The ability to read relies on the rapid mapping of perceived visual letters and their combinations (i.e., visual word forms) to phonology and meaning. The central role of the left ventral occipito-temporal cortex (VOTC) in processing letter strings, initially suggested by lesion studies, is now widely accepted. Although this brain region has been extensively studied with functional magnetic resonance imaging (fMRI), its causal role as a critical node of a cortical network for reading remains unclear. Here we report a comprehensive case of pure alexia during direct electrical stimulation (DES) of the left VOTC (patient SV, female, 38 yr old, implanted with intracerebral electrodes for refractory epilepsy). During DES of the left posterior occipito-temporal sulcus, but not of neighboring and remote cortical sites, SV was transiently impaired at reading single words while being able to slowly read letter-by-letter. However, SV was impaired when presenting a single letter in a rapid serial visual presentation, which showed that their letter reading is not entirely preserved. In contrast, DES to the same critical sites left performance for oral naming, auditory naming, reading numbers, writing, auditory lexical decision, and semantic matching of pictures unaffected. Intracerebral electrophysiological frequency-tagging investigations showed highly word-selective neural responses at the critical sites. These functional responses were abolished by concurrent DES, which also affected remote word-selective neural activity in the left VOTC. Altogether, these observations provide original evidence for word-selective representations of the left VOTC as a critical node of the cortical reading network.

Alexia without agraphia (AWA) is an acquired reading disturbance associated with left posterior cerebral artery (PCA) infarction. Based on autopsy and neuroimaging, there are two explanations for its pathogenesis: a visual cortex-language cortex disconnection and a visual word-form agnosia. Our goal was to discover if more refined brain imaging in a case-control study would provide further imaging support for either of these hypotheses. A neuroradiologist masked to the presence of AWA reviewed diffusion-weighted and fluid-attenuated inversion recovery brain MRIs in patients who had left PCA infarctions with AWA (9 patients) or without AWA (18 patients) to characterize lesions in the splenium, left forceps major, and left fusiform gyrus. Patients with AWA had various combinations of lesions in the splenium, left forceps major, and left fusiform gyrus. One of these regions was involved in 3 patients, 2 were involved in 3 patients, and 3 were involved in 3 patients. Most (89%) patients without AWA lacked involvement of any of these 3 regions. Our data provide imaging evidence for the two existing hypotheses of AWA. Involvement of any of these lesions on MRI imaging should encourage clinicians to obtain further neuropsychological testing.

The neuropsychological diagnosis and assessment of alexia remain formidable due to its multifaceted presentations and the intricate neural underpinnings involved. The current study employed a mixed-method design, incorporating cluster and thematic analyses, to illuminate the complexities of alexia assessment. We used the Web of Science and Scopus to retrieve articles spanning from 1985 to February 2024. Our selection was based on identified keywords in relation to the assessment and diagnosis of alexia. The analysis of 449 articles using CiteSpace (Version 6.3.R1) and VOSviewer (Version 1.6.19) software identified ten key clusters such as 'pure alexia' and 'posterior cortical atrophy', highlighting the breadth of research within this field. The thematic analysis of the most cited and recent studies led to eight essential categories. These categories were synthesized into a conceptual model that illustrates the interaction between neural, cognitive, and diagnostic aspects, in accordance with the International Classification of Functioning, Disability, and Health (ICFDH) framework. This model emphasizes the need for comprehensive diagnostic approaches extending beyond traditional reading assessments to include specific tasks like character identification, broader visual processing, and numerical tasks. Future diagnostic models should incorporate a diverse array of alexia types and support the creation of advanced assessment tools, ultimately improving clinical practice and research.

