 0.001). The increase in sural nerve sensory nerve amplitude potentials (SNAP) amplitudes was higher in the B12 deficiency group than in the other groups. Mean serum MMA levels were high in all groups. A correlation of nerve conduction study (NCS) changes with serum vitamin B12 and MMA was not observed in the groups after cold application. Conclusion: Vitamin B12 deficiency may cause subclinical sensorial and motor axonal nerve conduction changes. Nerve conduction changes may not always reach pathological values based on electrophysiological studies but may be detected after cooling administration even in the normal serum B12 levels. A correlation between serum MMA and vitamin B12 levels was found. Therefore, serum levels of vitamin B12, which is important for nerve conduction, should be carefully evaluated in clinical practice.

Cross‐sectional surface area of the nerve fibre layer in the optic nerve head in glaucomatous and non‐glaucomatous individuals

AbstractPurpose: To quantify the cross‐sectional surface area of the retinal gangion cell axons in the optic nerve had (ONH) in glaucomatous subjects with an AI‐based method.Methods: From each of 16 subjects aged 50–79, eight with early to manifest glaucoma and eight without glaucoma, one 3D OCT‐capture from one eye was analysed for cross‐sectional surface area. The segmentation model was based on the concept of measuring the minimal distance between the central limit of the pigmental epithelium (ONH Pigmental epithelium, Central Limit, OPCL), and the inner limit of the retina (Inner limit of the Retina, Closest Point, IRCP). The OCT volume was resampled into 500 radial slices at equidistant angles around the center of the ONH. In each angle, coordinates for OPCL and IRCP were recorded. The coordinates were then used to compute the area of surface elements in to each angle. For each subject, the average cross‐sectional surface area around the circumference of the ONH as the Pigmental epithelium – Inner limit of the retina Minimal Area (PIMA) was calculated as PIMA‐2π.Results: A 95% confidence interval for PIMA‐2π was estimated to 0.86 ± 0.12 mm2 (df = 7) in the glaucomatous group, and 1.85 ± 0.17 mm2 in the non‐glaucomatous control group (df = 7). There was a difference in means between the glaucomatous and non‐glaucomatous group (t‐test for independent groups; test statistic = −8.75, t0.05(2):14 = 2.15).Conclusions: In the glaucomatous group, PIMA‐2π was significantly smaller. Furthermore, the results agree with other similar studies. Points annotated by our deep learning algorithms can be used to compute cross‐sectional surface area of the nerve fibre layer in the ONH with accurate results.

Rapid presynaptic maturation in naturally regenerating axons of the adult mouse olfactory nerve.

Successful neuronal regeneration requires the reestablishment of synaptic connectivity. This process requires the reconstitution of presynaptic neurotransmitter release, which we investigate here in a model of entirely natural regeneration. After toxin-induced injury, olfactory sensory neurons in the adult mouse olfactory epithelium can regenerate fully, sending axons via the olfactory nerve to reestablish synaptic contact with postsynaptic partners in the olfactory bulb. Using electrophysiological recordings in acute slices, we find that, after initial recontact, functional connectivity in this system is rapidly established. Reconnecting presynaptic terminals have almost mature functional properties, including high release probability and strong capacity for presynaptic inhibition. Release probability then matures quickly, rendering reestablished terminals functionally indistinguishable from controls just 1week after initial contact. These data show that successful synaptic regeneration in the adult mammalian brain is almost a "plug-and-play" process, with presynaptic terminals undergoing a rapid phase of functional maturation as they reintegrate into target networks.

Discoidin domain receptor regulates ensheathment, survival and caliber of peripheral axons.

