Posterior Cortical Atrophy

Etiology

Alzheimer disease (AD) is the commonest underlying pathology, and hence it is frequently labeled as a "visual variant" of AD.[4] Lewy body disease, corticobasal degeneration, and the Heidenham variant of Creutzfeldt-Jakob disease (CJD) have also been described as less common alternative pathologies to posterior cortical atrophy.[5] 

A new consensus criterion for the diagnosis and classification of PCA was published in 2017. A classification framework has also been proposed that subtypes PCA into PCA-pure, PCA-plus, and other pathologic subtypes depending on the presentation and biomarker evidence of underlying pathology.[6] This facilitates the interpretation of data from research studies across a broad range of scenarios.

Epidemiology

Posterior cortical atrophy typically presents early (< 65 years). An international study of 302 patients with posterior cortical atrophy showed a peak onset between 50 and 65 years of age with diminishing incidence with age.[7] The mean age of onset was determined to be 58.9 years. A precise estimation of the incidence and prevalence of posterior cortical atrophy is difficult given the changing definitions and the relative rarity of the disorder.

The proportion of patients diagnosed with posterior cortical atrophy depends on the clinical context. It varies from 5% in specialty cognitive clinics to 13 % when looking at early-onset Alzheimer disease data.[8][9] Some studies have reported PCA to be more common in women, reflecting the increased prevalence of AD in women. While other studies have reported no sex differences.[10]

Pathophysiology

There is a clear difference in the distribution of senile plaques and neurofibrillary tangles in posterior cortical atrophy as compared to Alzheimer's disease. This can be seen in post-mortem findings where primary visual cortices and visual association areas are mainly involved compared to patients with typical Alzheimer disease.[11] 

There is a greater density of senile plaques and neurofibrillary tangles in the occipitoparietal area than in the frontal regions.[12] In contrast, no significant differences in amyloid burden have been reported across studies.[13] CSF biomarker levels of Aβ, T-tau, and P-tau are similar to that of Alzheimer disease.[14]

History and Physical

The course of posterior cortical atrophy is usually insidious and primarily affects the central visual deficits without peripheral visual deficits.[15] On average, there is a diagnostic delay of around four years.[13] Symptoms are often present for months or years before they present to the neurologists or psychiatrists. Initially, patients often present to optometrists/ophthalmologists, and it is not uncommon to see a history of several unsuccessful corrections to eyeglasses or even surgical procedures to correct the symptoms. Patients can often present with nonspecific anxiety very early on in the illness.

Further exploration of the functioning can reveal difficulties in judging distances and traffic speed while driving. History is also likely to show impairment in reading analog clocks and digitalized pixelated signs. It is not uncommon for patients to bump into door frames while walking or locating door knobs due to visual processing difficulties. Patients can also report anxiety while going down the escalators, especially when going down and difficulty with revolving doors. Considerable difficulty reading degraded letters and numbers compared to reading the same letters in a completed form is highly suggestive of apperceptive agnosia.[16] 

Patients can present with features of acalculia, agraphia, finger agnosia, and left-right disorientation, which are features of Gerstmann syndrome, or with Balint syndrome characterized by ocular apraxia, optic ataxia, and simultagnosia. Most of the patients present with components of these syndromes (simultanagnosia and acalculia) in the initial course of the disease. Patients with PCA often fail to see the picture as a whole and only see specific features.

There is a marked inability to describe a complex picture in its entirety, and this classic finding is referred to as simultanagnosia. These patients have defects in visual attention, thereby causing only 'local capturing and 'partonomic' errors. These cohorts show an inability to read pseudoisochromatic plates, despite intact color vision and have problems interpreting a Navon figure.[17]

Neurological examination is typically unrevealing. Mild gait abnormalities may be a consequence of poor balance due to visual processing difficulties. However, a small percentage of the patients may show myoclonus or other motor signs. Symptoms of parkinsonism may suggest underlying Lewy body disease. Asymmetric motor symptoms of dystonia, dyspraxia, myoclonus, and the alien limb may be secondary to underlying corticobasal degeneration. 

