Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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This article includes discussion of alexia, aphasic alexia, attentional alexia, deep alexia, frontal alexia, hemialexia, occipital alexia, parietal-temporal alexia, phonological alexia, spatial alexia, and surface alexia. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Brain pathology is frequently associated with disturbance in reading ability (alexia). Since the 19th century, 2 major types of alexias have been recognized (alexia with and without a preserved ability to write). In the mid-20th century, 2 additional types of alexias were proposed (alexia due to spatial disturbances and alexia associated with frontal pathology). During the 1970s and 1980s, a new approach to the analysis of alexia was developed. This new approach (psycholinguistic or cognitive perspective) shifted the focus from the anatomical correlates of acquired reading disturbances to the functional mechanisms underlying alexias. Some special types of alexias such as alexia for Braille reading have also been reported. Contemporary neuroimaging studies have significantly contributed to a better understanding of brain organization of reading processes and reading disturbances.
• Two major types of alexias were described during the late nineteenth century: alexia without agraphia and alexia with agraphia.
• During the mid-twentieth century 2 additional types of alexia were proposed: spatial alexia and frontal alexia.
• Psycholinguistic models of alexia distinguish between central and peripheral alexias.
• Excepting spatial alexia, acquired reading disturbances are associated with left hemisphere pathology – usually strokes, tumors, or traumas.
• Alexia rehabilitation is usually carried out simultaneously with aphasia rehabilitation.
Alexia (or acquired dyslexia) refers to an acquired disorder in reading caused by brain pathology (20). Alexia has been recognized for over a millennium, but only in the twentieth century did literacy become sufficiently widespread that alexia represented a significant medical problem. Two case reports published by Dejerine in 1891 and 1892 represent important milestones in the study of alexia (34; 33). In the 1891 paper, he described a patient who suffered a cerebrovascular accident that produced some degree of right-sided visual field defect and mild difficulty in naming and in understanding spoken language together with a complete loss of the ability to read. The patient could write nothing but his signature. Spoken language improved, but the alexia and agraphia remained basically unchanged until his death. Postmortem examination showed an old infarct in the left parietal lobe involving three quarters of the angular gyrus and extending deep to the lateral ventricle (34). One year later, Dejerine reported a second patient who noted an inability to read, but no other language disturbances. The only neurologic finding was a right hemianopia. Unlike the former case, this patient, although unable to read except for a few individual letters, could write adequately. Four years later, a second vascular accident led him to death. Postmortem examination revealed 2 different infarcts: 1 infarct was a large softening that involved the left angular gyrus and was obviously of recent origin, and the other infarct was an old gliotic infarct that involved the medial and inferior aspects of the left occipital lobe and the splenium of the corpus callosum. The old infarct was the source of the alexia without agraphia (33).
Alexia without agraphia (also known as occipital alexia or pure alexia) and alexia with agraphia (parietal-temporal alexia or central alexia) were extensively corroborated during the following years. They represent the classic alexic syndromes. A third, clinically distinct alexia syndrome, frontal alexia, which is associated with pathology in the frontal language areas, has been proposed (18). Reading difficulties in cases of right hemisphere pathology, on the other hand, have been noted since long ago. Some mentions of spatial alexia and visuospatial reading disorders associated with right-hemisphere damage are found in the neurology and neuropsychology literature (51). Only a few studies, however, have approached the visuospatial reading defects using large samples of patients with right hemisphere pathology (Hecaen 1972; 07).
These 4 types of alexias (without agraphia, with agraphia, frontal, and spatial) represent the neurologic, classic, or neuroanatomically based classification of alexias. Significant variability, however, in the pattern of disturbances is observed particularly in parietal-temporal alexia (with agraphia). During the 1970s and 1980s, a new approach to the analysis of alexia was developed (76; 24). This approach to alexias is usually known as the psycholinguistic or cognitive perspective of alexias. Interest shifted from the anatomical correlates of acquired reading disturbances to the functional mechanisms underlying alexias. It should be noted that, in the psycholinguistic or cognitive interpretation of alexias, the name "acquired dyslexia" is preferred, rather than "alexia."
The linguistic and cognitive approaches to alexia required the development of models for normal reading. Several partially coincidental cognitive models of normal reading have been proposed (28; 24). In general, most of these models propose that after the initial letter identification, reading proceeds along 2 linguistically different routes: (1) the direct route, wherein the written word is associated with a visual word in the lexicon memory; and (2) the indirect route, wherein the written word is transformed in a spoken word following a graphophonemic set of rules, and the meaning of the word is attained through its phonological mediation. If 1 or the other of these reading systems is altered, different error patterns can be observed. In some cases, both systems can be disrupted simultaneously.