Very few cases of Chinese pure alexia have been reported to date. We aim to summarize the linguistic features and neuropsychological profiles of Chinese pure alexia through a case series study. 11 consecutive patients with post-stroke Chinese pure alexia and 11 healthy controls were included. The Aphasia Battery of Chinese (ABC) and 68-Chinese character oral reading test (68-character test) were used to evaluate the reading and writing ability. Reading errors were classified based on the performance of 68-character test. Neuropsychological profiles were evaluated with corresponding scales. The possible correlation between the reading ability and the writing ability or neuropsychological performance was analyzed. The patients had a correct rate of 43.7 ± 23.2% in the 68-character test, significantly lower (P < 0.001) than that of controls. Shape-similar error was the most common type of reading error (101/209, 48.3%). The ABC total writing score rate of the patients ranged from 68.9% to 98.7% (median, 90.5%), significantly lower (P < 0.001) than that of the controls. The patients also showed worse performance in MMSE, auditory verbal learning test, Boston naming test, intersecting pentagons copying and clock-drawing test (all P < 0.05). In the patient group, the correct rate of 68-character test was significantly correlated with the ABC total writing score rate (P = 0.008), the score rate of Boston naming test (P = 0.017), and the clock-drawing test score (P = 0.010). Shape-similar errors may be a characteristic of Chinese pure alexia. The correlation between visuospatial dysfunction and pure alexia might explain the frequent occurrence of shape-similar errors in Chinese pure alexia.

Knowledge about the consequences of stroke on high-level vision comes primarily from single case studies of patients selected based on their behavioural profiles, typically patients with specific stroke syndromes like pure alexia or prosopagnosia. There are, however, no systematic, detailed, large-scale evaluations of the more typical clinical behavioural and lesion profiles of impairments in high-level vision after posterior cerebral artery stroke. We present behavioural and lesion data from the Back of the Brain project, to date the largest (N = 64) and most detailed examination of patients with cortical posterior cerebral artery strokes selected based on lesion location. The aim of the current study was to relate behavioural performance with faces, objects and written words to lesion data through two complementary analyses: (i) a multivariate multiple regression analysis to establish the relationships between lesion volume, lesion laterality and the presence of a bilateral lesion with performance and (ii) a voxel-based correlational methodology analysis to establish whether there are distinct or separate regions within the posterior cerebral artery territory that underpin the visual processing of words, faces and objects. Behaviourally, most patients showed more general deficits in high-level vision (n = 22) or no deficits at all (n = 21). Category-selective deficits were rare (n = 6) and were only found for words. Overall, total lesion volume was most strongly related to performance across all three domains. While behavioural impairments in all domains were observed following unilateral left and right as well as bilateral lesions, the regions most strongly related to performance mainly confirmed the pattern reported in more selective cases. For words, these included a left hemisphere cluster extending from the occipital pole along the fusiform and lingual gyri; for objects, bilateral clusters which overlapped with the word cluster in the left occipital lobe. Face performance mainly correlated with a right hemisphere cluster within the white matter, partly overlapping with the object cluster. While the findings provide partial support for the relative laterality of posterior brain regions supporting reading and face processing, the results also suggest that both hemispheres are involved in the visual processing of faces, words and objects.

Word blindness or pure alexia refers to a condition that occurs due to lesions of the dominant occipitotemporal lobe, which is also known as the visual word form area (VWFA). This happens most commonly due to infarction in the territory of the posterior cerebral artery. A 66-year-old right-handed female patient presented to us with alexia without agraphia accompanied by right homonymous hemianopia. On evaluation, she showed marked impairment in the ability to read with grossly normal vision. Magnetic resonance imaging (MRI) brain revealed an acute infarct of the left occipital lobe with occlusion of the posterior cerebral artery (PCA). Infarction of the occipital lobe on the dominant side (left) in a right-handed individual can disrupt the VWFA and clinically it is manifested as a disconnection syndrome with an inability to read with preserved writing skills (alexia without agraphia) and gross normal vision.

