Alexia

Etiology

The presentation of alexia ranges from a mild reading deficit to a complete inability to comprehend written language, often associated with agraphia, the inability to write. The most common cause of alexia is a stroke (embolic or ischemic cerebral vascular accident) affecting the dominant cerebral hemisphere. However, the disorder may be caused by other etiologies that disrupt that area, such as lesions, tumors, injury, or trauma.[7]

The specific area of the brain affected results in 3 distinct types of alexia characterized by specific deficits in reading comprehension with or without other neurocognitive deficits such as:

• Frontal or anterior alexia
• Central or parietal-temporal alexia
• Posterior or occipital alexia.[8]

Pure alexia, or word blindness, was the first disconnection syndrome described. The syndrome resulted from the loss of visual input to the language area without the involvement of the language area. The most common etiology is left posterior cerebral artery occlusion involved at the left occipital cortex and the splenium of corpus callosum, but it can also occur due to any lesion affecting the splenium of corpus callosum disrupting the white matter tracts from the left visual cortex to the angular gyrus.[9] A meta-analysis of magnetic resonance imaging (MRI) studies of visual mental imagery described a right-handed patient with an extensive occipitotemporal stroke in the left hemisphere, which provoked right homonymous hemianopia, alexia without agraphia, and color anomia.[10] 

A rare case of alexia was mentioned in an encephalitic immunocompromised patient with symptomatic focal hypodensity caused by a rare amoeba Balamuthia mandrillaris. MRI of the brain revealed a T2 hyperintense signal of the left occipital lobe with leptomeningeal enhancement and vasogenic edema. The patient developed imbalance, visual disturbances, night sweats, bradyphrenia, alexia without agraphia, and right hemianopsia.[11] Cases of cortical hematomas were also reported to lead to a rare pure alexia.[12] 

Epidemiology

The most common association is alexia with agraphia, which pertains to both writing and reading impairment that can occur with or without aphasia.[13] Isolated alexia without agraphia is uncommon, and statistics are limited. However, the disorder is often associated with other types of strokes and neurological deficits caused by cerebral vascular accidents. Strokes cause a significant amount of morbidity and mortality worldwide in both women and men. Statistics from 2017 show an incidence rate of stroke of 140.3 to 161.8 per 100,000 in 2017.[14][15]

Pathophysiology

Various degrees of comprehension deficit result in different types of alexia, including occipital or posterior alexia, central or parietal-temporal alexia, and frontal or anterior alexia. Pure alexia without visual or language accompanying deficits or isolated pure alexia was found infrequently in clinical practice. Although this type of alexia has been associated with lesions along the splenium of the corpus callosum, the results of studies showed occipitotemporal cortex damage in the absence of white matter implication. In cohesion, a functional region called the visual word form area (VWFA) has been linked to the posterior aspect of the occipitotemporal gyrus.[12] 

The visual word form area is the neural basis for visualizing letters and words for patients with pure alexia and rare right-sided lesions leading to pure alexia in right-handed individuals. In a case report of a patient with a hemorrhagic lesion to the right fusiform gyrus, limited recovery of reading skills occurred within 6 weeks post-onset. Functional MRI showed right-hemisphere dominance for language and bilateral reading-related activity in the fusiform gyri. This case emphasized that pure alexia may be due to right fusiform gyrus damage in right-handed patients (who still may have right hemisphere dominance for language and reading skills). The disorder may cause severe reading disability, just like the patients with left-hemisphere dominance for language.[16]

A study on the kanji (morphogram) and kana (phonogram) problems in Japanese alexia and agraphia showed dissociation in reading comprehension and writing. The results of this study also mentioned recent advancements in lesion-to-symptom analyses and functional imaging studies in some areas whose damage causes dissociative disturbances of reading or writing between kanji and kana as follows:

• Angular alexia with agraphia causes kanji agraphia; alexia of kana with an angular gyrus lesion is due to middle occipital gyrus damage.
• Alexia with agraphia for kanji is due to a posterior inferior temporal cortex (mid-fusiform/inferior temporal gyri; visual word form area) lesion, whereas pure agraphia for kanji is a result of posterior middle temporal gyrus lesion, and
• Pure alexia, particularly for kanji, is caused by a mid-fusiform gyrus lesion (Brodmann's Area [BA] 37), while pure alexia for Kana is due to a posterior fusiform/inferior occipital gyri lesion (BA 18/19).[17] 

Most language processing occurs around the angular gyrus of the left hemisphere, the dominant hemisphere for most of the population. Damage to these areas can result in multiple language-related deficits such as Broca aphasia, Wernicke aphasia, global aphasia, and alexia. A different brain area is damaged in each form of alexia. Three major classifications of alexia exist, with varying syndromes of alexia associated with each. The first presentation is known as alexia without agraphia, pure alexia, posterior alexia, or occipital alexia and is associated with damage to the occipital region. The visual word form area is affected, and visual input cannot be relayed to the language comprehension areas of the brain.

The communicating area between the auditory and language centers is maintained, resulting in the retained ability to interpret words spelled out to or by the individual.

• Associated with infarction to the left posterior cerebral artery and or hemorrhage in the occipital territory, usually affecting the splenium of the corpus callosum, which helps the visual cortex communicate with the brain's language centers. 
• Often associated with a contralesional visual field defect resulting in hemianopia (loss of sight to half the visual field), most commonly right visual field defect. 
• Individuals lose the ability to comprehend written language but maintain the ability to spell and write.
• The area of auditory input is unaffected, and the individual can interpret words spelled out to them or by them.[7]

Case reports of cortical hematomas were reported to lead to this rare pure alexia condition. The results of the study discussed the neuroanatomical evolution of this syndrome and proposed a new classification of pure alexia based on the neuroanatomical location of the lesion, such as:

• Disconnection alexia, after posterior and dorsal lesions involving the splenium of the callosal corpus or the paraventricular white matter, is often associated with visual deficits.
• After more anterior and ventral lesions in the occipitotemporal cortex with damage to the visual word form area, cortical alexia usually manifests as isolated pure alexia.[12] 

The second presentation, known as central or parietal-temporal alexia, is associated with damage to the angular gyrus. Central alexia involves damage to the pathways connecting the visual word form area and the auditory area to the language centers of the brain, resulting in word blindness as well as the inability to spell out or recognize spelled-out words.  

• Associated with infarction to the left posterior cerebral artery, middle cerebral artery, and or hemorrhage to the angular gyrus. 
• Associated with aphasia and agraphia. The individual will have difficulty with speech production and comprehension.
• Associated with right visual field defect and often contralateral hemisensory neglect or loss. 
• Complete loss of interpretation of written speech, inability to distinguish individual letters, inability to interpret words spelled out to them, or ability to spell words themselves.[5] 

The third presentation, frontal or anterior alexia, is associated with an anterior lesion to the left hemisphere. The visual word form area is spared, resulting in the ability to interpret written language through verbal working memory. The individual can recover word identity by recognition of common or content words. 

• Associated with infarction, hemorrhage, injury, or trauma to the anterior part of the left hemisphere. 
• Decreased reading comprehension with recognition of content words and short words but complete or partial letter blindness. 
• The inability to comprehend spelled-out words and spell words out themselves is associated with agraphia. 
• Associated with non-fluent aphasia. 
• Associated with right visual field defect and often contralateral hemisensory neglect or loss.[3][8]

History and Physical

Alexia without agraphia, pure alexia, posterior alexia, or occipital alexia is associated with damage to the occipital region. 

• Individuals lose the ability to comprehend written language but maintain the ability to spell and write. In this scenario, the individual can write a full sentence but then cannot read back what was just written.
• Individuals may recognize the letters, be able to spell out the words, and derive meaning from what is read by audition. The individual does not rely on the material read but rather on the sounds produced by spelling out or phonographically sounding out the individual letters and can, therefore, comprehend what is being heard, not read. If the individual were to read silently, no comprehension would occur.
• Often associated with hemianopia, individuals exhibit a right-sided visual field deficit. 
• Patients with pure alexia read words slower and showed more fixations, particularly the serial, letter-by-letter fixation strategy. 
• Showed word-length effect and problems in identifying letters or numbers in strings of symbols but normal in identifying isolated letters and in non-verbally categorizing even complex images such as faces or natural scenes.
• Perception of facial identity in a non-redundant fashion, focusing on the data in linear contours at higher spatial frequencies and the processing of facial speech patterns.[3][18][19][18][20]

Central or parietal-temporal alexia is associated with damage to the angular gyrus. 