Psycholinguistic models of alexias usually introduce a major distinction between central and peripheral alexias (116). In central alexias, the patient can perceive a word correctly but has difficulties recognizing it with either semantic or phonological processing. Three different types of central alexias are distinguished: (1) phonological, (2) surface, and (3) deep. Each features a specific pattern of reading errors (paralexias). In the peripheral alexias, the reading impairment corresponds more exactly to a perceptual disturbance. The patient has difficulty attaining satisfactory visual word processing (87). Usually, 3 different types of peripheral alexias are recognized: (1) letter-by-letter reading, (2) neglect alexia, and (3) attentional alexia.
The classic alexic syndromes will be initially described. The subtypes of alexias included in the psycholinguistic models are further presented. Finally, mention is made to alexia in aphasia, hemialexia following section of the posterior corpus callosum, and alexia in phonological and logographic writing systems.
Occipital alexia. The syndrome has been given many different names including alexia without agraphia, pure alexia, pure word blindness, agnosic alexia, occipital alexia, posterior alexia, verbal alexia, and letter-by-letter reading. The core clinical features include a serious disturbance in reading contrasted with a preservation of writing competency. Patients with occipital alexia find themselves unable to read what they have just written. Reading letters (literal reading) is significantly preserved, and reading words (verbal reading) is seriously impaired. However, it has been reported that some individuals with pure alexia may present an "implicit recognition effect" observed in their performance of semantic categorization (distinguishing semantic categories) and lexical decision (deciding if a string of letters correspond or not to a real word) (88).
Sometimes, the patient fragments the letter when reading and reads only the initial letter segment (eg, "K" is read as "l"). Letter-by-letter reading aloud eventually can result in word recognition. Bachoud-Levi and Bartolomeo (12) studied reading for words and for isolated letters in a pure alexic patient. When the patient read isolated letters, reaction times were slower for a subset of letters that cannot be recognized from their left part alone (eg, "b", an ambiguous letter, could be read "b" "h" "l" or "k," whereas "a" has no predictable confounders). This result suggests that the letter identification deficit can account for the slow, letter-by-letter reading behavior, insofar as each letter represents a perceptual problem. Moreover, patients with this type of reading disorder use an inefficient eye movement strategy in reading, fixating to the left of the usual normal viewing location of words; consequently, less of the word is processed, and refixation rate increases and reading becomes slower. It is notable that not only is the recognition of letters and words clearly impaired but also the recognition of fragmented pictures, suggesting an inefficient build-up of sensory representations (108).
Reading individual letters aloud to recognize the word is slow and open to error, particularly on long words. Moreover, there is a significant word-length effect, and reading time is proportional to the number of letters in a word, but this effect differs according to the degree of associated hemianopia (102; 56). Morphological paralexias, the misreading of the final morphemes, is a common characteristic of occipital alexia (eg, "closing" is read as "closed"). Patients with occipital alexia can recognize words spelled out loud to them, and they can recognize letters outlined on the palm of the hand. They can also match letters written with different writing forms. Congenitally and early blind subjects may present alexia for Braille reading associated with occipital cortex damage (50). Meada and colleagues (73) studied a patient who had been blind for 25 years due to retinal degeneration. The patient complained of elementary visual hallucination, during which it was difficult for him to read Braille. Brain magnetic resonance imaging showed marked atrophy of the bilateral striate cortex, supporting the recruitment of striate and prestriate cortex for Braille reading.
Two subtypes of pure alexia have been proposed (90). Disconnection alexia is associated with posterior and dorsal lesions involving the splenium of the corpus callosum or the paraventricular white matter. This subtype is frequently associated with visual deficits. Cortical alexia follows more ventral lesions in the occipito-temporal cortex. The visual word form area is damaged; an isolated pure alexia results.
Parietal-temporal alexia. Other names used to refer to this reading disorder are central alexia, literal alexia, letter-blindness, and alexia with agraphia. The characterizing features of this alexia are the impairments of reading and writing: alexia and agraphia. The ability to read aloud and to comprehend written language is disturbed. The alexia is a literal alexia (inability to read letters) resulting in a total alexia. Patients will fail to recognize a word when it is spelled aloud. The writing disturbance is usually equal in severity to the alexia. Their ability to copy written and printed words is far superior to their ability to write them spontaneously or from dictation. They also fail in transposing cursive to printed forms and vice versa (19). Some residual reading abilities (such as some preserved ability to recognize shape and canonical orientation of letters) have been reported, but these residual abilities probably are supported by the right hemisphere (114). However, these patients may have certain ability to know the specific position of letters in words (78). This type of alexia has been informally referred to as "acquired illiteracy." Reading of other symbolic systems, such as musical notation, is also likely to be impaired (58). Identifying digits is usually easier than letters (98).
Frontal alexia. For years, clinicians had noted that patients with Broca aphasia had either lost the ability to read or found the task difficult. Most patients with Broca aphasia do understand some written material, but this is usually limited to individual words. The words that can be recognized are almost exclusively content words (nouns and verbs). Reading, as well as spoken language, is agrammatical. The difficulty that patients with frontal alexia have comprehending written material closely resembles the auditory comprehension disturbance demonstrated in patients with Broca aphasia (18). Even though patients are able to read, they insist they cannot read and avoid reading. Patients with frontal alexia will read some meaningful words, but fail when asked to read the individual letters of a word. Although they can recognize some words spelled aloud, they fail in comprehending most. As a general rule, reading comprehension is superior to reading aloud. When reading aloud, the same speech defect observed in spontaneous language is noted.