Introduction: Ischemic stroke in young adults is less common than in older adults, but its occurrence warrants further investigation to determine the cause and appropriate treatment to improve outcome. One of the stroke manifestations is a disconnection syndrome, such as alexia without agraphia, a condition in which a patient cannot read but the ability to write remain relatively intact. Pure alexia is associated with the lesion in the medial occipitotemporal lobe in the dominant hemisphere, also known as the visual word form area (VWFA). Case Report: Here we report a case of a 30-year-old male, who presented with an acute complaint of inability to read without any difficulty in writing, accompanied by right homonymous hemianopia which occurred two days before admission. Initial brain scan was normal. However, the repeated brain scan two weeks after admission showed infarction in the left occipitotemporal lobe. He had no known previous vascular risk factors other than obesity. The evaluation during admission showed high blood pressure, dyslipidemia, and suggestive of autoimmune disease, all of which might contribute to the ischemic stroke occurrence. During follow-up he was referred for the neuropsychological assessment and rehabilitation as well as to the outpatient clinic for use of antithrombotic as secondary prevention. He showed gradual improvement in his symptoms after sixth months follow-up. Conclusion: Stroke in young adults is an increasing problem nowadays due to its rising incidence and more diverse pathogenetic mechanisms and related high morbidity. One of the neurological deficits found in stroke is a disconnection syndrome such as alexia without agraphia in which there is an acquired inability to read with relatively preserved writing ability. Pure alexia found in this case was due to an infarction of the occipitotemporal lobe that disconnects primary language areas from incoming visual information.

Abstract Dissociated performance in the reading/writing of kanji (morphogram) and kana (phonogram) in alexia and agraphia in Japanese has attracted attention because kanji and kana differently convey semantics, orthography, and phonology. Although the dissociation between kanji and kana is relative, but not absolute, detailed case studies, in addition to recent neuroimaging and neurophysiological studies, have revealed the partially separable mechanisms of the kanji and kana writing systems. Kanji words are processed mainly, not exclusively, via the orthographic–semantic route, and kana words are processed via both orthographic–semantic and phonological routes. Pure alexia with lesions in the left medial occipital lobe and splenium shows alexia for both kanji and kana, but at the chronic stage, alexia for either kanji or kana may remain depending on the compensatory mechanism. The left occipitotemporal area is important for reading/writing. The slightly different location and extent of lesions are associated with distinct symptoms: kanji alexia with the lesion in the mid‐fusiform gyrus (visual word form area; VWFA), kana alexia with lesions posterior to VWFA, and kanji alexia with kanji agraphia with lesions lateral to VWFA. The left angular gyrus has traditionally been considered important for writing. However, it is unclear whether the crucial site is the angular gyrus or the cortical and subcortical regions adjacent to it. In neurodegenerative diseases, reading/writing abilities are differentially impaired depending on the specific distribution of neuronal degeneration in each disease. Examining the reading/writing abilities of kanji and kana can facilitate understanding of the writing system and related disorders.

For over 150 years, the study of patients with acquired alexia has fueled research aimed at disentangling the neural system critical for reading. An unreached goal, however, relates to the determination of the fiber pathways that root the different visual and linguistic processes needed for accurate word reading. In a unique series of neurosurgical patients with a tumor close to the visual word form area, we combine direct electrostimulation and population-based streamline tractography to map the disconnectivity fingerprints characterizing dissociated forms of alexia. Comprehensive analyses of disconnectivity matrices establish similarities and dissimilarities in the disconnection patterns associated with pure, phonological and lexical-semantic alexia. While disconnections of the inferior longitudinal and posterior arcuate fasciculi are common to all alexia subtypes, disconnections of the long arcuate and vertical occipital fasciculi are specific to phonological and pure alexia, respectively. These findings provide a strong anatomical background for cognitive and neurocomputational models of reading.

