Journal ofNeurology, Neurosurgery, and 1991;54:443-448 4L43

Posterior cortical with alexia: J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.5.443 on 1 May 1991. Downloaded from neurobehavioural, MRI, and PET findings

L Freedman, D H Selchen, S E Black, R Kaplan, E S Garnett, C Nahmias

Abstract The syndrome of posterior cortical demen- A progressive disorder of relatively focal tia (PCD) described by Benson et al'4 and De but asymmetric biposterior dysfunction Renzi' is clinically dominated by disturbances is described in a 54 year old right handed in visual function including object , male. Initial clinical features included , alexia, and visuospatial dis- letter-by-letter alexia, visual anomia, orientation. The development of transcortical acalculia, mild , constructional sensory and a complete Gerstmann's apraxia, and visuospatial compromise. and Balint's syndrome was also present in Serial testing demonstrated relentless several patients. Computed tomography34 and deterioration with additional develop- MRI4 in PCD revealed prominent posterior ment of transcortical sensory aphasia, atrophy characterised by enlargement of the Gerstmann's tetrad, and severe occipital horns. However, the topography of visuoperceptual impairment. Amnesia cerebral metabolic dysfunction using positron was not an early clinical feature. Judg- emission tomography (PET) has yet to be ment, personality, insight, and aware- described for PCD. ness remained preserved throughout We examined a patient with serial neurobe- most of the clinical course. Extinction in havioural testing complimented by MRI and the right visual field to bilateral stimula- PET who exhibited PCD. The dementia was tion was the sole neurological abnor- notable for the presence of a severe letter-by- mality. Early CT was normal and late letter alexia and profound bioccipital (left > MRI showed asymmetrical bioc- right) hypometabolism verified by PET. cipitoparietal atrophy with greater involvement of the left hemisphere. Case report Results from positron emission A 54 year old, right handed man with two tomography (PET) showed bilaterally doctoral degrees was referred for neurological The Mississauga asymmetric (left > right) occipitotem- in 1986 after Hospital, Mississauga, examination February complain- Ontario poroparietal hypometabolism. The ing to his family physician of progressive Department of metabolic decrement was strikingly difficulty in , mathematical ability, and Psychology asymmetric with a 50% reduction in memory function over the previous three L Freedman

glucose consumption confined to the left years. These problems were at first mild, but http://jnnp.bmj.com/ Divisions of Neurosurgery and occipital cortex. The- picture of became disturbing- given his aptitude in occipitotemporoparietal compromise mechanical engineering and economics. He D H Selchen verified by MRI, PET, and neurobe- was aware of the impairments and was able to Department of havioural testing would be unusual for manage a private business despite his reduced Neurology, such degenerative as Alz- cognitive capabilities. Sunnybrook Medical Centre, University of heimer's (AD) and Pick's disease, alth- A neurological examination performed in Toronto, Toronto, ough atypical AD with predominant February 1986 revealed an alert and oriented Ontario involvement cannot be man with intact cranial nerves. There were no on October 2, 2021 by guest. Protected copyright. S E Black excluded. This case supports the con- orbital, cranial, or carotid bruits and visual Department of cepts of posterior cortical dementia full to Psychology, Chedoke- fields were confrontation. Sensoximotor McMaster Hospitals (PCD) as a clinicaily distinct entity and function, gait, and coordination were intact and Department of for the first time documents its corre- and primitive reflexes were absent. Examina- Psychiatry, McMaster sponding metabolic deficit using PET. tion of the skull, chest, and heart was University, Hamilton, Ontario negative. Haematological studies revealed a R Kaplan Focal and diffuse cortical syndromes distinct normal CBC, electrolytes, enzymes, thyroid, Department of from Alzheimer's and Pick's disease are B12, folate levels, VDRL, ESR, and ANF Nuclear Medicine, becoming increasingly recognised." Included counts. Analysis of the CSF- was normal. An Chedoke-McMaster are of in the tem- Hospitals, Hamilton, among these the syndromes progressive EEG showed non-specific slowing Ontario, Canada aphasia without dementia,' 2 5 progressive poral lobes, bilaterally, and CT revealed no E S Garnett apraxia,' dementia,67 argyrophilic focal lesions or significant atrophy. Medical C Nahmias grain disease,8 and a posterior dementia.'4 history was negative for cerebrovascular and Correspondence to: Dr While some scepticism still remains that some cardiovascular disease, subarachnoid Freedman, Department of Psychology, The Mississauga of these syndromes represent atypical variants haemorrhage, intracranial infection, cerebral Hospital, 100 Queensway of Alzheimer's (AD) or Pick's disease,9 11 tumour, hypertension, diabetes, and psy- West, Mississauga, Ontario, Canada L5B 1B8 evidence derived from metabolic,12 regional chiatric illness. Family history was negative Received 23 April 1990 and blood flow," and neuropathological'6-5 inves- for dementia. in revised form 1 October have their status as Serial neurobehavioural examinations were 1990. tigations clearly supported Accepted 15 October 1990 distinct neurological entities. conducted over a three year period beginning 444 Freedman, Selchen, Black, Kaplan, Garnett, Nahmias