Spatial alexia. Right hemisphere pathology can be associated with significant spatial disturbances. Spatial disturbances will be observed in different tasks, including reading, but specific representation of neglect for words may be independent of representational neglect for objects (10). Spatial alexia is characterized by defects in recognizing the visuospatial arrangement of words and texts, usually associated with hemineglect. Because of its association with hemineglect, frequently the name “neglect alexia” (or “neglect dyslexia”) is also used to refer to this reading disturbance. However, reading difficulties are not only due to neglect, but also to poor fixation accuracy that is associated with an abnormal oculomotor pattern that impairs the execution of the precise saccadic eye movements required for reading (86). Often, patients with reading impairments of a spatial type have considerable difficulty in comprehending written material. According to Hecaen and Marcie, spatial alexia is characterized by: (1) inability to fix the gaze on the word or text and to move from 1 line to another, and (2) neglect of the left side of the text (51). He reports that spatial alexia was observed in 23.4% of a series of 146 right-hemisphere damaged patients. In a series of 138 consecutive patients with right hemisphere stroke, Lee and colleagues found hemineglect in 58% of the cases and spatial alexia in 22.5% (67). Hemineglect severity and visual field defects significantly predicted reading difficulties. Lexical stress (word stress location) and lexical decision (deciding whether a series of letters correspond to a real word or a nonword), however, are usually preserved in neglect alexia. Spatial alexia has been reported usually in correlation with spatial agraphia, spatial acalculia, and other spatial defects (51). In a report by Ardila and Rosselli, 21 patients with right hemisphere damage were analyzed. Reading errors included literal errors (substitutions, additions, and omissions of letters), substitutions of syllables and pseudo-words for meaningful words, left hemispatial neglect, confabulation, splitting of words, verbal errors (substitutions, additions, and omission of words), grouping of letters belonging to 2 different words, misuse of punctuation marks, and errors in following lines (07). The authors proposed that spatial alexia is characterized by:
• Some difficulties in the recognition of the spatial orientation in letters.
• Left hemispatial neglect.
• Tendency to "complete" the sense of words and sentences.
• Inability to follow lines when reading texts and sequentially explore the spatial distribution of the written material.
• Grouping and fragmentation of words, most likely as a consequence of the inability to correctly interpret the relative value of spaces between letters.
It is notable that the duration of the stimulus can affect the reading neglect characteristics. If unlimited time is used for reading words and nonwords aloud, most of the reading errors involve the left side of the letter strings (neglect reading errors). Using timed conditions, the overall level of performance decreases, but errors are more evenly distributed across the whole letter strings (11).
Phonological alexia. Phonological alexia involves the inability to read legitimate pseudo-words, despite relatively well-preserved ability to read real words. This dissociation implies that the phonological (indirect) reading route is impaired, and reading must rely on the lexical (direct) route. Word frequency (probability of appearance) is crucial; high frequency words are likely to be read, whereas pseudo-words (zero frequency) are usually impossible to read. Real words are stored in lexical memory, whereas pseudo-words are not present in the lexicon (14). Patients with phonological alexia cannot use the spelling-to-sound correspondence (graphophonemic) rules in written language. When reading, visual paralexias are frequently observed; thus, that the patient will read real words as other words that are visually similar to the target word. The target word and the paralexic error have many letters in common (eg, "mild" is read as "slid"). Hamilton and Coslett (49) reported a patient with phonological alexia who was impaired in writing affixed words (ie, words including a root and an affix, such as “flowed”; “flow” corresponds to the root and “ed” to the affix) but did not demonstrate that defect when reading affixed words.
Surface alexia. The indirect route (graphophonemic) reading system is available to patients with surface alexia, whereas the lexical (direct) route is impaired. Surface alexia represents, in consequence, an acquired disorder characterized by the superior reading of regular words and legitimate pseudo-words in comparison to irregular words. Legitimate pseudo-words can be easily read, because they rely on the indirect (phonological) route. The overuse of the preserved phonological route will result in "regularization errors" (38). According to Friedman, surface alexia is characterized by (43):
• Regularization errors are always observed (irregular words are phonologically read), but frequency is variable.
• Frequency effects, grammatical category effect, and length effect are reported in only a few cases.
• Surface alexia is associated with lexical (surface) agraphia.
• Fluent aphasia is found in most cases.
• Almost all patients present a left temporal or temporoparietal lesion.
Deep alexia. If both the lexical (direct) and phonological (indirect) routes are impaired, only limited residual reading ability will remain. Some distinguishing characteristics have been proposed for deep alexia:
• Semantic paralexias are always observed (eg, "lawyer" is read as "attorney"). Varieties of semantic paralexias have been proposed (43).