Most invertebrate axons and small-caliber axons in mammalian peripheral nerves are unmyelinated but still ensheathed by glia. Here, we use Drosophila wrapping glia to study the development and function of non-myelinating axon ensheathment, which is poorly understood. Selective ablation of these glia from peripheral nerves severely impaired larval locomotor behavior. In an in vivo RNA interference screen to identify glial genes required for axon ensheathment, we identified the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr). In larval peripheral nerves, loss of Ddr resulted in severely reduced ensheathment of axons and reduced axon caliber, and we found a strong dominant genetic interaction between Ddr and the type XV/XVIII collagen Multiplexin (Mp), suggesting that Ddr functions as a collagen receptor to drive axon wrapping. In adult nerves, loss of Ddr decreased long-term survival of sensory neurons and significantly reduced axon caliber without overtly affecting ensheathment. Our data establish essential roles for non-myelinating glia in nerve development, maintenance and function, and identify Ddr as a key regulator of axon-glia interactions during ensheathment and establishment of axon caliber.

Translational Inhibition of Multiple Neurotoxic Proteins Leads to Improved Cognition in Alzheimer’s Disease

AbstractBackgroundOverexpression of neurotoxic proteins drives downstream events that dysregulate axonal transport, lead to inflammation, nerve cell death, and loss of function. By inhibiting the translation of amyloid precursor protein, tau and alpha‐synuclein, our drug restored axonal transport, lowered inflammation, and protected nerve cells from dying in animal models. Buntanetap’s reversal of the toxic cascade leading to nerve cell death did preserve and/or restore full function in 7 different animal models of neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD).MethodIn a double blind, placebo controlled Phase2a study, early AD patients were randomized into 80mg Buntanetap (n = 10) or placebo (n = 5) QD for 25±2 days. We evaluated the safety, pharmacokinetics of Buntanetap, biomarkers, and its efficacy.ResultIn clinical trials, Buntanetap was safe in over 200 subjects, both healthy volunteers and AD/PD patients. In our recent double‐blind, placebo controlled Phase2a study, patients randomized to either 80mg QD Buntanetap or placebo we measured biomarkers in AD patients and showed that Buntanetap can lower neurotoxic proteins, improve axonal integrity and synaptic function, and lower inflammation. Buntanetap has also improved AD patients’ cognitive functions as measured by ADASCog11 and WAIS coding test after 25±2 days treatment.ConclusionThese encouraging data support our further development of Buntanetap as a potential treatment for Alzheimer’s disease. We are planning three double‐blind, placebo‐controlled studies, a short 3‐month dose‐finding trial and two long‐term 12‐ and 18‐month trials in early and moderate AD patients.

Translational Inhibition of Multiple Neurotoxic Proteins Leads to Improved Motor Function in Parkinson’s Disease

AbstractBackgroundParkinson’s disease (PD) is a neurodegenerative disorder that affects predominately dopaminergic neurons in substantia nigra. Although alpha‐synuclein (αSYN) is the main component of Lewy bodies, TDP‐43, Aβ and tau are also detected in PD. Buntanetap has been shown to inhibit the translation of multiple neurotoxic proteins such as amyloid precursor protein, tau and alpha‐synuclein. It been shown in animal models to restore axonal transport, lower inflammation and protect nerve cells from dying. By reversing the toxic cascade leading to nerve cell death, Buntanetap preserves and restores full function in 7 different animal models of neurodegenerative diseases including PD.MethodIn our double‐blind, placebo‐controlled, dose‐finding Phase 2a trial, 5 different doses of Buntanetap (5mg, 10mg, 20mg, 40mg and 80mg QD) were tested compared to control after25±2 days treatment. Buntanetap’s safety, pharmacokinetics, biomarkers and efficacy were evaluated.ResultIn clinical trials, Buntanetap was safe in over 200 subjects, both in healthy volunteers and in AD/PD patient. In PD patients, Buntanetap lowers neurotoxic proteins, improves axonal integrity and synaptic function, and lowers inflammation. Buntanetap improves PD patients’ mobility shown by MDS‐UPDRS and WAIS coding test after 25±2 days treatment. Of the 5 different doses, 10 & 20mg Buntanetap QD showed the best clinical outcomes.ConclusionThese data supported us getting regulatory approval to develop next stage pivotal studies in larger population and for longer durations. The FDA consented us to move the development into two phase 3 clinical studies – one in early and one in advanced PD. Our first pivotal trial intends to treat 450 early PD patients at 1:1:1 ration for 10mg, 20mg Buntanetap QD or placebo for 6 months duration.

