Lesions Causing Alice in Wonderland Syndrome Map to a Common Brain Network Linking Body and Size Perception.

OBJECTIVE: Alice in Wonderland syndrome (AIWS) profoundly affects human perception of size and scale, particularly regarding one's own body and the environment. Its neuroanatomical basis has remained elusive, partly because brain lesions causing AIWS can occur in different brain regions. Here, we aimed to determine if brain lesions causing AIWS map to a distributed brain network. METHODS: A retrospective case-control study analyzing 37 cases of lesion-induced AIWS identified through systematic literature review was conducted. Using resting-state functional connectome data from 1,000 healthy individuals, the whole-brain connections of each lesion were estimated and contrasted with those from a control dataset comprising 1,073 lesions associated with 25 other neuropsychiatric syndromes. Additionally, connectivity findings from lesion-induced AIWS cases were compared with functional neuroimaging results from 5 non-lesional AIWS cases. RESULTS: AIWS-associated lesions were located in various brain regions with minimal overlap (≤33%). However, the majority of lesions (≥85%) demonstrated shared connectivity to the right extrastriate body area, known to be selectively activated by viewing body part images, and the inferior parietal cortex, involved in size and scale judgements. This pattern was uniquely characteristic of AIWS when compared with other neuropsychiatric disorders (family-wise error-corrected p < 0.05) and consistent with functional neuroimaging observations in AIWS due to nonlesional causes (median correlation r = 0.56, interquartile range 0.24). INTERPRETATION: AIWS-related perceptual distortions map to one common brain network, encompassing regions critical for body representation and size-scale processing. These findings lend insight into the neuroanatomical localization of higher-order perceptual functions, and may inform future therapeutic strategies for perceptual disorders. ANN NEUROL 2024.

Network Localization of Awareness in Visual and Motor Anosognosia.

OBJECTIVE: Unawareness of a deficit, anosognosia, can occur for visual or motor deficits and lends insight into awareness itself; however, lesions associated with anosognosia occur in many different brain locations. METHODS: We analyzed 267 lesion locations associated with either vision loss (with and without awareness) or weakness (with and without awareness). The network of brain regions connected to each lesion location was computed using resting-state functional connectivity from 1,000 healthy subjects. Both domain specific and cross-modal associations with awareness were identified. RESULTS: The domain-specific network for visual anosognosia demonstrated connectivity to visual association cortex and posterior cingulate while motor anosognosia was defined by insula, supplementary motor area, and anterior cingulate connectivity. A cross-modal anosognosia network was defined by connectivity to the hippocampus and precuneus (false discovery rate p < 0.05). INTERPRETATION: Our results identify distinct network connections associated with visual and motor anosognosia and a shared, cross-modal network for awareness of deficits centered on memory-related brain structures. ANN NEUROL 2023;94:434-441.

Barriers to increasing paid parental leave in U.S. neurology residencies: a survey of program directors.

BACKGROUND: The American Board of Psychiatry and Neurology (ABPN) and the Accreditation Council for Graduate Medical Education (ACGME) require that residency programs allow at least 6 weeks of parental leave. The American Medical Association (AMA) recommends 12 weeks of paid parental leave. Despite these recommendations, there is little information about parental leave policies across U.S. neurology residencies. The objective of our study was to assess parental leave policies in U.S. adult neurology residencies and barriers to increasing the duration of leave. METHODS: We distributed an anonymous online survey to U.S. adult neurology program directors (PDs) to assess demographics, components and length of parental leave, perceived impact on residents' clinical training and academic development, and barriers to increasing the length of leave. RESULTS: We contacted 163 PDs and received 54 responses (response rate of 33%). 87% reported policies for both childbearing and non-childbearing residents. The average maximal length of leave allowed without extension of training was 8.5 weeks (range 0-13) for childbearing and 6.2 weeks (range 0-13) for non-childbearing residents. Most PDs felt that parental leave had a positive impact on resident wellness and neutral impact on clinical competency, academic opportunities, and career development. The most common barriers to providing a 12-week paid policy were concerns about equity in the program (82%), staffing of clinical services (80%), and impact on clinical training (78%). CONCLUSIONS: Although most programs in our study have parental leave policies, there is significant variability. Policies to improve parental leave should focus on addressing common barriers, such as additional solutions to staffing clinical services.