• Success in reading a word is affected by the grammatical category and imageability (concrete nouns are read better than abstract nouns).
• Pseudo-words cannot be read.
• Visual and derivational (ie, morphological) paralexias are always observed.
• Deep alexia is always associated with aphasia and agraphia.
Deep alexia has been suggested to involve reading that relies extensively on right-hemisphere orthographic and semantic processing (29). Colangelo and Buchanan studied a patient with deep alexia who was able to read aloud a series of ambiguous (eg, bank) and unambiguous (eg, food) words and who performed a lexical decision task using these same items (27). When required to explicitly access the items (ie, naming), the patient showed relative impairment for ambiguous compared to unambiguous words. The authors proposed that errors in production were due to a failure to inhibit spuriously activated candidate representations (27). Warrington and Crutch reported a subject who presented a better ability to read concrete than abstract words; furthermore, reading concrete words corresponding to living items was more accurate than reading concrete words corresponding non-living items (115). The authors interpreted this pattern of performance as evidence for a degree of autonomy for the semantic processing of written words.
Attentional alexia. Shallice and Warrington reported 2 patients who were able to read single words but unable to read multiword displays or to name the constituent letters of the word. They presented deep left parietal tumors and right homonymous hemianopia (101). Their impairment was not specific for letters, but included all the stimuli in which more than 1 item of the same category was simultaneously present in the visual field (numbers and even pictorial material). The underlying problem in attentional alexia is attributed to a deficit in selective attention, which is not specific to orthographic (ie, written) material.
Aphasic alexia. Aphasic patients present characteristic reading difficulties that can be related directly to their basic language defect. In conduction aphasia, for example, reading comprehension is better than reading aloud, just as auditory comprehension is superior to repetition of spoken language. When reading aloud, literal paralexias are observed, parallel to the literal paraphasias in spoken language. Patients with extrasylvian motor aphasia may show "frontal deficits" when reading; thus, they can misread a phrase due to perseveration. They usually read pseudo-words as real words (the pseudo-word is mispronounced to sound like a visually similar real word) (09). Reading defects in Broca aphasia are usually significant, particularly for reading grammatical words and reading aloud. Alexia in Broca aphasia corresponds to so-called frontal alexia. Patients with Wernicke aphasia may produce substitutions, omissions, additions, and even neologistic reading. Comprehension of written language is often severely impaired. Most extrasylvian sensory aphasias are associated with some reading difficulties, even though severity of alexia can vary. Anomic aphasia patients have defects in interpreting the meaning of written words. When damage extends posteriorly, some degree of occipital alexia may be present.
Hemialexia. Following surgical section of the posterior corpus callosum, some patients have significant difficulties in reading material visualized to the left visual field, but normal reading for the material presented to the right visual field can be observed. This condition has been termed as hemialexia. Hemialexia can occur with any pathology (eg, tumors) that destroys the splenium of the corpus callosum.
Alexia in phonological and logographic writing systems. Characteristics of alexia have been suggested to be affected by idiosyncrasies of writing systems (30). The lexical organization and processing strategies that characterize skilled reading in different orthographies are affected by different developmental constraints in different writing systems (123). In bilinguals, alexia can be restricted to only 1 language (64). Alexias, however, have been studied mostly in Indo-European language writing systems, and cross-linguistic analyses are scarce. Psycholinguistic models of alexias have been developed specially in English and French, 2 languages with rather irregular writing systems. In English, with a significant amount of irregular words (words that cannot be read using grapheme-to-phoneme correspondence rules and can only be recognized as a whole), the existence of 2 different reading strategies or reading routes (indirect and direct) is understandable. Developmental dyslexia is more frequent in irregular writing systems, such as English or French, than in shallow orthographic systems, such as Italian (81). The applicability of the double route reading models to regular (phonologic) writing systems has been challenged (Ardila 1998; 71; 57; 52).
Reports about alexia in logographic writing systems (eg, Chinese) are scarce. With the exception of some studies on the Japanese Kana and Kanji reading systems, comparative research on alexias and agraphias in non-Indo-European languages has been extremely limited (121; 120; 93). Pure alexia, selectively impairing Kana (but not Kanji) reading, has been reported in cases of left posterior occipital lobe damage (95) similar to the anatomy of pure alexia in other phonographic systems. Conversely, alexia with agraphia in Korean Hanja (logographic), but preserved Hangul (phonographic) reading and writing have been reported after a left posterior inferior temporal lobe infarction (65). Senaha and colleagues studied a bilingual Portuguese-Japanese aphasic patient with impaired reading in the logographic system (Kanji) and when reading irregularly spelled Portuguese words, but with no effects on reading regular words and nonwords in syllabic (Kana) and alphabetic (Portuguese) writing systems (100). Sakurai and colleagues distinguished 2 different types of pure alexia: pure alexia for kanji (and kana; fusiform type: pure alexia for words) characterized by impairments of both whole-word reading, as represented in kanji reading, and letter identification; and different from pure alexia for kana (posterior occipital type: pure alexia for letters) in which letter identification is primarily impaired (96). Thus, individuals using 2 different writing systems (eg, ideograms and phonograms as found in Japanese and Korean) may present a dissociated alexia. Yamawaki and colleagues (122) observed in a specific form of alexia that oral reading of kanji words significantly correlates with naming pictures corresponding to the words. They propose to name this type of alexia "anomic alexia of kanji,” suggesting that naming the objects and reading the logographic kanji words share common underlying mechanism.