Commentary: Dysthyroid optic neuropathy: A lurking danger in thyroid eye disease.

Poonam et al., in their retrospective study, highlighted male gender, hyperthyroidism, and smoking as risk factors of developing dysthyroid optic neuropathy (DON) over four years. They highlighted the potential of recurrence of DON in patients with diabetes.[1] DON is the most dreaded complication of thyroid eye disease (TED), warranting an urgent intervention. Fortunately, the occurrence of DON is noted only in 5%–7% of TED cases.[2] The diagnosis of established DON is majorly clinical, but the diagnosis of subclinical DON may need detailed ophthalmic examination and imaging. Patients with subclinical DON may not experience a sudden diminution of vision, abnormal pupillary reflexes, and features of orbital inflammation—classical of severe TED.[2] The risk factors for clinical and subclinical DON include older age, male gender, smoking, diabetes (controlled or uncontrolled), radioisotope therapy, hyperthyroidism or Grave’s ophthalmopathy, and high level of thyroid autoantibodies.[12] The pathogenesis of DON involves mechanical, inflammatory, and vascular factors causing damage to the nerve cells and axons of the optic nerve.[2] TED patients can be classified as type I (predominantly fat enlargement) or type II disease (predominantly extraocular muscle enlargement). In type II TED, the mechanical compression of optic nerve blood supply and axonal flow at the crowded orbital apex occurs due to enlarged extraocular muscles. The reduced arterial supply to the optic nerve and sluggish outflow of the blood from the superior ophthalmic vein comprises of major vascular insults contributing to the DON.[2] Moreover, these phenomena occurring at the orbital apex do not contribute much to clinical proptosis; hence many remain underdiagnosed. In ophthalmic examination, relative afferent pupillary defect (RAPD), blue-yellow (Tritan) color deficiency, and reduced contrast sensitivity in patients of TED are sensitive parameters for detecting DON. Clinical examination of the optic disc and optic disc imaging are important for the monitoring of DON.[2] Orbital magnetic resonance imaging with or without contrast may provide sufficient details about the extraocular muscles, orbital fat, optic nerve, orbital apex, superior ophthalmic vein, and other essential orbital structures. Apparent diffusion coefficient readings from magnetic resonance imaging (MRI) may provide the activity details in the extraocular muscles. Barrett’s muscle index of >60% is considered highly sensitive and specific for DON.[3] It is calculated on coronal computed tomography (CT) or MRI at a mid-point between the posterior globe and the orbital apex. Barrett’s index includes two indices, horizontal and vertical, and the larger of the two is taken as significant. Other parameters are extraocular muscle volume/orbital volume (MV/OV) and crowding index (CI) are considered reliable indicators of DON. The 3D MRI-based volumetric analysis showed the larger extraocular muscle volume as the most relevant factor in DON.[4] Optical coherence tomography angiography (OCTA) has been used to measure retinal nerve fiber layer thickness and peripapillary capillary vessel density (whole image and radial vessel density) as DON parameters. The patients with subclinical DON have shown significantly lower vessel densities as compared to normal individuals.[25] Intravenous steroids and orbital decompression surgery remain the mainstay of treatment in DON patients. The best outcomes for DON patients are provided by combined intravenous methylprednisolone and 3-wall orbital decompression, as vision is successfully preserved in most cases with a reduction in proptosis.[6] The advent of teprotumumab, a targeted insulin-like growth factor 1 (IGF-1) receptor-based therapy, is slowly establishing itself as “medical orbital decompression” therapy. It reduces the levels of thyroid stimulating hormone (TSH) receptors and IGF-1 receptors on fibroblasts and reduces the release of pro-inflammatory cytokines like interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α) responsible for severe TED.[26] Hence, an ophthalmologist should be aware of the clinical features of subclinical DON and maintain a low threshold for aggressive treatment. For the holistic management of DON, a multidisciplinary team involving an ophthalmologist, endocrinologist, and otolaryngologist should be working in coordination to avoid blindness.