• With complete letter and word blindness, the individual is unable to read or recognize words or letters. Therefore, they cannot create a phonographic interpretation of what is written, unlike what is seen with occipital alexia.  
• Associated with the inability to interpret words spelled out to them and to spell out words themselves. 
• Associated with agraphia is the inability to write.
• Associated with aphasia of varying forms, fluent vs nonfluent.
• It is often associated with hemiparesis and visual field defects. 

Frontal or anterior alexia is associated with an anterior lesion to the left hemisphere. 

• Individuals can guess content words and short words but have limited comprehension of the reading material.
• Inability to recognize individual letters, loss of letter interpretation when words are spelled out to them, and failure to spell words themselves. 
• Associated with nonfluent aphasia.
• Associated with right visual field defect and often contralateral hemisensory neglect or loss.[8]

Evaluation

Evaluating a patient with alexia includes a thorough physical examination to assess reading fluency and comprehension. A baseline reading level before the insulting injury is beneficial to assess the patient. Patients should be asked to read short stories and evaluated on comprehension of the material and the speed at which the material was read. Patients should also be assessed on their ability to spell out words, comprehend spelled words, and write. A comprehensive neurological examination should be completed to evaluate for additional neurocognitive dysfunction.

Neuroimaging with a computed tomography (CT) scan or MRI is completed to localize the affected area, severity, and acuity of the condition. A study evaluated a patient with pure alexia but no difficulty speaking, paresthesias, or hemiparesis, with 20/20 visual acuity in both eyes. Automated perimetry showed right homonymous hemianopsia. Neuroimaging revealed a left occipital ischemic infarction with involvement of the splenium of the corpus callosum, producing the classic disconnection syndrome of alexia without agraphia.[21]

A stat head CT scan is recommended on anyone presenting with new-onset alexia to assess for acute cerebral vascular accidents.[3][4] MRI has a higher sensitivity than a head CT and must be considered if the head CT is non-diagnostic. On the other hand, a computerized tomography angiogram (CTA) may be helpful since it can detect left posterior cerebral artery (PCA) abnormalities that can cause cerebral infarctions. Moreover, infarction of the occipital lobe on the dominant side (left) in a right-handed individual may affect the visual word form area manifested by an inability to read with no abnormalities in visual acuity.[5]

Cases of patients with moyamoya disease with alexia with agraphia, specifically for Japanese kanji, have been reported. These patients had impaired perfusion in the left inferior temporal and lateral occipital lobes.[22] In another case report, a patient with symptoms of alexia accompanied by aphasia and agraphia after carbon monoxide intoxication was also reported.[23] Investigation of possible reversible causes is needed if initial imaging studies do not explain the neurologic deficit.

Treatment / Management

Treatment and management of alexia are focused on rehabilitation strategies to improve reading. The treatment modality for alexia depends on the neuroanatomical area affected, as described above. For individuals with intact letter recognition, a letter-by-letter approach to reading is used where each letter is sounded out. For patients with intact writing skills, a kinesthetic approach is used. In this approach, the patient will trace or outline the letters and sound them out by the tactile input of writing the letter. These tactics can be used to increase reading speed. Although the method may improve symptoms, a definite cure for the disorder is yet to be discovered.[24] 

Many studies elaborated on reading therapy, namely:

