Neuro-ophthalmology

Chwalisz BK. Cerebral amyloid angiopathy and related inflammatory disorders. J Neurol Sci 2021;424:117425.Abstract
Inflammatory cerebral amyloid angiopathy is a largely reversible inflammatory vasculopathy that develops in an acute or subacute fashion in reaction to amyloid protein deposition in the central nervous system blood vessels. There are two recognized pathologically characterized variants: cerebral amyloid angiopathy-related inflammation (CAAri) and A beta-related angiitis (ABRA). Both variants produce a clinical picture that resembles primary angiitis of the CNS but is distinguished by a characteristic radiologic appearance. Although originally defined as a clinicopathologic diagnosis, it can now often be diagnosed based on clinicoradiologic criteria, though confirmation with brain and meningeal biopsy is still required in some cases. This disorder typically responds to steroids but addition of other immune suppressants may be needed in some cases to control the disease.
Kanu LN, Ciolino JB. Nerve Growth Factor as an Ocular Therapy: Applications, Challenges, and Future Directions. Semin Ophthalmol 2021;36(4):224-231.Abstract
Nerve growth factor (NGF), the prototypical neurotrophin first discovered in the 1950s, has recently garnered increased interest as a therapeutic agent promoting neuronal health and regeneration. After gaining orphan drug status within the last decade, NGF-related research and drug development has accelerated. The purpose of this article is to review the preclinical and clinical evidence of NGF in various applications, including central and peripheral nervous system, skin, and ophthalmic disorders. We focus on the ophthalmic applications including not only the FDA-approved indication of neurotrophic keratitis but also retinal disease and glaucoma. NGF represents a promising therapy whose therapeutic profile is evolving. The challenges related to this therapy are reviewed, along with possible solutions and future directions.
Mukharesh L, Chwalisz BK. Neuro-ophthalmic Complications of Immune-Checkpoint Inhibitors. Semin Ophthalmol 2021;36(4):241-249.Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the field of oncology by modulating the immune cell-cancer cell interaction and thereby promoting immune system disinhibition in order to target several types of malignancies. There are three classes of immune checkpoint inhibitors (ICIs): anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), anti-programmed cell death protein-1 (PD-1), and anti-programmed cell death ligand-1 (PD-L1).It is not uncommon for physicians across all specialties to encounter a patient with a history of malignancy and ICI exposure, necessitating familiarity with their potential complications. In this review article, we discuss the most common immune-related adverse events (irAEs) pertaining to the central and peripheral nervous systems and their potential afferent and efferent neuro-ophthalmic manifestations. Early recognition and treatment of these irAEs, and discontinuation of the offending ICI are all critical steps to prevent morbidity and mortality.
Webb BD, Manoli I, Engle EC, Jabs EW. A framework for the evaluation of patients with congenital facial weakness. Orphanet J Rare Dis 2021;16(1):158.Abstract
There is a broad differential for patients presenting with congenital facial weakness, and initial misdiagnosis unfortunately is common for this phenotypic presentation. Here we present a framework to guide evaluation of patients with congenital facial weakness disorders to enable accurate diagnosis. The core categories of causes of congenital facial weakness include: neurogenic, neuromuscular junction, myopathic, and other. This diagnostic algorithm is presented, and physical exam considerations, additional follow-up studies and/or consultations, and appropriate genetic testing are discussed in detail. This framework should enable clinical geneticists, neurologists, and other rare disease specialists to feel prepared when encountering this patient population and guide diagnosis, genetic counseling, and clinical care.
Douglas VP, Douglas KA, Reinshagen KL, Chwalisz BK. Case 292. Radiology 2021;299(1):234-236.Abstract
History A 24-year-old right-handed woman presented to a neuro-ophthalmology clinic in Massachusetts in the summer with acute binocular diplopia when looking down and to the left, which started about 1 month earlier. Her medical history was notable for Raynaud syndrome, recurrent streptococcal pharyngitis, and an allergy to amoxicillin. Three days prior to developing diplopia, she presented to an outside emergency department due to fever, chills, and back pain. She received ciprofloxacin for presumed urinary tract infection based on urinalysis, which demonstrated few bacteria and was negative for leukocyte esterase, nitrites, and white blood cells. She then presented again to an outside emergency department for diplopia evaluation. Initial MRI and MR angiography of the brain at that time did not demonstrate any relevant findings, and the patient was referred to our department for neuro-ophthalmic evaluation, where she was seen 4 weeks later. Neuro-ophthalmic examination revealed 20/20 visual acuity in both eyes, and a right hypertropia in left gaze, downgaze and right head tilt, with right eye excyclotorsion. There were no ocular signs of myasthenia gravis or thyroid eye disease, nor did the patient report ocular or systemic symptoms. She denied recent travel. High-spatial-resolution MRI of the brain and orbit were performed (Figs 1, 2).