These studies, as a whole, indicate that reading strategies and alexia characteristics are affected by the idiosyncrasies of the individual reading systems (57).
Some special forms of alexia. Alexia has been reported in blind people for Braille reading following bilateral (50) or right-sided occipital damage (82). Therefore, in blind people, reading Braille depends at least in part on occipital lobe activity. The right occipital area, in particular, seems to play a major role in reading Braille; however, paralexias for Braille reading have also been observed in cases of right parietal pathology (79). Braille alexia might be interpreted as a tactile agnosia (66). Kinesthetic alexia (inability to read following the letter with the fingers) with preserved visual reading has been associated with left parietal damage (55).
There are a few reports of alexia in languages reading from right to left, such as Hebrew (45).
In general, some recovery in reading ability is expected in alexic patients. The severity of alexia and the pattern of recovery can vary. Recovery may depend on the size of the lesion and the etiology of the damage. Additional factors influencing recovery include age and handedness. Alexia associated with global aphasia usually has a poor prognosis. In occipital alexia, reading ability improvement parallels the recovery in visuoperceptual abilities. Recovery in parietal-temporal alexia and frontal alexia is variable, but at least some recovery is expected. Improvement in spatial abilities and diminishing of hemineglect result in superior ability to read in cases of spatial alexia associated with right hemisphere pathology. In 1 study, 22% of stroke patients with alexia, agraphia, acalculia, or combinations fully recovered 24 months later (124). The main factors influencing recovery were initial severity of reading, writing, and calculation impairment; age; neglect; and level of education.
The patient, a 23-year-old male, had a medical history that was unremarkable prior to a serious car accident. The patient sustained multiple fractures, but without loss of consciousness or cognitive deficits. Subsequently the patient experienced a fat embolism, probably due to the multiple fractures, which occluded the posterior cerebral arteries. This initially resulted in cortical blindness. Sometime later, the patient was diagnosed with Balint syndrome, as evidenced by ocular apraxia, optic ataxia, and simultanagnosia. The patient remained hospitalized for several months. Twelve months after the occlusion, brain scans indicated significant parietal-occipital atrophy. At this point, he was oriented to person, place, and time. Speech was abundant and contained no articulatory, grammatical, or prosodic errors and no deficits in comprehension within conversational language. The patient recognized handwritten as well as palpated letters. However, occasionally when reading letters he read just a fragment of the letter (eg, "m" was read as "n"). He also recognized words spelled aloud by the examiner and could spell words aloud himself, but he failed to read any word. A letter-by-letter reading was evident, sometimes resulting in deducing the correct word (eg, "cat" is read as "This is a C, and this is an A, and I think this is a T. Oh! It has to be ‘cat’"). The patient was able to write spontaneously as well as from dictation, but was unable to copy words or phrases. Given his visuoperceptual difficulties, the distribution of his writing was erratic. In general, his spontaneous writing was found to be well preserved, but his copying was deficient, and on occasions, impossible. He also could not locate a point in the center of a circle and had severe difficulty with visual integration. In attempting to describe a complicated figure, he could only describe individual details and was unable to recognize the integration of the figure (simultanagnosia). He also presented significant difficulties in identifying photographs of famous people.
During the following 18 months, the patient attended a rehabilitation program 2 hours a week. This time was significantly devoted to presenting exercises that the patient should continue practicing at home. Exercises included:
• Visually following objects moved by an examiner.
• Reading of words by following the index finger and saying all the letters out loud.
• Visuokinetic functioning. Letters were shown to the patient, and the patient reproduced them in the air with the index finger, followed by saying the name of the letter. When following the words with the index finger, he simultaneously performed the movements of writing the words.
• Exercises of visual search. The patient looked for letters and words in a mixture of letters presented together at various angles. Each request became more complex. He was asked to withdraw special designs from this mixture.
• Exercises of writing. The patient was asked to write with large letters to facilitate subsequent reading of the letters previously written. A measurement of reading advancement should progress as the size of the letters diminishes.
The program was concluded when the patient regained some ability to read and returned to work in an activity not requiring special visual abilities.
Alexia is most often caused by a stroke, tumor, or trauma. Reading aloud can be relatively preserved in dementia, but reading comprehension is defective (semantic alexia). Slowly progressive alexia is observed in neurodegenerative disorders (80; 105). Alexia has been documented as a paroxysmal phenomenon (06), as well as a postictal phenomenon (72). Pure alexia has been reported after a biopsy for a malignant glioma involving the left thalamus (111) and in some other unusual conditions such as neurocysticercosis (113), corticobasal syndrome (53), multiple sclerosis (85), and Creutzfeldt-Jakob disease (02). Reversible pure alexia can occur with migraine with aura (22).
