Neurology: Case of the Month

Check Your Diagnosis — Patient 85

Corey Goldsmith, M.D. and Jay Volpi, M.D.

Diagnosis

Posterior Cortical Atrophy

Clinical Summary

This 53 year old gentleman presented with early-onset dementia and showed evidence of profound visual-spatial difficulty as well as trouble performing multi-step tasks. There were no hallucinations, Parkinsonian features, or bladder dysfunction. There was evidence of ocular apraxia and simultagnosia on exam, both of which are components of Balint's syndrome. There were also elements of Gerstman's syndrome with acalculia and right-left disassociation. Reversible dementia workup was negative, as were basic labs and CSF analyses. Brain MRI showed cortical atrophy, especially over occipital and parietal areas which were out of proportion to temporal and frontal areas. Brain SPECT showed decreased metabolism over analogous parieto-occipital regions. Neuropsychological testing revealed severe difficulty with visual-spatial abilities with right-left disassociation, mild-to-moderate memory dysfunction, as well as executive dysfunction.

Differential Diagnosis

  1. Neurodegenerative causes of dementia: Alzheimer's disease is the most common cause of dementia and thus should be considered in the differential. However, Alzheimer's disease would typically have much more severe memory dysfunction at this point in the disease course, in addition to his visual-spatial deficits. The SPECT and MRI abnormalities would also be more localized to the temporal and parietal areas rather than the occipital area. Therefore, the prominence of visual-spatial deficits and parieto-occciptal atrophy in this case evidence toward alternative neurodegenerative conditions, such as the consideration of posterior cortical atrophy.
  2. The Parkinsons-plus syndromes: Lewy-body disease and progressive supranuclear palsy (PSP) were considered in this patient. However, he did not have Parkinsonian symptoms of bradykinesia, tremor, or rigidity. He did not demonstrate any visual hallucinations or fluctuations in his clinical course. While OKN can be abnormal prior to the full manifestations of vertical supranuclear palsy in PSP, this patient had OKN abnormalities in all directions of gaze, making the presentation not consistent with PSP.
  3. Cerebrovascular causes of dementia: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can present with early dementia and migraines in a patient with or without a family history for such symptoms. However, there are usually clear brain MRI findings, mainly in the anterior temporal lobes, which were not evident in this patient. The CADASIL genetic mutation was sent given patient's history of possible migraines and was negative. CNS vasculitis is a rare cause of early-onset dementia secondary to multiple ischemic events. The normal serum ESR and CRP, the absence of CSF inflammatory signs, and the minimal white matter disease on brain MRI all lower the likelihood of CNS vasculitis.
  4. Infectious causes of dementia: Creutzfeldt?Jakob disease (CJD) is always a consideration in young-onset dementia, especially when the clinical progression is relatively rapid. This patient's relatively slow clinical progression (over 5 years), absence of myoclonus, and lack of characteristic EEG findings (ie. GPEDs or BiPLEDs) would all appear to lower the suspicion for CJD in this case. Chronic fungal or TB meningitis can also be considered. These differentials were ruled out with the brain MRI and CSF findings.
  5. Toxic/Metabolic causes of dementia: In this patient, severe hypothyroidism could present like a dementia secondary to severe apathy, but his TSH was normal. The prior history of alcoholism in a patient with extra-occular movement abnormalities raises the consideration for Wernicke-Korsakoff syndrome. However, the typical severe short-term memory deficits coupled with confabulation were not evident in this patient.

Discussion

Introduction

Posterior cortical atrophy (PCA) is a dementia syndrome that may potentially represent a precursor or variant of Alzheimer's disease (AD). It is, however, clinically distinct in that patients with posterior cortical atrophy do not manifest the same degree of memory impairment as in AD and instead demonstrate striking visual-spatial deficits. This disorder is variably described in the literature as progressive posterior cortical dysfunction, posterior cortical dementia, and posterior cortical atrophy. Debate persists over whether it is a distinct dementia syndrome or a variant of AD.

Historical Background

One of the earliest descriptions of PCA came from a case series of five patients who were found to have "progressive dementia heralded by disorders of higher visual function".[1] These patients universally developed alexia, agraphia, and visual agnosia. Interestingly, the patients' memory, insight, and judgment were not significantly affected as these functions were "relatively preserved until late in the [disease] course.[1] At the time of this early report, there were no pathologic specimens, but available radiography did not support a vascular etiology.