Network Localization of Unconscious Visual Perception in Blindsight.

OBJECTIVE: Blindsight is a disorder where brain injury causes loss of conscious but not unconscious visual perception. Prior studies have produced conflicting results regarding the neuroanatomical pathways involved in this unconscious perception. METHODS: We performed a systematic literature search to identify lesion locations causing visual field loss in patients with blindsight (n = 34) and patients without blindsight (n = 35). Resting state functional connectivity between each lesion location and all other brain voxels was computed using a large connectome database (n = 1,000). Connections significantly associated with blindsight (vs no blindsight) were identified. RESULTS: Functional connectivity between lesion locations and the ipsilesional medial pulvinar was significantly associated with blindsight (family wise error p = 0.029). No significant connectivity differences were found to other brain regions previously implicated in blindsight. This finding was independent of methods (eg, flipping lesions to the left or right) and stimulus type (moving vs static). INTERPRETATION: Connectivity to the ipsilesional medial pulvinar best differentiates lesion locations associated with blindsight versus those without blindsight. Our results align with recent data from animal models and provide insight into the neuroanatomical substrate of unconscious visual abilities in patients. ANN NEUROL 2022;91:217-224.

Fluorescein Angiography Findings in Susac Syndrome: A Multicenter Retrospective Case Series.

BACKGROUND: Susac syndrome is a vasculopathy, resulting in the classic triad of branch retinal artery occlusion (BRAO), inner ear ischemia, and brain ischemia. In this retrospective chart review, we characterize fluorescein angiography (FA) findings and other ancillary studies in Susac syndrome, including the appearance of persistent disease activity and the occurrence of new subclinical disease on FA. METHODS: This multicenter, retrospective case series was institutional review board-approved and included patients with the complete triad of Susac syndrome evaluated with FA, contrasted MRI of the brain, and audiometry from 2010 to 2020. The medical records were reviewed for these ancillary tests, along with demographics, symptoms, visual acuity, visual field defects, and findings on fundoscopy. Clinical relapse was defined as any objective evidence of disease activity during the follow-up period after initial induction of clinical quiescence. The main outcome measure was the sensitivity of ancillary testing, including FA, MRI, and audiometry, to detect relapse. RESULTS: Twenty of the 31 (64%) patients had the complete triad of brain, retinal, and vestibulocochlear involvement from Susac syndrome and were included. Median age at diagnosis was 43.5 years (range 21-63), and 14 (70%) were women. Hearing loss occurred in 20 (100%), encephalopathy in 13 (65%), vertigo in 15 (75%), and headaches in 19 (95%) throughout the course of follow-up. Median visual acuity at both onset and final visit was 20/20 in both eyes. Seventeen (85%) had BRAO at baseline, and 10 (50%) experienced subsequent BRAO during follow-up. FA revealed nonspecific leakage from previous arteriolar damage in 20 (100%), including in patients who were otherwise in remission. Of the 11 episodes of disease activity in which all testing modalities were performed, visual field testing/fundoscopy was abnormal in 4 (36.4%), MRI brain in 2 (18.2%), audiogram in 8 (72.7%), and FA in 9 (81.8%). CONCLUSIONS: New leakage on FA is the most sensitive marker of active disease. Persistent leakage represents previous damage, whereas new areas of leakage suggest ongoing disease activity that requires consideration of modifying immunosuppressive therapy.

Does Tocilizumab Influence Ophthalmic Outcomes in Giant Cell Arteritis?

BACKGROUND: Despite appropriate use of corticosteroids, an important minority of patients with giant cell arteritis (GCA) develop progressive vision loss during the initial stages of the disease or during corticosteroid tapering. Tocilizumab is the only clearly effective adjunctive treatment to corticosteroids in the management of GCA, but questions regarding its efficacy specifically in the neuro-ophthalmic population and its role in mitigating vision loss have not been broached until recently. EVIDENCE ACQUISITION: The authors queried Pubmed using the search terms "GCA" and "tocilizumab" in order to identify English-language publications either explicitly designed to evaluate the influence of tocilizumab on the ophthalmic manifestations of GCA or those which reported, but were not primarily focused on, ophthalmic outcomes. RESULTS: Recent retrospective analyses of populations similar to those encountered in neuro-ophthalmic practice suggest that tocilizumab is effective in decreasing the frequency of GCA relapse, the proportion of flares involving visual manifestations of GCA, and the likelihood of permanent vision loss. Data regarding the utility of tocilizumab to curtail vision loss at the time of diagnosis are limited to case reports. CONCLUSIONS: Compared with conventional corticosteroid monotherapy, treatment of GCA with both corticosteroids and tocilizumab may decrease the likelihood of permanent vision loss. Further prospective, collaborative investigation between rheumatologists and neuro-ophthalmologists is required to clarify the ophthalmic and socioeconomic impact of tocilizumab on the treatment of GCA.