• Multiple oral re-reading therapy adjunct with transcranial direct current stimulation (tDCS) in improving reading recovery of a patient with pure alexia without agraphia following a stroke. MRI revealed an area of infarct with microhemorrhages at the left occipitotemporal region. The patient showed better reading comprehension, average reading time, and word per minute, suggesting that multiple oral re-reading therapy and tDCS therapy may speed up the recovery of patients with pure alexia.
• The multi-component program included sight word drills, modified multiple oral reading procedures, functional reading tasks, and modified copy and recall treatment, effectively promoting substantial improvement. However, surface alexia and agraphia persisted after 2 months of treatment.
• Audio-visual reading training in patients with pure alexia testing the effect on reading speed and functional reorganization essential to the therapy-induced behavioral changes using magnetoencephalography. Findings include increased bidirectional connectivity between the left occipital and ventral occipitotemporal perilesional cortex and increased feedback connectivity from the left inferior frontal gyrus. However, weaker connection strengths were seen between right hemisphere regions.
• Novel training app 'iReadMore,' and anodal transcranial direct current stimulation of the left inferior frontal gyrus, on word reading ability among post-stroke patients with central alexia. The iReadMore improved reading ability for trained words, with good maintenance of the therapy effect. Anodal stimulation resulted in a small facilitation of learning and was also generalized to untrained items.[25][26][27][28]
(A1)

In the treatment of patients with both reading and writing impairments, adults with acquired alexia and agraphia showed significant improvement in the subset of treatment steps intended to address lexical access and representations, sublexical conversion mechanisms, and the graphemic or phonological buffer processes in both reading and writing. These results elaborated on the efficacy of a novel, comprehensive treatment protocol and suggested that the combination of both multiple reading and writing processes may facilitate extensive generalization.[29] 

In some cases, reversible causes of alexia have been found, and treatment of these causes improves symptoms. Case reports of patients with moyamoya disease with alexia with agraphia, specifically for Japanese kanji, showed impaired perfusion in the left inferior temporal and lateral occipital lobes. Findings showed noticeable improvement of symptoms after superficial temporal artery-middle cerebral artery bypass; correction of hypoperfusion may be effective in adult patients presenting with language dysfunction.[22] In a patient with symptoms of alexia accompanied by aphasia and agraphia after carbon monoxide intoxication, a combined treatment of speech and hyperbaric oxygen therapy resulted in the complete disappearance of aphasia with agraphia and alexia.[23] 

Differential Diagnosis

Alexia is the inability to comprehend written language due to focal brain injury in the temporal lobe. It is important to distinguish alexia from other disease processes that impair reading. These may include:

• Visual impairment
• Visual agnosia
• Eye trauma or injury
• Cataracts or blindness
• Other neurocognitive disorders such as global aphasia, dementia, intoxication, mutism, and psychiatric conditions such as catatonia, depression, or schizophrenia.[30][31][32]

A recent study observed reading deficits in dementia and traumatic brain injury, but often with less consistent deficit patterns than in patients with focal lesions.[33] Another study showed that patients made some letter substitution errors characterized by visual similarity in pure alexia and phonological similarity in semantic dementia. Findings revealed that the reading deficits in pure alexia and semantic dementia arise from visual processing impairments and knowledge of word meaning, respectively.[34] Gerstmann syndrome is a tetrad of agraphia, acalculia, finger agnosia, and right-left disorientation. However, a case presented this syndrome as an incomplete tetrad of symptoms or accompanied by cognitive deficits, including aphasia, alexia, apraxia, and some perceptual disorders.[35] 

Prognosis

The prognosis for patients suffering from alexia is variable and highly dependent on multiple variables. The type of alexia, cause of injury, and amount of rehabilitation after the insulting injury play a critical role in determining prognosis. Although individuals may improve their reading comprehension, complete resolution is rare.[24] The findings of a study on patients with pure alexia discussed recovery in some reading abilities over time. However, most never regain their premorbid reading skills, particularly a case of remission from severe reading problems immediately following a posterior cerebral artery stroke to mild pure alexia. Few studies also cited some behavioral and imaging correlates of such remission but limited reports on the patient's experience of their reading impairment.[36]

Complications

Complications of alexia encompass a spectrum of reading disabilities that range from permanent loss of comprehension to mild reading impairment. Alexia almost always accompanies other neurocognitive deficits associated with the inciting insult. These conditions include but are not limited to complete aphasia, hemineglect, visual field deficits, and death.[4][8]