Table I Language and reading data: serialfindings plete Gerstmann's syndrome (acalculia, agra- phia, finger agnosia, right-left disorientation) J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.5.443 on 1 May 1991. Downloaded from February December April October and ocular , which is one component Measure 86 86 88 88 of Balint's syndrome. Despite evolving WRAT reading 39th% 37th% - - visuoperceptual compromise, he was able to PIAT reading recognition - 3rd% < lst% PIAT reading comprehension - 1st% < lst% - recognise inanimate objects but had difficulty Boston Naming Test (60-items) - 33 22 19 identifying animals. He was, however able to Tactile Naming Test* - - - 5/16 Token Test (36-items) - 22 9 - point to photographs of inanimate and Word discrimination (BDAE) - 60/72 52/72 - animate objects named aloud by the examiner Written naming (BDAE) 8/10 6/10 4/10 - Word-picture matching (BDAE) - 8/10 0/10 - without error using a multiple-choice format. Writing-to-Dictation 15/19 13/19 3/10 - The matching of black and white photographs Word repetition (BDAE) - 90% - 100% High-phrase repetition (BDAE) - 100% - 40% of unfamiliar faces29 was relatively intact Low-phrase repetition (BDAE) - 75% - 25% (80%) and he was able to recognise 14/19 (73%) photographs of famous faces using a WRAT = Wide range achievement test. PIAT = Peabody individual achievement test. BDAE = Boston diagnostic aphasia examination. WRAT and PIAT scores in percentiles. multiple choice format. He never failed to *Naming of 16 common objects using the right hand. recognise the examiner (LF) over the serial examinations. He was totally unable to locate any continents, oceans, or countries on a large in February 1986. Initial testing of language world map and did not exhibit any environ- function (table 1) showed a mild anomia and mental agnosia' until late in the course. He agraphia. He also exhibited a severe alexic did not exhibit any colour agnosia, disturbance. Latency and accuracy in oral achromatopsia, or ideomotor apraxia. Person- reading of single words'4 as a function of ality, insight, judgment, comportment, and word-length revealed a positive linear awareness remained intact throughout most of relationship consistent with a letter-by-letter the clinical course until the development of or pure alexia (fig la-b). Further analysis of paranoid ideation three years after the initial his oral reading ability revealed a reading rate neurological evaluation. of approximately one second per letter which Repeat neurological testing performed five, is in keeping with the word-length effect 27, and 39 months after the initial examina- of previously described letter-by-letter tion revealed normal cranial nerves, sen- readers who had focal left occipitotemporal sorimotor function, reflexes, and gait. lesions.'""8 Visual paralexias were common17 However, visual confrontation testing and he committed right-sided derivational revealed persistent right visual field extinc- reading errors'9 as well. Both oral reading and tion. MRI scanning performed in September comprehension20 of letters and words even- 1988 showed bilateral occipitoparietal atrophy tually became impossible. The early anomia progressed into a severe transcortical sensory 90- aphasia with considerably compromised nam- 0 ing2' and auditory comprehension.22 Single 80- 0 word repetition remained intact. Tactile nam- 70- ing was also severely defective although he o 60- was able to correctly pantomime the function 0 50- http://jnnp.bmj.com/ of objects he failed to name. Ca 40- 0 Results of the general neurobehavioural . assessment (table 2) revealed moderate com- ae30 36 20 r=0 promise in overall IQ23 characterised by a p< 0Q05 large discrepancy between average verbal and 10 his severely impaired visuospatial abilities. He 0 4- and 5 6 7 8 9 10 11 12 exhibited a profound constructive apraxia 10- acalculia and subsequent examination on October 2, 2021 by guest. Protected copyright. revealed significant interval declines in both 9. 0 the verbal and spatial domains. Further IQ 8- testing was precluded because of his severe and visuoperceptual compromise, but - 7- aphasia Q-6 . low-level cognitive screening24 conducted two M 6- after the initial examination showed X 5- years 0) 0 r- severe impairments in attention, calculation, 'O 4. m was CL) and constructional skills. Memory ability ac 3. moderately impaired initially for both verbal 2- r=0*36 and nonverbal material25 and later became 0 p< 0.01 untestable due to severe aphasia. Despite his 1 - impaired psychometric memory, he was not 0 - amnestic in his everyday functioning until 3 4 5 l (te very late in the clinical course. Visuospatial Word length (letters) reasoning,26 hemispatial search,27 and copying Figure I Oral reading performance at second ability28 (Fig 2a-c) were also severely com- examination, December 1986. A) Reading accuracy as a promised. In addition, evidence of right function of word length on the reading subtest of the Wide Range Achievement Test. B) Scattergram showing was seen on visuocon- relationship between reading latency of 35 words (7 sets structive copy of relatively simple stimuli.25 x 5 words) as afunction ofword length. Regression The patient eventually developed a com- equationfor latency data is Y = 1.3 + 0 79 X. Posterior cortical dementia with alexia: neurobehavioural, MRI, and PETfindings 445