Optic Neuropathy Due to Compression by an Ectatic Internal Carotid Artery Within the Orbital Apex.

ABSTRACT: Neurovascular compression is a rare but potentially treatable cause of optic neuropathy. Although incidental contact of the cisternal optic nerve and internal carotid artery (ICA) is common, compressive optic neuropathy occurring within the orbital apex has not been comprehensively described. We report a case of intra-orbital and intracanalicular optic nerve compression due to an ectatic ICA in a patient with congenital absence of the contralateral ICA. This report describes the complementary roles of advanced neuroimaging and neuro-ophthalmologic examination in rendering the diagnosis.

What You Need to Know About AQP4, MOG, and NMOSD.

Neuromyelitis optica (NMO) is an antibody-mediated inflammatory disease of the central nervous system with a predilection for the optic nerves, spinal cord, and certain brain regions. While NMO was previously considered a variant of multiple sclerosis (MS), it is now known to have distinct clinical, pathological, and immunological features. The identification of AQP4-IgG, a pathogenic antibody against aquaporin-4 (AQP4), delineated NMO from MS and markedly advanced insights into the unique features of this disease. The specificity of this antibody has allowed an expanded view of the clinical presentations of NMO-spectrum disorders (NMOSD), without requiring all the clinical features that were previously essential to make a clinical diagnosis. Early, accurate diagnosis of patients with NMOSD permits treatment with appropriate acute and long-term immunosuppressive agents that are critical to mitigate the risk of disability associated with this disease. More recently, a subset of patients with the NMOSD phenotype have been found to have autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG), which has a different pathogenesis and expected outcome. Better understanding of the distinct pathophysiology of these disorders has laid the foundation for targeted efforts to develop novel, disease-specific treatments. In this review, we discuss the revised diagnostic criteria for NMOSD, appraise the diagnostic significance of the AQP4-IgG and MOG-IgG tests, review evidence supporting the use of available treatments for acute episodes and long-term disease modification, and highlight key emerging immunotherapies.

Emerging Treatments for Leber's Hereditary Optic Neuropathy and Other Genetic Causes of Visual Loss.

Leber's hereditary optic neuropathy (LHON) and other genetic causes of visual loss are important clinical entities that can cause profound visual loss. To date, therapeutic options have been quite limited, but insights into the genetic basis of these diseases and advances in the ability to deliver effective and safe gene therapy have opened the door for new therapeutics that may revolutionize the approach to treating these conditions. This article reviews emerging gene therapies of LHON and other inherited ophthalmological diseases, addressing the technical, clinical, and ethical challenges that researchers and clinicians will encounter as new treatments become available for these conditions.

Migraine Aura: Pathophysiology, Mimics, and Treatment Options.

Recent insights into the clinical presentation and pathophysiology of migraine aura have paved the way for new treatments for this common but frequently debilitating condition. Marked efflux of cellular potassium and glutamate contributes to the cortical spreading depression that forms the electrophysiological basis of migraine aura phenomena. Secondary vascular perturbations also contribute to the various symptoms of a migraine attack. Calcitonin gene-related peptide (CGRP) plays a key role in many of these steps, and a growing class of CGRP-antagonists have emerged as a novel, efficacious preventative therapy. It is still not fully understood why a preponderance of migraine aura symptoms is visual, and this issue is an active area of research. In addition, the pathophysiological changes responsible for visual snow syndrome are under investigation. Before diagnosing a patient with migraine aura, it is important to consider the differential diagnosis of transient visual phenomena, with attention to clinical features that may suggest conditions such as retinal disorders, transient ischemic attack, or occipital epilepsy.

Infectious ocular motor neuropathies.