The inferior longitudinal fasciculus (ILF) is a large association white matter tract that interconnects, in a bidirectional manner, the occipital cortex to anterior temporal structures. In view of both its pattern of cortical projections and its recently evidenced multilayered anatomical organization, the ILF has been supposed to be vital for maintaining a wide range of cognitive and affective processes operating on the visual modality. As tumors commonly damage the temporal cortex, an updated knowledge of the functional anatomy of this ventral tract is needed to better map and monitor on-line its potential functions and thus to improve surgical outcomes. In this review, we first describe the gross anatomy of the ILF, its array of cortical terminations and its different layers. We then provide a comprehensive review of the functions that have been assigned to the tract. We successively address its role in object and face recognition, visual emotion recognition, language and semantic, including reading, and memory. It is especially shown that the ILF is critically involved in visually-guided behaviors, as its breakdown, both in sudden neurosurgical and progressive neurodegenerative diseases, is commonly associated with visual-specific neuropsychological syndromes (e.g. prosopagnosia and pure alexia, and so on). In the last section, we discuss the extent to which the ILF can reorganize in response to glioma infiltration and to surgery, and provide some reflections on how its intraoperative mapping may be refined.

Complementary deficits in perceptual classification in pure alexia and acquired prosopagnosia – New insights from two classic cases

Chapter 12 - Reading and alexia

Chapter 19 - Rehabilitation of visual disorders

The aim of this study was to analyze a case series with acquired alexia after stroke within the posterior areas of the left hemisphere, in the context of the current criteria for pure alexia and their relevance to the set of symptoms observable in clinical practice. Seven patients with ischemic strokes and an initial diagnosis of pure alexia were enrolled for detailed analysis. The evaluation consisted of neuropsychological assessment in the form of standardized tests and non-standardized reading tasks, while oculomotor activity during reading was measured. Language functions, visual object and space perception, verbal and nonverbal memory, and visuospatial constructional ability were among the domains assessed. In five of the participants, pure alexia was recognized based on sig- nificant and specific discrepancies between test scores, indicating primary abnormalities in the visual processing of letter strings as a basic mechanism of the disorder. In most of the patients, coexisting cognitive deficits were revealed; however, these were dispropor- tionately milder and less functionally significant than reading disturbances. Pure alexia is a relatively rare disorder after a stroke, but it considerably affects the quality of everyday independent functioning. Its clinical characteristics in practice rarely meet all the criteria proposed in the subject literature. The differential diagnosis of this form of alexia and other reading disorders requires detailed clinical analysis.

ABSTRACT Patients with pure alexia have major difficulties in reading aloud. However, they often perform above chance level in reading tasks that do not require overt articulation of the target word – like lexical decision or semantic judgment – a phenomenon usually known as “implicit reading.” There is no agreement in the literature on whether implicit reading should be attributed to relative sparing of some left hemisphere (LH) reading centers or rather to signs of compensatory endeavors by the right hemisphere (RH). We report the case of an 81-year-old patient (AA) with pure alexia due to a lesion involving the left occipital lobe and the temporal infero-mesial areas, as well as the posterior callosal pathways. Although AA’s reading was severely impaired and proceeded letter by letter, she showed an above-chance-level performance for frequent concrete words in a tachistoscopic lexical decision task. A structural disconnectome analysis revealed that AA’s lesion not only affected the left occipital cortex and the splenium: it also disconnected white-matter tracts meant to connect the visual word-form system to decision-related frontal areas within the LH. We suggest that the RH, rather than the LH, may be responsible for patient AA’s implicit reading.

ABSTRACT We report a patient with alexia with agraphia accompanied by letter-by-letter reading after hemorrhage in the left middle and inferior occipital gyri that spared the angular gyrus and the fusiform gyrus. Kanji (Japanese morphograms) and kana (Japanese phonetic writing) reading and writing tests revealed that alexia with agraphia was characterized by kana-predominant alexia and kanji-predominant agraphia. This type of “dorsal” letter-by-letter reading is discernable from conventional ventral type letter-by-letter reading that is observed in pure alexia in that (1) kinesthetic reading is less effective, (2) kana or literal agraphia coexists, and (3) fundamental visual discrimination is nearly normal.