Except for spatial alexia, most reading disturbances are associated with left hemisphere pathology. At least 2 cases of “crossed” pure alexia (alexia due to right hemisphere damage) in a right-handed subject with right-hemisphere dominance for language has been reported (70; 89). In most cases, occipital alexia is due to occlusion of the posterior cerebral artery. It can also occur with either intracerebral or extracerebral tumors, arteriovenous malformations, or progressive multifocal leukoencephalopathy (46). It has also been reported in cases of progressive multifocal leukoencephalopathy (46). Damage usually includes the medial and inferior occipital region, particularly the fusiform and lingual gyri and the posterior segment of the geniculocalcarine pathway. A so-called “visual word form area” corresponding to the posterior left occipitotemporal cortex adjacent to the fusiform gyrus has been hypothesized (32). It is frequently assumed that this area mediates word recognition. A case of pure alexia associated with 2 different infarcts (left lateral thalamus and left splenium of the corpus callosum) has also been reported (74). Leff and colleagues found that left occipital damage may result in alexia for 2 reasons, which may coexist depending on the distribution of the lesion (69). A lesion of the left lateroventral prestriate cortex or its afferents impairs word recognition ("pure" alexia). If the left primary visual cortex or its afferents are destroyed, resulting in a complete right homonymous hemianopia, rightward saccades during text reading are disrupted ("hemianoptic" alexia). Some defects attributed to impaired letter recognition may actually be due to the right homonymous hemianopia usually associated with pure alexia (13). Impairments in oculomotor behavior during reading have been documented in this group of patients; they present a disproportionate increase in the number and duration of fixations per word and in the regressive saccades per word (17). The amplitude of the rightward saccades during text reading seems to depend on visual field defect, but visuomotor difficulties, such as the increase in fixation frequency and viewing time, probably are not related to the hemianopia (84). This suggests that pure alexia could result from a general reduction of visual speed and span (109; 83). Some researchers caution against assuming that a patient’s pure alexia must be due to right homonymous hemianopia because some hemianopic patients also could not read words in the unimpaired left visual field (91). Similarly, visual impairment due to posterior cortical atrophy does not always result in alexic reading impairment (21), and at least 1 patient presented with pure alexia in the absence of deficits in perceiving complex visual stimuli, suggesting a nuanced relationship between general visual or identification deficits and pure alexia (107).
Positron emission tomography has demonstrated that the left occipitotemporal junction in the inferior temporal gyrus (sometimes called the “visual word form area”) is most active during normal reading. This area is also activated in patients with hemianopic alexia but no reading deficit. This same area is damaged in patients with pure alexia and no hemianopia, who read words slowly using a letter-by-letter strategy (68; 112). Similarly, left-lateralized occipitotemporal atrophy has been found in patients with progressive alexia (118). Tractography and voxel-based morphometry have shown that this area in mainly connected to the occipital lobe through the inferior longitudinal fasciculus and to the supramarginal gyrus through the arcuate fasciculus (40). Brain lesions in patients with pure alexia and functional imaging data suggest that the abstract letter identities (visual word forms) are subtended by a restricted patch of left-hemispheric fusiform cortex, which is reproducibly activated during reading (26; 37; 63). Ffytche and colleagues described a patient with bilateral occipitotemporal infarcts who presented visual hallucinations of grammatically correct, meaningfully written sentences or phrases (41). In addition to the pure alexia, the patient showed achromatopsia, prosopagnosia, and associative visual agnosia. Cortical stimulation of the left posterior fusiform and inferior temporal gyri results in pure alexia (75). Cohen and colleagues analyzed a case of pure alexia associated with a left occipito-temporal lesion affecting the visual word form area (25). The reading defect was due to a small left fusiform lesion associated with loss of visual word form area responsivity and degeneration of the associated white matter pathways. Progressive improvement in reading ability over 2 years was correlated with increasing responses in spared occipital lobe posterior to the damage and in the contralateral right occipital lobe. The authors suggested that there is an alternative occipital route potentially involved in reading, bypassing the visual word form area; this route, however, is less efficient.
Although it has been traditionally assumed that faces and words are processed by independent neural mechanisms located in the occipital cortex in the right and left hemisphere respectively, Behrmann and Plaut observed in 7 patients (4 pure alexic, 3 prosopagnosic) that prosopagnosic patients demonstrated mild but reliable word recognition deficits, and pure alexic patients revealed mild but reliable face recognition deficits (16). McCarty and colleagues reported the case of a right-handed patient presenting prosopometamorphopsia (altered perception of faces) associated with alexia following infarction of the left splenium in the corpus callosum (77). However, there is also evidence that pure alexia and acquired prosopagnosia may rely on different visual mechanisms; a study by Sand and colleagues showed abnormal crowding in foveal vision in 2 patients with acquired prosopagnosia, but not in 2 patients with alexia (97).