Cohen DA, Gise R, Gaier ED. Serum Biomarkers in Neuro-Ophthalmology: When to Test. Semin Ophthalmol 2021;36(4):322-328.Abstract
Discovery and characterization of serologic biomarkers has revolutionized the diagnostic framework of systemic and paraneoplastic autoimmune neuro-ophthalmic diseases. Expanding recognition of the multiple ocular and visual manifestations of these conditions highlights the important role of the referring provider in identifying potential cases. Increasing ease of access to serologic testing also enables these practitioners to initiate the diagnostic work-up in suspected cases. We aimed to provide an update on the current knowledge surrounding and use of relevant autoimmune biomarkers by correlating specific clinical neuro-ophthalmic manifestations with autoantibody biomarkers. The utility of select biomarkers for myasthenia gravis, neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein-IgG-associated disorder, opsoclonus-myoclonus syndrome, anti-collapsin-response mediator protein-5 optic neuropathy, and glial fibrillary acidic protein-IgG-associated disease are discussed with particular focus on the clinical contexts in which to consider testing.
Douglas VP, Douglas KA, Rapalino O, Champion SN, Chwalisz BK. Nelson Syndrome: Clival Invasion of Corticotroph Pituitary Adenoma Resulting in Alternating Sixth Nerve Palsies. J Neuroophthalmol 2021;41(1):114-118.Abstract
ABSTRACT: A 44-year-old woman presented with 2 painful and self-limited episodes of binocular horizontal diplopia within 1 year that at the beginning were thought to be secondary to microvascular insult. Her medical history was significant for Cushing syndrome status post transsphenoidal resection with bilateral adrenalectomy 4 years prior, hypertension, and diabetes mellitus. Neuro-ophthalmic evaluation was significant for left abduction deficit and incomitant esotropia consistent with left abducens nerve palsy. Of note, the patient had experienced a similar episode but on the contralateral side a few months prior. Although initially MRI of the brain demonstrated stable residual postoperative finding in the sella, upon review, an heterogenous T-1 hypointense marrow in the clivus was noted. Hypermetabolism of the clivus was also noted on computed tomography positron emission tomography of the skull base. A clival biopsy demonstrated a corticotroph adenoma with elevated proliferation index and scattered mitoses. A corticotroph pituitary adenoma after adrenalectomy, also known as Nelson syndrome, was diagnosed. Radiation therapy was offered to the patient, and resolution of symptoms was gradually observed.
Abbasi B, Rizzo JF. Advances in Neuroscience, Not Devices, Will Determine the Effectiveness of Visual Prostheses. Semin Ophthalmol 2021;36(4):168-175.Abstract
Background: Innovations in engineering and neuroscience have enabled the development of sophisticated visual prosthetic devices. In clinical trials, these devices have provided visual acuities as high as 20/460, enabled coarse navigation, and even allowed for reading of short words. However, long-term commercial viability arguably rests on attaining even better vision and more definitive improvements in tasks of daily living and quality of life. Purpose: Here we review technological and biological obstacles in the implementation of visual prosthetics. Conclusions: Research in the visual prosthetic field has tackled significant technical challenges, including biocompatibility, signal spread through neural tissue, and inadvertent activation of passing axons; however, significant gaps in knowledge remain in the realm of neuroscience, including the neural code of vision and visual plasticity. We assert that further optimization of prosthetic devices alone will not provide markedly improved visual outcomes without significant advances in our understanding of neuroscience.
Xie L, Yin Y, Benowitz L. Chemokine CCL5 promotes robust optic nerve regeneration and mediates many of the effects of CNTF gene therapy. Proc Natl Acad Sci U S A 2021;118(9)Abstract
Ciliary neurotrophic factor (CNTF) is a leading therapeutic candidate for several ocular diseases and induces optic nerve regeneration in animal models. Paradoxically, however, although CNTF gene therapy promotes extensive regeneration, recombinant CNTF (rCNTF) has little effect. Because intraocular viral vectors induce inflammation, and because CNTF is an immune modulator, we investigated whether CNTF gene therapy acts indirectly through other immune mediators. The beneficial effects of CNTF gene therapy remained unchanged after deleting CNTF receptor alpha (CNTFRα) in retinal ganglion cells (RGCs), the projection neurons of the retina, but were diminished by depleting neutrophils or by genetically suppressing monocyte infiltration. CNTF gene therapy increased expression of C-C motif chemokine ligand 5 (CCL5) in immune cells and retinal glia, and recombinant CCL5 induced extensive axon regeneration. Conversely, CRISPR-mediated knockdown of the cognate receptor (CCR5) in RGCs or treating wild-type mice with a CCR5 antagonist repressed the effects of CNTF gene therapy. Thus, CCL5 is a previously unrecognized, potent activator of optic nerve regeneration and mediates many of the effects of CNTF gene therapy.