Objective: To describe the characteristics of post-stroke Chinese pure alexia and associated neuropsychological profiles. Methods: All patients with post-stroke pure alexia from the neurology department of our hospital were enrolled from June 2018 to July 2019. Brain MRI was performed to evaluate the stroke radiologically. The Aphasia Battery of Chinese (ABC) was used to evaluate the general language functions. A Chinese individual character reading test including 68 commonly used characters was used to evaluate the ability to read individual Chinese characters. The numbers of correct reading and misreading were recorded, and the error types of misreading were analyzed. MMSE, auditory verbal learning test, cube copying task, clock drawing test, and picture copying tests were performed to evaluate other cognitive impairments. Results: A total of 5 male patients were included, with a median age of 58 years (50-64 years). They all had Chinese pure alexia with intact verbal comprehension and speech and relatively preserved writing skills. The etiologies were all acute infarction involving the left temporo-parietal lobe and splenium of corpus callosum. In the Chinese individual character reading test, the median number of correct reading was 21 (18-44) out of 68 characters, with many shape-similar errors (one character was read as another one with a similar shape but different meaning and pronunciation). The percentage of shape-similar errors among all type errors was 81.5%, 60.0%, 23.7%, 18.5%, and 57.9% respectively, and 43.1% overall, much higher than other type errors. All the patients had obvious impairment in memory and visuospatial function with an exception that one patient had relatively preserved visuospatial ability. Conclusion: Shape-similar error is a remarkable feature of Chinese pure alexia. Chinese pure alexia is associated with impaired visuospatial function, but visuospatial dysfunction is not necessary for the development of Chinese pure alexia.

ABSTRACTAfter a stroke involving the left occipitotemporal cortex our patient shows a word-length effect and has problems to identify letters or numbers in strings of symbols. But he is normal in identifying isolated letters and in non-verbally categorizing even complex images such as faces or natural scenes. His cortical lesion is stretching from the visual word form area (VWFA) anteriorly causing additional problems to name visual stimuli and to match acoustic stimuli with images. We conclude that our patient suffers from pure alexia without deficits to identify even complex visual stimuli. Our results directly contradict several explanations for letter-by-letter reading.

Central alexia (CA) is an acquired reading disorder co-occurring with a generalized language deficit (aphasia). The roles of perilesional and ipsilesional tissue in recovery from poststroke aphasia are unclear. We investigated the impact of reading training (using iReadMore, a therapy app) on the connections within and between the right and left hemisphere of the reading network of patients with CA. In patients with pure alexia, iReadMore increased feedback from left inferior frontal gyrus (IFG) region to the left occipital (OCC) region. We aimed to identify whether iReadMore therapy was effective through a similar mechanism in patients with CA. Participants with chronic poststroke CA (n = 23) completed 35 h of iReadMore training over 4 weeks. Reading accuracy for trained and untrained words was assessed before and after therapy. The neural response to reading trained and untrained words in the left and right OCC, ventral occipitotemporal, and IFG regions was examined using event-related magnetoencephalography. The training-related modulation in effective connectivity between regions was modeled at the group level with dynamic causal modeling. iReadMore training improved participants' reading accuracy by an average of 8.4% (range, -2.77 to 31.66) while accuracy for untrained words was stable. Training increased regional sensitivity in bilateral frontal and occipital regions, and strengthened feedforward connections within the left hemisphere. Our data suggest that iReadMore training in these patients modulates lower-order visual representations, as opposed to higher-order, more abstract representations, to improve word-reading accuracy.SIGNIFICANCE STATEMENT This is the first study to conduct a network-level analysis of therapy effects in participants with poststroke central alexia. When patients trained with iReadMore (a multimodal, behavioral, mass practice, computer-based therapy), reading accuracy improved by an average 8.4% on trained items. A network analysis of the magnetoencephalography data associated with this improvement revealed an increase in regional sensitivity in bilateral frontal and occipital regions and strengthening of feedforward connections within the left hemisphere. This indicates that in patients with CA iReadMore engages lower-order, intact resources within the left hemisphere (posterior to their lesion locations) to improve word reading. This provides a foundation for future research to investigate reading network modulation in different CA subtypes, or for sentence-level therapy.

Seeing is not believing