PURPOSE OF REVIEW: Describe the range of infectious causes of ocular motor neuropathies, from common presentations to unusual manifestations of diseases less frequently seen in the developed world. Provide information on recent developments in diagnostic testing for pathogens that may cause ocular motor neuropathies. RECENT FINDINGS: Antigen detection in serum or CSF has improved the diagnosis of cryptococcal disease. Cartridge PCR testing for tuberculosis has increased diagnostic accuracy, though tuberculous meningitis remains difficult to diagnose. Rapid, multiplex PCR and unbiased sequencing allow for diagnosis of a wider range of organisms. SUMMARY: Infectious ocular motor neuropathies can occur anywhere along the length of cranial nerves III, IV, and VI. Characteristic clinical findings and imaging can be used to localize infections. Infectious causes may have characteristic clinical, laboratory, or imaging findings, but must still be carefully separated from inflammatory or neoplastic conditions.

Neuroimaging diagnostic and monitoring approaches in ophthalmology.

PURPOSE OF REVIEW: We review new applications of optical coherence tomography (OCT) technology in neuro-ophthalmology. We also describe new technologies for visualizing the extracranial vessels in the diagnosis of giant cell arteritis (GCA). RECENT FINDINGS: Newer OCT modalities are expanding the evaluation of the optic disc, and are being applied to a number of neurologic conditions such as demyelinating and neurodegenerative disease. Swept-source OCT and enhanced-depth imaging OCT are refining the fine-grained analysis of the optic nerve head in the diagnosis of papilledema and optic nerve drusen. OCT-angiography is opening up new avenues to the study of the vasculature of the optic nerve head and its disorders, including ischemic optic neuropathy. Newer technologies in the diagnosis of GCA include vascular ultrasound, magnetic resonance imaging (MRI) of the extracranial vasculature and PET imaging of the large vessels. SUMMARY: OCT and several of its derivations are advancing diagnosis, and in some cases prognostication, in a variety of inflammatory, ischemic and compressive optic neuropathies. These technologies hold potential in the laboratory as well, yielding insights into the mechanisms of a variety of neurological conditions. In addition, further developments in MRI and ultrasonography techniques are shaping the approach to the diagnosis of GCA.

Finding the imposter: brain connectivity of lesions causing delusional misidentifications.

SEE MCKAY AND FURL DOI101093/AWW323 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Focal brain injury can sometimes lead to bizarre symptoms, such as the delusion that a family member has been replaced by an imposter (Capgras syndrome). How a single brain lesion could cause such a complex disorder is unclear, leading many to speculate that concurrent delirium, psychiatric disease, dementia, or a second lesion is required. Here we instead propose that Capgras and other delusional misidentification syndromes arise from single lesions at unique locations within the human brain connectome. This hypothesis is motivated by evidence that symptoms emerge from sites functionally connected to a lesion location, not just the lesion location itself. First, 17 cases of lesion-induced delusional misidentifications were identified and lesion locations were mapped to a common brain atlas. Second, lesion network mapping was used to identify brain regions functionally connected to the lesion locations. Third, regions involved in familiarity perception and belief evaluation, two processes thought to be abnormal in delusional misidentifications, were identified using meta-analyses of previous functional magnetic resonance imaging studies. We found that all 17 lesion locations were functionally connected to the left retrosplenial cortex, the region most activated in functional magnetic resonance imaging studies of familiarity. Similarly, 16 of 17 lesion locations were functionally connected to the right frontal cortex, the region most activated in functional magnetic resonance imaging studies of expectation violation, a component of belief evaluation. This connectivity pattern was highly specific for delusional misidentifications compared to four other lesion-induced neurological syndromes (P < 0.0001). Finally, 15 lesions causing other types of delusions were connected to expectation violation (P < 0.0001) but not familiarity regions, demonstrating specificity for delusion content. Our results provide potential neuroanatomical correlates for impaired familiarity perception and belief evaluation in patients with delusional misidentifications. More generally, we demonstrate a mechanism by which a single lesion can cause a complex neuropsychiatric syndrome based on that lesion's unique pattern of functional connectivity, without the need for pre-existing or hidden pathology.

Historical Trends in the Diagnosis of Peduncular Hallucinosis.

