16ournal ofNeurology, Neurosurgery, and Psychiatry 1994;57:1366-1370 Primary amnesia of insidious onset with subsequent stabilisation F Lucchelli, E De Renzi, D Perani, F Fazio Abstract A patient had a slowly developing amnesic syndrome that remained sub- stantially unchanged during the two and a half years of observation. Intellectual skills were excellent and there was no lan- guage, perception, praxis, or calculation deficit. The memory impairment involved verbal and visual learning, spar- ing spatial learning and, to a large extent, retrograde memory. Magnetic resonance imaging was normal, but PET showed a hypometabolism of the left temporal mesial region and thalamus. This case extends the spectrum of monosympto- matic cognitive disorders, previously reported in the area of language, praxis, and visual recognition, to amnesia. (3 Neurol Neurosurg Psychiatry 1994;57: 1366-1370) Neurology Department, Ospedale S Carlo Borromeo, Milan, Italy F Lucchelli Neurology Department, University ofModena, Italy E De Renzi INB CNR, University ofMilan, Scientific Institute H San Raffaele, Milan, Italy D Perani F Fazio Correspondence to: Dr E De Renzi, Clinica Neurologica, Via del Pozzo 71, 41 100 Modena, Italy. Received 15 October 1993 and in revised form 16 February 1994. Accepted for publication 25 March 1994 In 1982 a report by Mesulaml rekindled inter- est on a syndrome characterised by slowly progressive aphasia in the absence of other cognitive deficits. This syndrome had, until then, been largely neglected by neurologists. Its clinical status has now been confirmed by several case reports, although the question remains as to whether slowly progressive aphasia is an autonomous entity, consequent to a degenerative process confined to the left hemisphere speech region, or the early mani- festation of a more generalised disease, even- tually resulting in global mental deterioration. Clinical and pathological findings seem to indicate that the aetiology and evolution. of slowly progressive aphasia is heterogeneous, with a few cases showing aphasia as the only symptom for long periods and possibly for the rest of their lives and others evolving towards more common forms of degenerative demen- tias, such as Alzheimer's and Pick's disease.2 With the upsurge of interest in slowly pro- gressive aphasia, neurologists have begun to turn their attention to the possibility that there may be other progressive cognitive dis- ord'ers confined to a single ability. Cases of isolated apraxia3 4 or agnosia35 have been reported, although they are fewer than those of aphasia and lack pathological documenta- tion. In this paper we report a patient with an amnesia not accompanied by other cognitive disorders, that progressed over a few years, reached a plateau, and then remained unchanged during the two and half years of follow up. A PET study of cerebral metabo- lism showed a selective memory related structures. impairment of Case report The patient is a 69 year old right handed woman with a degree in pharmacology who was referred to our outpatient clinic in November 1990 for memory complaints. A grandfather, an aunt, and two first cousins, all belonging to her father's side of the family, were reported to have had cognitive disorders late in life; unfortunately these could not be better specified. One of her father's brothers was affected with Down's syndrome. The patient married at the age of 27, had four chil- dren (one of them is schizophrenic), and worked as a junior high school teacher of mathematics and science until 1984, when she retired. Her medical history is unremark- able, apart from hypertension that has been treated successfully for 10 years. She was uncertain when her memory disorder had started, but tended to date it back to the last years of teaching, when she had had increas- ing difficulty in preparing her lessons. They were not initially perceived by her husband, who became aware of them from 1987, when he noticed that she tended to repeat the same questions at short intervals, often missed appointments, and had to rely on shopping lists. She never lost her way in familiar sur- roundings. Although her relatives were uncer- tain about the rate of progression. of the disease, they were adamant in stating that it had developed slowly and that its onset could not be dated