Crutch et al. described it as a clinical-radiological syndrome with the following core features: Clinically presenting as insidious onset with gradual progression and visual disturbances being prominent early in the course (with or without other posterior cognitive functions). The following cognitive features are seen in the decreasing order of frequency: Deficits in space perception, simultanagnosia, deficits in the perception of objects, constructional dyspraxia, environmental agnosia, oculomotor apraxia, dressing apraxia, optic ataxia, alexia, inability to differentiate left and right side, acalculia, limb apraxia, apperceptive prosopagnosia, agraphia, homonymous visual field defects, and finger agnosia. At least three of the above cognitive features must be present as a presenting feature or early in the course of illness with or without evidence of impairment in activities of daily living. 

The criteria emphasize the relative sparing of all of the following: anterograde memory, speech, and nonvisual language functions, executive functions, personality, and behavior. On neuroimaging (MRI/FDG-PET/SPECT), occipitoparietal or occipitotemporal atrophy/hypometabolism/hypoperfusion is predominant. Exclusion criteria include the presence of structural lesions, including brain tumor or vascular lesions, and afferent visual pathology involving optic nerve, optic chiasm, or optic tract. The presence of other causes of cognitive impairment, such as renal failure, also needs to be ruled out.

The PCA should always be considered among patients presenting with:

1. Spatial disorientation
2. Problem with Ishihara charts despite a normal color vision
3. Homonymous visual field defects
4. Omission of letters on the acuity chart[6]

Evaluation

Visual field testing: Typically shows normal acuity and fundi. But can also show hemifield impairments or constrictions and variable field deficits that may not be typical of classical cortical lesions.[18] Homonymous hemianopia or quadrantanopia is seen in almost 50% of the cases.[6]

Neuropsychological testing will demonstrate preservation of orientation, repetition, and recall, with difficulties in calculation, spelling, copying figures, and clock drawing dependent on parietal lobe functioning. Right parietal dysfunction is also evidenced through difficulties in dot counting, line bisection, or clock drawing. Neuropsychological research criteria for PCA require fulfillment of clinical criteria with an impaired performance below the 5th percentile in at least two of the following four parietal tests object perception, space perception, calculation, spelling, AND evidence of performance above the 5th percentile in recognition memory.[19]

Structural neuroimaging: The distribution of amyloid deposition as noted in amyloid PET is typically widespread and is very similar to that of patients with typical Alzheimer's disease.

Functional Neuroimaging: Fludeoxyglucose PET scan is likely to demonstrate hypometabolism in parietooccipital cortices. However, when there is a typical history of PCA, an absence of marked parietooccipital atrophy should not exclude the diagnosis.[16] Cortical blood flow as measured by arterial spin labeling MRI may also present a similar pattern reflecting low blood flow than metabolism.[20]

Genetic testing: Testing for autosomal dominant forms of the disease and APOE testing is typically not indicated. Regarding APOE ε4 testing, the presence of the APOE ε4 allele may be less likely when compared to the typical cases and hence not recommended.[7]

CSF testing: CSF amyloid-β (Aβ) is typically decreased, and both total and phosphorylated tau increase. This is reflective of the underlying AD pathophysiology. However, some studies suggest that the degree of total and phosphorylated tau elevation is not as high as in typical AD. Hence, the tau to Aβ ratios may be lower than typical AD.[21]

Recent advances:[6]

1. Tau-PET is more specific since it is a tauopathy, thereby mirrors the regions of hypometabolism and atrophy compared to PET-amyloid scan.
2. 11C-PBR28-PET, microglia-specific imaging, shows higher binding in the occipital cortex bilaterally.
3. The visual evoked potential (VEP) may be a good adjunct in the diagnosis.

The proposed algorithmic steps suggested during the evaluation of PCA include:[22]

1. Is it neurodegenerative pathology?
2. Is it a posteriorly based cortical entity?
3. Is it pure PCA or PCA plus Alzheimer disease (AD), Lewi body dementia (LBD), corticobasal degeneration (CBD), or prion lesion?
4. Does it have positivity to any pertinent biomarkers such as cerebrospinal fluid (CSF) Ab 1-42, Tau, p-Tau for AD, and 14-3-3 protein for prion disease? 

Treatment / Management

Pharmacological management: Data on anticholinesterase inhibitors in PCA is lacking. However,  since the majority of the cases of PCA are secondary to underlying AD pathology, targeting the underlying pathophysiology using anticholinesterase inhibitors and memantine is an appropriate choice. There are individual case reports that describe the responsiveness of PCA to anticholinesterase inhibitors.[23] (B3)

As the visual impairment progresses with preservation of insight and the emergence of increasing dependence, patients commonly deal with significant feelings of overwhelming anxiety and depression.[24] Patients may benefit from selective serotonin reuptake inhibitors (SSRIs) to cope with anxiety and mood changes. 