Table 2 Neurobehavioural data: serialfindings regions, bilaterally (fig 4c-d). The degree of hypometabolism was significantly greater in J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.5.443 on 1 May 1991. Downloaded from February December Age-normal the left hemisphere in all PET images showing Measure 86 86 values bilaterally reduced glucose consumption. WAIS-R FSIQ 83 73 100 (±15) Hypometabolism was also noted in the left WAIS-R VIQ 94 85 100 (±15) WAIS-R PIQ 68 59 100 (±15) (fig 4a) and there was a 10% general- WMS MQ 79 75 100 (±15) ised reduction in metabolism involving the RAVLT (Total 1-5) 16/75 10/75 52/75 (±2) RAVLT Recognition 90% 66% 96% (±1) entire left hemisphere. Raven's Matrices 18/36 11/36 31/36 (±4) Visual Search Right* 17 14 4-6 (± 1) Visual Search Left 5 14 5 3 9 (± 1) WRAT arithmetic 19th% 10th% - Discussion The emergent clinical picture presented by our *Score reflects median hemispatial search time in seconds. WAIS-R = Wechsler adult intelligence scale-revised. patient best exemplified a PCD. The pattern of RAVLT = Rey auditory-verbal learning test (5 trials). neurobehavioural impairments including let- WMS MQ = Wechsler menory scale memory quotient. Standard deviation in parentheses. ter-by-letter alexia, acalculia, agraphia, spatial- perceptual compromise, constructive apraxia, transcortical sensory aphasia, Gerstmann's which was more prominent in the left hemis- syndrome, ocular dysmetria, and right visual phere (fig 3a-c). The sulcal enlargement field extinction unequivocally conformed to a extended into the left temporal region and topography of posterior hemispheric in- there was asymmetric dilatation of the volvement. This pattern was substantiated by occipital horns which was greater on the left. the MRI findings of bilateral occipitoparietal atrophy and by the PET results of bilateral PET methods andfindings occipitotemporoparietal hypometabolism using The patient had glucose metabolic scanning of 18-FDG. the in May 1988. Cerebral glucose utilisa- The clinical, radiological, and neurobe- tion was measured using the McMaster havioural findings in our patient bear a striking positron emission tomograph which has a spatial resolution of 8 mm (full width at half maximum) in the plane and 12 mm in the axial direction. Additional technical details and per- formance characteristics of the tomograph are described elsewhere.31 For this study, the patient was administered 2-0 mCi of [18F]-2-Fluoro-2-deoxyglucose (18 FDG) intravenously while lying on a comforta- ble stretcher. He was instructed to keep his eyes closed and background ambient noise was kept to a minimum. The patient's head was held in a perspex restraining device so that it could be positioned reproducibly within the tomograph. in the left to axis was assured Aligment right http://jnnp.bmj.com/ by inspection of a preliminary scan taken at the level ofthe thalamus. Scanning was started one hour after administration of the [18F] FDG. Twenty three sequential scans were taken at three minute intervals in a plane parallel to the orbitomeatal line. Each PET slice was 15 mm thick and overlapped its predecessor by 10 mm.