with precision. We saw the patient for three sessions between November 1990 and March 1991 and again in follow up examinations carried out in October 1992 and August 1993. Throughout this period the neurological examination remained unremarkable. She was a gentle, well groomed, and cooperative per- son, aware of her memory problems and con- cerned about her future. She was oriented to time and space, paid close attention to ques- tions, and quickly understood them. She spoke fluently and properly without any sign of anomia. The memory deficit was easily brought out in conversation. She was unable to report what she had eaten at lunch, did not remember from one session to the next the tasks she had been given, sometimes asked the examiner to repeat the instructions during the execution of a task, as she had forgotten what to do, and had a vague and patchy recollection of famous 1366 o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y co p yrig h t. h ttp ://jn n p .b m j.co m / J N e u ro l N e u ro su rg P sych ia try: first p u b lish e d a s 1 0 .1 1 3 6 /jn n p .5 7 .1 1 .1 3 6 6 o n 1 N o ve m b e r 1 9 9 4 . D o w n lo a d e d fro m http://jnnp.bmj.com/ Primary amnesia of insidious onset with subsequent stabilisation Table 1 Language, cakulation, visual perception, and praxis tests Token test 32/36 Boston naming test 69/85 Verbal fluency (P, F, L) 47 Calculation 25/27 Unknown face identification 23/27 Figure ground discrimination 33/33 Limb praxis 70/72 Oral praxis 24/24 Constructional praxis 20/20 public events that had occurred in the past months. FIRST NEUROPSYCHOLOGICAL EXAMINATION (NOVEMBER 1990-MARCH 1991) The patient had an IQ of 132 on the WAIS (revised) with a VIQ of 133 and a PIQ of 127. She scored 44/48 on Raven PM38, found all of the six criteria of classification on the Wisconsin test with 98 cards and produced 47 names in three minutes on verbal fluency on phonetic cues (P, F, L). ILanguage, calculation, visual perception, and oral and limb praxis were assessed with appropriate tests, on all of which she scored well in the normal range (table 1). The only area in which she performed poorly was learn- ing. Table 2 reports the scores, corrected for age and educational level, achieved on learn- ing tests, for most of which a cut off point dis- criminating a normal from a pathological performance is available, based on the score distribution of 100 normal controls.6 Partial regression coefficients of the scores on age and education provided the correction for these variables. The verbal tests were story recall (immediate and after a 10 minute filled delay), paired associate learning (five easy and five difficult associations) over three trials, and 10 word learning (carried out to the crite- rion of two successful consecutive recalls, the score being the sum of words recalled over trials divided by the number of trials to criterion). Table 2 Learning tests 1991 1992 1993 Cut offpoint Digit span 7 6 7 Story recall 1-15 5 4 40 15-76 Paired associates 4-38 3-5 4-45 8-73 Learning 10 words 7 93 5-55 6-86 6-58 Recurring face recognition 29 56 30-66 24-60 33-37 Rey figure 6-84 - 0 12-39 Cube span 7 6 6 - Cube supraspan (trial to criterion) 4 10 - Maze learning 11 - - Table 3 Retrograde memory tests 1991 1992 1993 Cut offpoint Questionnaire 40 53 - 35-17 41-53 Famous names - 57/60 - - Familiar faces 1-22 - 1-32 2-05 Famous faces 1-00 - 2-15 2-99 The scores of both face tests refer to standardised error scores, corrected for age and education.. Thus the lower the score, the better the performance. The two visual memory tests were Rey's figure reproduction from memory after a 10 minute filled delay, and a test of recurring unknown face recognition, in which eight tar- get faces had to be identified from among 12 foil faces in three successive presentations. Its score is the sum of hits minus the sum of false positives. The patient's scores, corrected for age and education, fell below the cut off point on two out of three verbal memory tests6 and on both visual memory tests.7 In contrast, her performance on two spatial learning tests- supraspan learning on Corsi's block tapping test and maze learning on a stepping stone visual maze test-was within the normal range (controls' means 13 trials to criterion in both cases). Retrograde memory was investigated