BACKGROUND: Peduncular hallucinosis (PH) describes the clinical syndrome of vivid, dream-like visual hallucinations that intrude on normal wakefulness. Additional clinical deficits, especially ophthalmoparesis, have historically been an important part of the diagnosis and localization of this syndrome. We examined how modern neuroimaging has impacted the diagnosis of PH. METHODS: We reviewed all available cases of PH, including 3 of ours and all previously reported in the literature. We determined whether other eye movement abnormalities were part of the clinical presentation and whether a neuroimaging study was performed to make the diagnosis. RESULTS: A total of 85 cases were identified and evaluated. Eye movement abnormalities were present in 12/15 (80%) without a neuroimaging study but in only 24/70 (34%) of cases in which a neuroimaging study was performed (P = 0.001). CONCLUSIONS: Although eye movement abnormalities historically have been considered a key localizing clinical feature supporting the diagnosis of PH, we found that in the era of modern neuroimaging, co-occurring eye movement abnormalities are far less frequent and are not a requisite feature of the diagnosis.

Rehabilitation of Visual Loss: Where We Are and Where We Need to Be.

BACKGROUND: Spontaneous recovery of visual loss resulting from injury to the brain is variable. A variety of traditional rehabilitative strategies, including the use of prisms or compensatory saccadic eye movements, have been used successfully to improve visual function and quality-of-life for patients with homonymous hemianopia. More recently, repetitive visual stimulation of the blind area has been reported to be of benefit in expanding the field of vision. EVIDENCE ACQUISITION: We performed a literature review with main focus on clinical studies spanning from 1963 to 2016, including 52 peer-reviewed articles, relevant cross-referenced citations, editorials, and reviews. RESULTS: Repetitive visual stimulation is reported to expand the visual field, although the interpretation of results is confounded by a variety of methodological factors and conflicting outcomes from different research groups. Many studies used subjective assessments of vision and did not include a sufficient number of subjects or controls. CONCLUSIONS: The available clinical evidence does not strongly support claims of visual restoration using repetitive visual stimulation beyond the time that spontaneous visual recovery might occur. This lack of firm supportive evidence does not preclude the potential of real benefit demonstrated in laboratories. Additional well-designed clinical studies with adequate controls and methods to record ocular fixation are needed.

Tacrolimus Optic Neuropathy.

BACKGROUND: Tacrolimus (FK506, Prograf) is a potent immunosuppressant, which inhibits cytokine synthesis and blocks T-cell development. Optic neuropathy from tacrolimus toxicity is very uncommon but, when present, can result in severe vision loss. METHODS: Case series and review of the literature. RESULTS: We present 3 patients with tacrolimus optic neuropathy after bone marrow transplantation complicated by graft-vs-host disease and demonstrate the differing clinical and radiologic presentation of this presumed toxic optic neuropathy. CONCLUSIONS: Tacrolimus optic neuropathy can manifest in a multitude of clinical presentations and can have devastating visual consequences.

Short Follow-up Bias Confounds Estimates of the "Typical" Clinical Course of Susac Syndrome.

BACKGROUND: To evaluate the validity of the prevailing concept that Susac syndrome (SS), a rare microvasculopathy of the brain, retina, and inner ear, is a self-limiting disease. METHODS: We performed a literature search to identify all cases of SS reported between 1973 and October 2015. If available, we determined their demographics, duration of follow-up, and the clinical course that was labeled as monocyclic or polycyclic. We attempted to determine the number of relapses and the relapse rate in patients with polycyclic disease. RESULTS: Our literature search yielded 185 relevant publications reporting 405 cases of SS. The duration of follow-up could be determined in 247/405 cases, with a range 0.5-312 months. The mean was 41 months but the distribution was skewed, with a median of 24 months. Defining the clinical course as monocyclic or polycyclic was possible in 102 patients who were followed for greater than 24 months; 53 were identified as having a polycyclic course. Patients labeled polycyclic were followed longer than those labeled monocyclic (median 62 vs 42 months, P < 0.001). The number or frequency of attacks per patient could not be determined. CONCLUSIONS: The follow-up of published cases of SS is short, creating an inherent bias toward the impression that the disease is self-limiting. Our findings suggest that stratification of SS into monocyclic, polycyclic, and chronic continuous courses may oversimplify the phenotype of SS; instead, the possibility of a relapsing-remitting course must be considered in all patients with this disorder.