By adopting this procedure, the slice with the on October 2, 2021 by guest. Protected copyright. greatest volume ofgrey matter ofinterest could be identified and selected. The twenty three scans were interpreted by one of the authors (ESG) by comparing the pattern of global and regional distribution of glucose utilisation to a 0D data base of normal control values.

Results The patient's PET scan demonstrated bilateral asymmetric occipitotemporoparietal hypo- metabolism (fig 4a-d). Based on right/left com- parisons of homologous brain regions, there was a 50% reduction in glucose metabolism in the left occipital lobe (fig 4a-b). A lesser, yet still marked degree of hypometabolism was revealed bilaterally in the medial occipital and Figure 2A-C Copy of the Rey-Osterrieth Complex temporal regions, including the hippocampus Figure. A) February 1986. B) December 1986. C) April (fig 4a). Glucose consumption was also reduced 1988. Note the progressive impairment in spatial and in the temporoparietal and parieto-occipital visuoconstructive ability over time. 446 Freedman, Sekhen, Black, Kaplan, Garnett, Na#mias J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.5.443 on 1 May 1991. Downloaded from

Figure 3A-C T-2 weighted MRI images in the axialplane (1 5 Tesla, TR 2000ms, TE 80ms, 5mm slice thickness, display matrix 256 x 256). The MRI images reveal marked bilateral occipitoparietal atrophy. The atrophy is asymmetrically more prominent in the left occipital region (right side of image) and extends into the ipsilateral posterior temporal area. resemblance to three previously reported absent in some cases.332 The differences in studies describing PCD.34 32 The patients des- clinical presentation and expression of cog- cribed in these reports presented with early nitive deficits in our patient compared with deficits in complex visual processing including others with PCD could be attributed to alexia, agnosia, spatial-perceptual com- behavioural heterogeneity and variability in the promise, Balint's syndrome, and environmen- rate of disease progression. CT in two cases3 tal agnosia. Acalculia was also a common find- and MRI in two others4' showed bilateral and ing although Gerstmann's tetrad, transcortical symmetric occipitoparietal atrophy. Regional sensory aphasia, and Balint's syndrome were cerebral metabolic function, however, was not examined in any of these studies. A salient finding of our case was the PET results of bilaterally asymmetric occipitotem- poroparietal hypometabolism. To our knowledge, this is the first report describing the topography of metabolic impairment in PCD. The left hemisphere showed a greater degree of decreased metabolism than the right. This was most marked in the inferior and lateral occipital regions, the inferior, middle, and superior gyri ofthe posterior temporal lobes, and the inferior parietal regions encompassing the angular and http://jnnp.bmj.com/ supramarginal gyri. The presence of letter-by- letter alexia, Gerstmann's syndrome, transcor- tical sensory aphasia, and right visual field extinction correlate well with the anatomic distribution of left posterior hypometabolism while the profound visuoperceptual and spatial