with four tests (table 3). The first two were verbal and comprised a famous event questionnaire and a famous name recognition test. The questionnaire, given in a recognition format, consisted of eight questions for the biennium 1965 to 1985, with four choices for questions (the target and three foils).8 For name recog- nition 30 famous names (Christopher Columbus, Wolfgang Mozart, etc) intermin- gled with 30 unknown names were presented one at a time. The two visual tests were a face familiarity test and a famous face recognition test.9 The first required the patient to select the one face that was familiar from an array of four photographs, the second to point to the face of a famous person named by the exam- iner, when it was presented with three distrac- tors belonging to the same sex and semantic area (for example, four Italian presidents). Cut off points, corrected for age and educa- tion, have been determined for all of these tests,89 except that dealing with famous and unknown names. Table 3 shows that she scored below the normal range on the questionnaire, but not on the other tests. Autobiographical memory was investigated with a structured interview, covering events of her past life from youth to recent years. Information provided by her husband and daughter was used in the preparation. Episodes occurring before the onset of disease were recollected fairly accurately and the for- gotten details were recovered when a cue was provided. Recall was much patchier and less accurate for the events of the past two or three years (for instance, she had forgotten the holi- days spent in Greece during the previous summer). FOLLOW UP EXAMINATIONS (OCTOBER 1992 AND AUGUST 1993) The patient was re-examined in October 1992 and August 1993. Both she and her husband were of the opinion that the memory deficit was unchanged and that there was no impair- ment in other cognitive areas. This was con- firmed by formnal testing. Raven PM38 (44/48 and 40/48) and language scores were still high and no definite evidence of further deteriora- tion was found in her performance on mem- ory tests (tables 2 and 3). 1 367 o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y co p yrig h t. h ttp ://jn n p .b m j.co m / J N e u ro l N e u ro su rg P sych ia try: first p u b lish e d a s 1 0 .1 1 3 6 /jn n p .5 7 .1 1 .1 3 6 6 o n 1 N o ve m b e r 1 9 9 4 . D o w n lo a d e d fro m http://jnnp.bmj.com/ Lucchelli, De Renzi, Perani, Fazio Figure 1 MRI section showing the integrity of the F hippocampus. A CT, ..... ... M.' N P or evidence of brain damage. Fi 1h*..- - ......._ ...... ............... ^.^.^ ........... . : X3S°§ ! - - ..................... E... NeiheC nor MRI shwe ventricuaro orEviec of brai daae Fiur sow an MRI coronal section to demonstrate the integrity of the hippocampal region. An ['8F]FDG PET study was performed in the resting state with open eyes and unplugged ears, using a Siemens/CPS, 931-04/12 positron emission tomograph. Image analysis was performed with software Table 4 Mean (SD) ofLCMRG1c (mgl1OOglmzn) Left hemisphere Right hemisphere Regions Patients Controls Patients Controls Cingulus 5 06 6 76 (0 58) 4 98 5 84 (0 82) Frontal: Basal 6 03 6 25 (0 75) 6 48 6 16 (0 66) Lateral 6 73 6 81 (0 76) 6 63 6-73 (0 62) Rolandic 7 15 6 62 (0 64) 7 19 6-59 (0-52) Parietal 6 69 6 52 (0-56) 6 74 6-57 (0 56) Temporal: Polar 5-06 4 70 (0 48) 5 25 4 42 (0 45) Superior 6-28 6 17 (0 52) 6 59 6 16 (0 52) Middle/inferior 6 11 5 94 (0 62) 6 37 5 83 (0 58) Mesial (hippocampus) 3.71* 4 54 (0-39) 4 67 4-58 (0 41) Occipital: Lateral 7-11 6 41 (0-89) 7 10 6 43 (0 68) Calcarine 8 35 7 61 (1-04) 8 30 7 74 (0 98) Caudate 6 67 6-76 (0 81) 6-85 6 63 (0-73) Putamen 8 11 7-27 (0 78) 7 82 7 21 (0 60) Thalamus (whole) 5.02* 6 66 (0 65) 5 69 6 67 (0-71) Anterior sector 4-59* 6 12 (0-64) 5 16 6 54 (0 74) Middle sector 4.86* 6 75 (0-81) 6 15 6 89 (0-82) Posterior sector 5-62 7-01 (0-79) 5 77 6 91 (0 80) Cerebellum 6-42 5 78 (0-71) 6 66 5 71 (0 59) *LCMRGlc values below the cut off score. Figure 2 PJET showing left thalamic and temporal mesial region hypometabolism (arrows). Top: axial sections; bottom: coronal sections. (Analyze BRU/Mayo Clinic) on a SUN (SPARC) workstation (see Fazio et all' for details). Numerical data were obtained from a circular region of interest with a diameter cor- responding