Parietotemporal alexia can result from cerebrovascular disease involving the angular branch of the left middle cerebral artery. Trauma, abscess, tumor, or any pathology involving the posterior parietal area and the temporal-parietal region can also be associated with alexia (39). Similarly, damage involving the Brodmann area 19 and the white matter in the left inferior parietal lobe can result in alexia with agraphia (103). It has been suggested, however, that alexia occurs only when the lesion involves the adjacent lateral occipital gyri (94). Alexia with agraphia has also been associated with thalamic pathology (31). A study using principal components analysis showed a dissociation, in patients with central alexia, between reading aloud and reading for meaning, with preserved ability in the former associated with grey matter density in part of the dorsal visual stream, and the latter with the left ventral visual stream (04). Any abnormal condition affecting the posterior area of the left frontal lobe can result in a frontal alexia.
Right parietal, parietal-occipital, and parietal-temporal pathology usually results in significant spatial disturbances, including spatial alexia. Lee and colleagues observed that in patients with hemineglect, brain lesions were located in the superior and middle temporal gyri, inferior parietal lobule, and posterior insular cortex of the right hemisphere; when reading disturbances were found, additional lesions in the lingual and fusiform gyri were also disclosed (67).
Phonological alexia has been reported in cases of diverse brain pathology. In general, however, the middle cerebral artery territory is involved, most frequently the superior temporal lobe and angular and supramarginal gyri of the left hemisphere. Functional neuroimaging studies have suggested that the left frontal operculum is more active when normal subjects read pronounceable pseudo-words as compared to most word types. Damage in this area results in defects at reading pseudo-words associated with a relatively intact word reading ability, a pattern observed in phonological alexia (42). In cases of surface alexia, lesions tend to involve the temporoparietal cortex and frontal association cortex and Broca area. No region is invariably affected, though the superior temporal gyrus is most frequently injured (44). Significant activation in the left anterior middle temporal gyrus is associated with healthy subjects reading irregular words (which is impaired in surface alexia) (117).
Anatomical lesions causing deep alexia are commonly extensive left-hemisphere insults, including the Broca area. Using functional MRI, it has been reported that different neural circuits may subserve reading before and after therapy for alexia, suggesting that it is possible to alter brain physiology with therapy for acquired language disorders (104). Adair and colleagues observed that before therapy, the right hemisphere is inactive during nonword reading relative to a linguistic task. After treatment, nonword reading increases cerebral blood flow in the posterior right perisylvian cortices homologous to the dominant hemisphere areas engaged by reading (03).
Alexia needs to be differentiated from developmental dyslexia. Alexia has been reported as the initial clinical symptom in cases of posterior cortical atrophy (08; Delgado and Donoso 2009). Reading comprehension defects represent a significant component in global cognitive disorders, usually observed in dementia and in cases of traumatic brain injury. Reading ability is strongly correlated with educational level. People with low education levels may have difficulties understanding complex written information.
Testing for alexia is included in most language assessment test batteries (eg, Boston Diagnostic Aphasia Examination) (48). Traditionally, the following tests are included when assessing for alexia:
• Reading aloud: letters, syllables, words, pseudo-words, sentences, and paragraphs
• Identification: letters, syllables, words, pseudo-words, sentences, and paragraphs
• Logographic reading: words with extremely high frequency (eg, the country name, the patient’s name)
• Matching different types of writing: script, block letters, etc.
• Spelling: spelling of words out loud, comprehension of orally spelled words
• Reading comprehension: matching written words with objects, carrying out written commands, paragraph comprehension
• Reading of other symbolic systems: traffic signals, musical notations, chemical symbols
The psycholinguistic models of alexias emphasize that reading words aloud represents the most informative reading test. Words to be read, however, should be controlled according to some variables:
• Frequency: high frequency, low frequency, and zero frequency pseudo-words should be used.
• Regularity: regular and irregular words should be presented to the patient.
• Grammatical class: content words (eg, nouns) and function words (eg, prepositions) are to be used.
• Imageability: it is advisable when testing for alexia to include words with high imageability (concrete words) and low imageability (abstract words).
Reading comprehension of texts can also be used, particularly in certain pathological conditions such as traumatic head injury (106).
During the past few decades, formal language rehabilitation programs have become widely available. Most individuals with language disturbances receive formal diagnostic evaluations, and many attempt remedial therapy programs. Alexia rehabilitation is carried out simultaneously with aphasia rehabilitation. Several case reports describing rehabilitation programs with alexic patients have been published during the last 2 decades (92; 01; 15; 62; 99; 54). New rehabilitation techniques have been proposed for different types of reading defects. As an example, spatial alexia (neglect dyslexia) can improve following a short period of adaptation to wedge prisms. An increased left-sided exploration of the letter strings and increased amplitude of the first left-sided saccade have been reported (05). In pure alexia, tactile/kinesthetic training (the letter is traced in the patient’s hand/the patient makes the movements required to form the letter) can benefit letter identification (110). In phonological alexia, so-called “phonomotor treatment” (phonological processing and oral reading of words) improves reading (23). Noteworthy, eye movement tracking can be an adjunct to traditional behavioral outcomes when analyzing the results of reading therapy (61). It has been also reported that transcranial direct current stimulation has a small but significant facilitatory effect on word reading in patients with post-stroke central alexia (60). DeMarco and colleagues recorded brain activation during pseudoword reading in a patient with phonological alexia and agraphia (36). Improvements were associated with greater activation in residual left dorsal language areas; additional activation was observed bilaterally in regions involved in attention.