Non-pharmacological management: The mainstay of the treatment approach is non-pharmacological, with interventions geared toward providing more coping strategies, psychological support, and care.[17] The goal would be to compensate at least partially for deficits with improved daily functioning, everyday skills, self-care, and quality of life.[25] (B3)

It is of paramount importance that an early diagnosis is made so that safety measures are implemented on time, such as ensuring safety by avoiding driving, removing unsafe furniture, and ensuring safety adaptations to the home settings. Encouraging audiobooks can help compensate for deficits in reading as the disease progresses.

Use of voice recognition, smartphone apps, labeling around doorknobs and hallways, home adaptions in the kitchen, bathroom, and staircase can help compensate for the visuospatial deficits and navigate everyday living. In addition, referring patients and families to support groups for PCA can immensely benefit. 

Differential Diagnosis

Posterior cortical atrophy needs to be differentiated from the typical Alzheimer disease. Patients with posterior cortical atrophy tend to be younger with early and marked involvement of visuospatial tasks, reading, and writing with relative preservation of memory.[15] 

History should also be directed at ruling out other alternative etiologies such as Lewy body disease, corticobasal syndrome, and Creutzfeldt-Jakob disease (CJD). Features that suggest dementia with Lewy bodies include REM sleep behavior disorder, fluctuation of mental status, visual hallucinations, parkinsonism, and neuroleptic sensitivity. Clinical features favoring corticobasal syndrome include asymmetrical parkinsonism, myoclonus, muscle stiffness/dystonia, sensory deficits, motor apraxia, eyelid opening apraxia, and a feeling that a limb does not belong to the patient ("alien" limb phenomenon). Symptoms secondary to involvement of the pyramidal tract, such as spasticity, hyperreflexia, and weakness, are likely to be present in corticobasal degeneration.

Diagnosing Creutzfeldt-Jakob disease (Heidenhain variant) may be more challenging as the presentation can be variable. The disease follows a rapid course leading to death typically within a year. Patients may present with visual impairment secondary to involvement of the visual cortex, features of Balint syndrome (optic ataxia, oculomotor apraxia, and simultagnosia), or Gerstmann syndrome (agraphia, acalculia, finger agnosia, and left-right disorientation). These may also be accompanied by ataxia, myoclonus, and atypical sensory phenomenon. Cortical blindness (Anton syndrome) is not a feature of posterior cortical atrophy and is generally seen in Creutzfeldt-Jakob disease. The most striking feature of CJD in MRI is the presence of a "cortical ribbon sign" in the parieto-occipital region.[26]

Salient Differences from the Common Differential of the Entity

1. PCA has more significant atrophy within the visual association cortex, contrary to the hippocampal atrophy observed in amnestic AD. Patients often have a good insight into their symptoms, contrary to anosognosia observed among patients with AD.[6]

2. Lewi body dementia has visual hallucinations and parkinsonian features. FDG-PET scan shows an extension to involve the orbitofrontal and temporal cortex. Dopamine transporter SPECT shows low uptake within the basal ganglia.

3. Heidenhain variant of Creutzfeldt-Jakob disease characteristically has a fulminant course and presents with Anton's syndrome. The CSF analysis is positive for 14-3-3 protein.

4. Asymmetric parkinsonism,  eyelid opening apraxia, and alien limb syndrome are hallmarks of Corticobasal degeneration.[22]

Prognosis

Patients with posterior cortical atrophy have progressive deterioration of visuospatial and visuoperceptual abilities. The cognitive symptoms invariably and inevitably worsen with patients becoming functionally blind, leading to considerable distress, especially in those who retain insight into the deficits and are aware of the increasing dependency for self-care and day-to-day activities. It can also lead to significant depression and feelings of disempowerment.[24] As the cognitive decline proceeds to later stages, PCA is indistinguishable from advanced typical Alzheimer disease.

Complications

Early recognition of the deficits and making a prompt diagnosis are essential in preventing falls and avoiding driving accidents. Making changes to the home environment and ensuring adequate supervision in challenging situations due to functional impairment from visuospatial deficits will prevent these disastrous complications.