to 1-5 FWHM (9-6 mm) manu- ally drawn on all cortical areas, the main subcortical nuclei, and deep structures; aver- age values of local cerebral metabolic values of glucose (LCMRGlc) were then calculated from multiple circular regions of interest included within the major anatomical subdivi- sions identified on the Talairach and Tournoux atlas (table 4) .l The averaged LCMRGlc values for the same regions of interest in eight normal subjects (mean age 55-43 (SD 9-45 years)) were used as control values. Values for LCMRGlc in the patient were considered pathological when outside 2 SD from corresponding values obtained in normal controls. Significant hypometabolism (LCMRG1 c values below the cut off score of the mean (2 SD)) was present in the thalamus and tempo- ral mesial region on the left side (table 4, fig 2). The thalamus was also divided into three parts to differentiate anterior, middle, and posterior regions. The metabolic reduction was by 24% and 18% respectively for the whole left thalamus and the temporal mesial region, compared with the controlateral side. Only the LCMRGlc values in the anterior and middle sectors of the left thalamus were below the cut off scores. The right thalamus showed metabolic values within the normal range, but slightly reduced. Values for LCMRGlc in the frontal, temporal, parietal, and occipital cortex of both cerebral hemi- spheres were within the normal range. Discussion The history and clinical profile of this patient is characterised by the slow development of an amnesia of moderate intensity, which con- trasts with the preservation of excellent intel- lectual abilities and of normal skills in other cognitive domains (language, perception, praxis, etc). This pattern of deficits is well known in patients with global amnesia and the features of the memory impairment also tally with those classically reported in that condi- tion-namely, dissociation between intact short term memory and impaired long term memory, prevalence of anterograde over ret- rograde amnesia, preservation of spatial mem- ory in the face of poor recollection of verbal and visual stimuli. What makes the history of the patient remarkable is the early slow pro- gression of the disease and then its stabilisa- tion spanning the period of observation. That in the early years of disease amnesia had developed gradually was the firm belief both of the patient and her relatives. They only dis- agreed on its onset, that the patient tended to date back to an earlier time than her husband and children. Among the possible causes of amnesia, tumour, encephalitis, alcohol mis- use-namely, trauma, infarct, and haemor- rhage were ruled out by the patient's history and the negative neurological, CT and MRI 1 368 o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y co p yrig h t. h ttp ://jn n p .b m j.co m / J N e u ro l N e u ro su rg P sych ia try: first p u b lish e d a s 1 0 .1 1 3 6 /jn n p .5 7 .1 1 .1 3 6 6 o n 1 N o ve m b e r 1 9 9 4 . D o w n lo a d e d fro m http://jnnp.bmj.com/ P1imary amnesia of insidious onset with subsequent stabilisation findings. The slow development of amnesia and the absence of other neurological deficits is suggestive of a degenerative process involving cortical associative areas, although a diagnosis of Alzheimer's or Pick's disease seems unlikely. Amnesia is one of the earliest mani- festations of degenerative dementias, but, by the time that the patient comes to the neurolo- gist's attention and is submitted to thorough neuropsychological examination, more wide- spread deterioration of cognitive functions has usually started. To the best of our knowledge, a case of amnesia that remains "pure" seven years after its onset, without signs of more widespread cognitive decline, has not been reported in follow up studies of Alzheimer's disease. In recent years, there have been case reports of patients showing a progressive breakdown of a single cognitive ability (lan- guage, praxis, visual recognition) with preser- vation of other mental functions.12 The most often reported form is slowly progressive aphasia' and for some of the cases13 14 there is evidence not only of clinical, but also of pathological autonomy with respect to classic degenerative dementias. We submit that the present case represents an instance of a degenerative process