impairment is likely to reflect the bilateral on October 2, 2021 by guest. Protected copyright. posterior deficits seen on PET. The most striking deficit in our patient was his alexia. The alexic disturbance was charac- terised by a letter-by-letter decoding strategy'8 and to our knowledge, this type of reading disorder has not been described in patients with progressive dementias. Cogan32 described three patients, one with demonstrated AD pathology (distribution unknown), who presented with progressive perceptual distur- bances, including alexia without agraphia, although the qualitative features of the reading disorder were not described. Our patient showed a significant word-length effect""'8 and Figure 4A-D Positron emission tomographic sections at the level of the hippocampal made visual paralexic6' 7 and right-sided gyri A), the thalamus B), the upper border of the caudate nuclei C), and the corpus derivational errors'9 on measures of oral read- callosum D). In each section, the patient's nose is towards the top of the picture and the left hemisphere is on the reader's right. Areas depicted in white represent regions of ing. His alexia therefore resembled the type of highest glucose consumption; those in black represent areas of lowest glucose consumption. reading disorder usually seen in patients having The PET images reveal bilaterally asymmetric occipitotemporoparietal hypometabolism focal damage to the left occipitotemporal (left > right) with prominent reduction in glucose consumption confined to the left occipital lobe. region33 and the hypometabolism in this Posterior cortical dementia with alexia: neurobehavioural, MRI, and PETfindings 447

astrocytosis two of the left anatomic area can be presumed to underlie the involving layer J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.5.443 on 1 May 1991. Downloaded from alexia. inferior frontal gyrus. No pathological changes Alexia can be an early manifestation ofPCD4 resembling AD, Pick's disease, or Creutzfeldt- although the nature of the reading disorder has Jakob disease (CJD) were observed. In another not been well delineated. The alexic distur- recent report, Mandell et al" described a bance in PCD serves to distinguish it from patient with necropsy findings of Creutzfeldt- other progressive cortical syndromes. Oral Jakob disease who initially presented with an reading ability is usually spared until the later isolated progressive aphasia who suffered gen- stages in AD."'3 Oral reading ability in Pick's eralised cognitive decline one year after onset of disease and progressive aphasia without the language disturbance. The time course in dementia has received little attention, and any our patient (seven years) and other cases of reading disturbance would most likely be PCD would not support classic CJD as an secondary to the prominence ofaphasia in these underlying aetiology although several cases of disorders.'34 Goulding et al' recently reported atypical, long-duration CJD have been the absence of any oral reading disturbance in a documented47. Thus the possibility exists that case of progressive aphasia without dementia PCD may represent a posterior variant of a accompanied by right-sided extrapyramidal focal spongiform disorder or an atypical symptoms. The description of oral reading presentation of CJD. performance in patients with frontal lobe In conclusion, our findings and previous dementia and grain argyrophilic disease has yet reports,34 support the concept of PCD as a to be reported, although a letter-by-letter clinically distinct neurological entity. PCD is alexia would not likely be present given the clinically, radiologically, metabolically, and absence of significant occipital lobe pathology neurobehaviourally distinct from other in these disorders.68 varieties of progressive cortical syndromes. The pattern of metabolic dysfunction in Whether PCD represents a posterior variant of PCD differs significantly from that described a focal spongiform disorder or an atypical in other progressive cortical syndromes. PET expression of AD, Pick's disease, CJD, or an as findings in AD have consistently demonstrated yet unrecognised entity ultimately awaits path- bilateral temporoparietal/frontal hypo- ological verification. metabolism,37" which is occasionally asym- metric depending on whether language or We thank Dr Attila Gyorody for initially referring the patient. visuospatial disturbances predominate along Portions ofthis paper were presented at the 17th annual meeting with global memory dysfunction.37"l The of the International Neuropsychological Society, Vancouver, metabolic picture in Pick's disease, which is British Columbia, Canada, February 1989. characterised by frontotemporal atrophy, is less studied, but a recent report revealed a 1 Mesulam M-M. Slowly progressive aphasia without gen- marked frontal lobe hypometabolic defect.43 In eralised dementia. Ann Neurol 1982;11:592-8. 2 Heath PD, Kennedy P, Kapur N. 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