In 1989, two more cases of PCA were added to the literature with features similar to those describe in the earlier case series.[2] Shortly thereafter, editorials began to question whether this entity was clinically distinct from AD, or whether it was a variant or precursor to AD.[3] Despite multiple pathologic and clinical reports almost two decades later, this debate continues.[4]

Pathologic and Genetic Findings

In 1994, the pathologic findings of three patients with PCA were reported, including subcortical gliosis in one patient, neurofibrillary tangles and plaques in another, and spongiform degeneration in the third.[5]

Genetic findings in a larger series of 40 patients with PCA were reported in 2004.[6] This study found no difference in apoE ?4 haplotype or tau haplotype frequency among patients with PCA compared to those with AD. On nine postmortem exams, seven had neurofibrillary tangles, but these were limited to the parieto-occipital region, unlike a typical AD specimen. The two remaining cases had corticobasal degeneration and tau positive glial pathologies which were again predominantly located in the posterior parietal lobe.

Another pathologic series of 21 patients presenting with predominantly posterior cortical dysfunction described AD-only pathology in 13 patients, AD plus cortical Lewy body pathology in two patients, AD plus Parkinson's disease pathology in one patient, Lewy bodies plus progressive subcortical gliosis of Neumann in one patient, corticobasal degeneration in two patients, and prion associated diseases in two patients.[7]

There is no known genetic factor that is uniquely associated with PCA. A single report of suspected familial PCA has been described in two Japanese sisters.[8] Both sisters had imaging findings of predominantly occipital atrophy with symptom onset at age 70 and 80.

Clinical Presentation

The patient with PCA has a striking deficit of higher order visual processing with relatively preserved memory. The syndrome typically consists of predominantly visual agnosia and overlaps with the syndromes of Balint (gaze apraxia, optic ataxia, and simultagnosia) and Gerstmann (alexia, agraphia, acalculia, finger agnosia, and right-left confusion). Both syndromes are the result of posterior cortical dysfunction: Balint's syndrome most often results from bilateral lesions to the occipital-parietal-temporal interface (as in a watershed infarct); and, Gerstmann's syndrome usually results from lesion involving the dominant angular and supramarginal gyri at the parietal and temporal interface. In addition to the visual deficits, a transcortical sensory aphasia localizing to dysfunction at the posterior portion of the temporal region has been described.[1]

Not surprisingly, visual hallucination is also a finding in approximately 25% of patients with PCA.[9] In one study, patients with PCA and visual hallucinations more frequently have accompanying Parkinsonism, REM sleep behavior disorder, and myoclonic jerks compared to those without hallucinations.[9]

In a comparison study of 15 patients with PCA (by imaging and history) and 30 patients with AD, a study found that patients with PCA had significantly better verbal fluency, less memory difficulty, more depression, and greater insight into their illness compared to the AD controls.[10] Both groups had similar familial and apolipoprotein E risk factors.

In another comparison study between 15 patients with PCA and 15 patients with AD, symptoms of visual disturbance and dyslexia were observed to be more common in PCA cases while memory disturbances were more common in AD cases. Both groups were impaired in verbal learning, but delayed recall was worse in patients with AD compared to those with PCA. Based on these findings, the authors suggest that "performance on simple tests of visual perception and copying can be used to distinguish the two disorders even a few years after initial symptoms".[11]

Radiographic Appearance

The radiographic appearance of posterior atrophy was recognized early as a hallmark of diagnosis.[1] In fact, subsequent studies have considered this feature as an inclusion criterion.[9,10,11] In a comparison study of PCA and AD, the brain MRI of PCA often showed occipito-parietal atrophy without detectable mesial temporal atrophy.[10] Another study confirmed and expanded these observations upon comparing 38 cases of AD with 38 cases of PCA. In the PCA group, this study found a pattern of atrophy affecting occipital, parietal and posterior temporal lobes greater than the typical pattern in the AD group. Interestingly, the atrophy appeared greater on the right than the left side. In the AD group, the study found greater atrophy in the left hippocampus than in the PCA group.[12] In another study, the subgroup of patients with PCA and visual hallucinations showed greater atrophy in a network of structures, including the primary visual cortex, lentiform nuclei, thalamus, basal forebrain, and midbrain compared to the PCA subgroup without visual hallucinations.[9]

One study investigated the 18F-FDG-PET findings of 6 patients with PCA.[13] This study uncovered hypometabolism in essentially the same areas that had been previously implicated clinically: the lateral and medial parietal associative cortex, the adjacent temporal cortex, and occipital associative cortex. Interestingly, this study also found a minority of the patients with frontal lobe hypometabolism, which were thought to possibly be related to "deafferenting of areas related to the control of eye movements".[13] Similar to the previously mentioned study,[12] these investigators also observed marked right-left brain asymmetry in some patients.