circumscribed to the cortical areas subserving memory function. Although no alteration in structural anatomy was shown by CT and MRI, the metabolic pattern disclosed by PET is consis- tent with the assumption of an autonomous disease. It differs from that reported in associ- ation with Alzheimer's disease.15 Impaired metabolism of temporoparietal cortices in patients with early, possible Alzheimer's dis- ease is a frequent finding and is held to pre- cede the onset of non-memory dysfunction.'6 These regions were comparatively spared in our patient. Conversely, thalamic metabolism, which is within normal limits in early Alzheimer's disease,'7 was severely affected. The reduction of glucose metabolism was selectively confined to the left thalamus and the left mesial temporal cortex (hippocam- pus), which are known to be specifically related to episodic memory function.'8 As for the thalamus, the anterior and middle parts were particularly involved, even if a selective functional depression in some thalamic nuclei, such as the anterior and dorsomedial nuclei, is beyond the spatial resolution of PET. Thalamic structures involved in mem- ory function include not only the mammil- lothalamic tracts and anterior nucleus, which are components of the Papez circuit, but also the dorsomedial nucleus and the internal medullary lamina, as suggested by the finding of amnesia after focal thalamic damage.'9 The temporal mesial hypometabolism is possibly another functional correlate of the severe impairment of episodic memory in this patient. The confinement of damage to the left side may account for the dissociation between impaired verbal memory and pre- served spatial memory. It must be admitted, however, that the con- cept of degenerative disease, whether diffuse in the associative cortex or confined to some of its sectors, meets with difficulty in account- ing for the other feature marking the temporal profile of this patient's disease-namely, the stabilisation of amnesia a few years after its insidious onset. Although the period of obser- vation (three years) may be too short to pre- dict the future course of the disease, this lack of deterioration is at variance with the patterns of relentless development usually found in degenerative processes. Confronted with a similar clinical picture presented by three patients, Kritchevsky and Squire20 opted for an ischaemic aetiology. Amnesia had developed in one week in one patient and in one to two years in two others, and then it remained unchanged for six to seven years. Magnetic resonance imaging showed a profound, bilateral reduction of the hippocampal formation in all of them. It was hypothesised (but not documented) that episodes of hypotension had occurred in the patient who had the shortest onset, and resulted in a reduced blood flow of the hip- pocampal formation. The same pathophysio- logical mechanism was tentatively extended to the two patients with the longer development of amnesia, despite the absence of any inde- pendent evidence that they had cardiovascular problems. The idea that cerebral blood insuffi- ciency may be responsible for a slowly pro- gressive cognitive decline, not punctuated by a stepwise course, was entertained in the past, but does not find any support in the current body of knowledge on the pathophysiology of cerebrovascular diseases. Nor is it easy to understand why such a mechanism, after hav- ing caused a progressive amnesia in the early years of disease, would no longer exert a dele- terious effect on memory function in the sub- sequent six or seven years. We believe, therefore, that, despite the plateau reached by all these patients in the course of their disease, a circumscribed degenerative process remains a more likely interpretation of their amnesia than an ischaemic aetiology. Only neuropathological findings will pro- vide an unequivocal answer to the aetiology of these cases. For the time being, we must be satisfied with the contention that slowly pro- gressive amnesia must be added to the gamut of already known monosymptomatic forms of progressive cognitive decline (aphasia, apraxia, agnosia). Its temporal profile is, how- ever, peculiar and requires a close follow up. This study was supported by grants from CNR and MURST 40% to EDR. 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