Vinken K, Op de Beeck H. Using deep neural networks to evaluate object vision tasks in rats. PLoS Comput Biol 2021;17(3):e1008714.Abstract
In the last two decades rodents have been on the rise as a dominant model for visual neuroscience. This is particularly true for earlier levels of information processing, but a number of studies have suggested that also higher levels of processing such as invariant object recognition occur in rodents. Here we provide a quantitative and comprehensive assessment of this claim by comparing a wide range of rodent behavioral and neural data with convolutional deep neural networks. These networks have been shown to capture hallmark properties of information processing in primates through a succession of convolutional and fully connected layers. We find that performance on rodent object vision tasks can be captured using low to mid-level convolutional layers only, without any convincing evidence for the need of higher layers known to simulate complex object recognition in primates. Our approach also reveals surprising insights on assumptions made before, for example, that the best performing animals would be the ones using the most abstract representations-which we show to likely be incorrect. Our findings suggest a road ahead for further studies aiming at quantifying and establishing the richness of representations underlying information processing in animal models at large.
Brommer B, He M, Zhang Z, Yang Z, Page JC, Su J, Zhang Y, Zhu J, Gouy E, Tang J, Williams P, Dai W, Wang Q, Solinsky R, Chen B, He Z. Improving hindlimb locomotor function by Non-invasive AAV-mediated manipulations of propriospinal neurons in mice with complete spinal cord injury. Nat Commun 2021;12(1):781.Abstract
After complete spinal cord injuries (SCI), spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. However, it is unknown whether selective manipulation of these circuits can restore locomotor function in the absence of brain-derived inputs. By taking advantage of the compromised blood-spinal cord barrier following SCI, we optimized a set of procedures in which AAV9 vectors administered via the tail vein efficiently transduce neurons in lesion-adjacent spinal segments after a thoracic crush injury in adult mice. With this method, we used chemogenetic actuators to alter the excitability of propriospinal neurons in the thoracic cord of the adult mice with a complete thoracic crush injury. We showed that activating these thoracic neurons enables consistent and significant hindlimb stepping improvement, whereas direct manipulations of the neurons in the lumbar spinal cord led to muscle spasms without meaningful locomotion. Strikingly, manipulating either excitatory or inhibitory propriospinal neurons in the thoracic levels leads to distinct behavioural outcomes, with preferential effects on standing or stepping, two key elements of the locomotor function. These results demonstrate a strategy of engaging thoracic propriospinal neurons to improve hindlimb function and provide insights into optimizing neuromodulation-based strategies for treating SCI.
Styliadis C, Leung R, Özcan S, Moulton EA, Pang E, Taylor MJ, Papadelis C. Atypical spatiotemporal activation of cerebellar lobules during emotional face processing in adolescents with autism. Hum Brain Mapp 2021;42(7):2099-2114.Abstract
Autism spectrum disorder (ASD) is characterized by social deficits and atypical facial processing of emotional expressions. The underlying neuropathology of these abnormalities is still unclear. Recent studies implicate cerebellum in emotional processing; other studies show cerebellar abnormalities in ASD. Here, we elucidate the spatiotemporal activation of cerebellar lobules in ASD during emotional processing of happy and angry faces in adolescents with ASD and typically developing (TD) controls. Using magnetoencephalography, we calculated dynamic statistical parametric maps across a period of 500 ms after emotional stimuli onset and determined differences between group activity to happy and angry emotions. Following happy face presentation, adolescents with ASD exhibited only left-hemispheric cerebellar activation in a cluster extending from lobule VI to lobule V (compared to TD controls). Following angry face presentation, adolescents with ASD exhibited only midline cerebellar activation (posterior IX vermis). Our findings indicate an early (125-175 ms) overactivation in cerebellar activity only for happy faces and a later overactivation for both happy (250-450 ms) and angry (250-350 ms) faces in adolescents with ASD. The prioritized hemispheric activity (happy faces) could reflect the promotion of a more flexible and adaptive social behavior, while the latter midline activity (angry faces) may guide conforming behavior.
Maleki N, Szabo E, Becerra L, Moulton E, Scrivani SJ, Burstein R, Borsook D. Ictal and interictal brain activation in episodic migraine: Neural basis for extent of allodynia. PLoS One 2021;16(1):e0244320.Abstract
In some patients, migraine attacks are associated with symptoms of allodynia which can be localized (cephalic) or generalized (extracephalic). Using functional neuroimaging and cutaneous thermal stimulation, we aimed to investigate the differences in brain activation of patients with episodic migraine (n = 19) based on their allodynic status defined by changes between ictal and interictal pain tolerance threshold for each subject at the time of imaging. In this prospective imaging study, differences were found in brain activity between the ictal and interictal visits in the brainstem/pons, thalamus, insula, cerebellum and cingulate cortex. Significant differences were also observed in the pattern of activation along the trigeminal pathway to noxious heat stimuli in no allodynia vs. generalized allodynia in the thalamus and the trigeminal nucleus but there were no activation differences in the trigeminal ganglion. The functional magnetic resonance imaging (fMRI) findings provide direct evidence for the view that in migraine patients who are allodynic during the ictal phase of their attacks, the spinal trigeminal nucleus and posterior thalamus become hyper-responsive (sensitized)-to the extent that they mediate cephalic and extracephalic allodynia, respectively. In addition, descending analgesic systems seem as "switched off" in generalized allodynia.

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