Natural History

There are currently no large, longitudinal series of patients with PCA. Furthermore, the heterogeneity of underlying pathology would imply a similar heterogeneity in overall outcomes. Nonetheless, a subgroup of PCA patients with AD-type pathology demonstrated better long-term outcomes compared to those with typical amnestic AD.[15] This may be due in part to the earlier age of onset that has been described in PCA compared to AD (mean age of 59 in one study).[14]

Treatment

There are no studies regarding therapies directed specifically for patients with PCA. The observation that patients with PCA have more prominent depression than typical AD patients portends an important role for antidepressant medications, in addition to centrally acting acetyl-choline esterase inhibitors.[1] Also, since many patients with PCA have preserved insight into their deficits, visual aids and visual rehabilitation may offer substantial benefit.

References

  1. Benson DF, Davis RJ, Snyder BD. Posterior cortical atrophy. Arch Neurol. 1988;45:789-93.
  2. Delamont RS, Harrison J, Field M, Boyle RS. Posterior cortical atrophy. Clin Exp Neurol. 1989;26:225-7.
  3. Fehrer EP, Mahurin RK, Inbody SB, Pirozzolo FJ. Posterior cortical atrophy: a new clinical entity or Alzheimer's disease? Arch Neurol. 1989;46(8):843-4.
  4. Tang-Wai DF, Mapstone M. What are we seeing? Is posterior cortical atrophy just Alzheimer disease? Neurology. 2006;66(3):300-1
  5. Victoroff J, Ross GW, Benson DF, Verity MA, Vinters HV. Posterior cortical atrophy: neuropathologic correlations. Arch Neurol. 1994;51:269-74.
  6. Tang-Wai DF, Graff-Radford NR, Boeve BF, Dickson DW, Parisi JE, Crook R, Caselli RJ, Knopman DS, Petersen RC. Clinical, genetic, and neuropathologic characteristics of posterior cortical atrophy. Neurology. 2004;63:1168-74.
  7. Renner JA, Burns JM, Hou CE, McKeel DW Jr, Storandt M, Morris JC. Progressive posterior cortical dysfunction: a clinicopathologic series. Neurology. 2004;63(7):1175-80.
  8. Otsuki M, Soma Y, Tanaka M, Tanaka K, Tanno Y, Uesugi Y, Tsuji S. Familial posterior cortical atrophy with visual agnosia and Bálint's syndrome. No To Shinkei. 1995;47(12):1185-90.
  9. Josephs, KA, Whitwell JL, Boeve BF, Knopman DS, Tang-Wai DF, Drubach DA, Jack CR Jr, Petersen RC. Visual hallucinations in posterior cortical atrophy. Arch Neurol. 2006;63(10):1427-32.
  10. Mendez MF, Ghajarania M, Perryman KM. Posterior cortical atrophy: clinical characteristics and differences compared to Alzheimer's disease. Dement Geriatr Cogn Disord. 2002;14(1):33-40.
  11. Charles RF, Hillis AE. Posterior cortical atrophy: clinical presentation and cognitive deficits compared to Alzheimer's disease. Behav Neurol. 2005;16(1):15-23.
  12. Whitewell JL, Jack CR Jr, Kantarci K, Weigand SD, Boeve BF, Knopman DS, Drubach DA, Tang-Wai DF, Petersen RC, Josephs KA. Imaging correlates of posterior cortical atrophy. Neurobiol Aging. 2007;28(7):1051-61.
  13. Schmidtke K, Hüll M, Talazko J. Posterior cortical atrophy: variant of Alzheimer's disease? A case series with PET findings. J Neurol. 2005;252(1):27-35.
  14. McMonagle P, Deering F, Berliner Y, Kertesz A. The cognitive profile of posterior cortical atrophy. Neurology. 2006;66:331-8.
  15. Karner E, Jenner C, Donnemiller E, Delazer M, Benke T. The clinical syndrome of posterior cortical atrophy. Nervenarzt. 2006;77(2):208-14.

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