Telerehabilitation has been proposed to treat language disorders, but the evidence, thus far, has been limited. Getz and colleagues successfully treated the reading deficits remotely of 2 participants with phonological alexia (47). The authors concluded that telerehabilitation may be as equally effective as in-person treatment for reading disorders. Woodhead and colleagues have also tested a training app called “iReadMore” in a randomized trial with chronic stroke patients with central alexia, in conjunction with anodal transcranial stimulation of the left inferior frontal gyrus (119). The app improved reading on trained (but not untrained) words, facilitated by stimulation. Furthermore, iReadMore improved reading accuracy in central alexics on trained but not untrained words, and it also examined the impact on left and right hemisphere reading network connectivity. Connectivity between regions was predominantly improved within the left hemisphere, in a feedforward direction from occipital regions to the left inferior frontal gyrus, as well as strengthening of connections from the right to the left occipital cortex; feedback connections from the left inferior frontal gyrus to occipital regions did not improve. The authors suggest that the improvement in reading after iReadMore therapy is modulated by lower order visual representations, perhaps via tuning of visual cortex to trained words as participants receive feedback across repeated trials in the app (59).
Alia Martin PhD
Dr. Martin of Victoria University of Wellington has no relevant financial relationships to disclose.See Profile
Victor W Mark MD
Dr. Mark of the University of Alabama at Birmingham has no relevant financial relationships to disclose.See Profile
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Jan. 18, 2022
After carpal tunnel syndrome, the most common median nerve entrapment is the pronator teres syndrome. The most common features of the pronator teres syndrome are insidious proximal forearm fatigability, pain, and tenderness amplified by exercise and, at times, radiating to the shoulder. Other less common entrapment sites include the ligament of Struthers, lacertus fibrosus, and the tendinous origin of the flexor digitorum superficialis.
Jan. 02, 2022
Huntington disease (HD) is a neurodegenerative disorder characterized by a combination of progressive motor, cognitive, and psychiatric symptoms. Chorea is the most common movement disorder in HD, and it tends to slow and may be replaced by dystonia-rigidity in the end stages. Cognitive and behavioral changes may occur years prior to the onset of definitive motor signs, simultaneously with or after motor manifestation of the disease.
Dec. 30, 2021
Neurovascular injury is a broad topic that includes injury to different neuroanatomical sites. They can occur either extracranially or intracranially and can manifest as an arterial dissection, pseudoaneurysm, fistula formation, and thrombosis or occlusion of the involved vessel. A high index of suspicion is needed to diagnose vascular injuries in an accurate and timely manner because most patients have no focal neurologic deficit on presentation.
Dec. 08, 2021
Sleep disturbances are common after traumatic brain injury, affecting 30% to 84% of individuals, with varying degree of head injury. Not only can they
Dec. 04, 2021
Neuro-Ophthalmology & Neuro-Otology
Toxic or nutritional optic neuropathy is classically characterized by gradual painless progressive vision loss, bilateral central or cecocentral scotomas, marked dyschromatopsia, loss of high spatial frequency contrast sensitivity, temporal pallor, and loss of papillomacular bundle. A thorough history of medication use, toxic exposure, substance abuse, dietary deficiency, past surgeries, family history, and peripheral neurologic symptoms should be documented. Early recognition, removal of toxic agents, and supplementation of nutritional deficiencies may lead to protracted visual recovery.
Dec. 02, 2021
Most traumatic spinal cord injuries occur in association with impact to the vertebral column, resulting in direct compression or disruption of the spinal cord. Secondary injuries may ensue, resulting from ischemic and inflammatory processes, disrupted homeostasis, and apoptosis. The American Spinal Injury Association (ASIA) Impairment Scale is an international classification of spinal cord injury based on neurologic deficits, including motor function and sensation, as well as bowel and bladder control from the S4 and S5 segments.
Dec. 01, 2021
Behavioral & Cognitive Disorders
Normal pressure hydrocephalus (NPH) is characterized by gait disorder, cognitive decline, and urinary incontinence. Hydrocephalus in NPH is a consequence of the disequilibrium between production and absorption of CSF. In the majority of cases, ventricular enlargement results from an obstruction of the CSF flow around the brain convexities and insufficient absorption through the arachnoid granulations and arachnoid villi of the superior sagittal sinus.
Dec. 01, 2021