The World Journal of Biological Psychiatry ISSN: 1562-2975 (Print) 1814-1412 (Online) Journal homepage: http://www.tandfonline.com/loi/iwbp20 Report of Three Cases of Alzheimer's Disease with Focal Motor Symptoms: Clinical Correlates of IMeuroimaging Findings Katsuji Kobayashi, Kazuki Shimoda, Masato Higashima, Hiroyuki Nakano, Kenji Mlyazu, Masahlro Hayashi, Osamu Labata & Yoshifumi Koshino To cite this article: Katsuji Kobayashi, Kazuki Shimoda, Masato Higashima, Hiroyuki Nakano, Kenji Mlyazu, Masahlro Hayashi, Osamu Labata & Yoshifumi Koshino (2000) Report of Three Cases of Alzheimer's Disease with Focal Motor Symptoms: Clinical Correlates of IMeuroimaging Findings, The World Journal of Biological Psychiatry, 1:3, 164-169, DOI: 10.3109/15622970009150586 To link to this article: http://dx.doi.org/10.3109/15622970009150586 Published online: 12 Jul 2009. Submit your article to this journal Article views: 5 View related articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iwbp20 Download by: [University of Sydney Library] Date: 15 March 2016, At: 08:15 World I Biol Psychiatry (2000)1, 164 - 169 CASE REPORTKASE SERIES b Report of Three Cases of Alzheimer's Disease with Focal Motor Symptoms: Clinical Correlates of Neuroimaging Findings Katsugi Kobayashi', Kazuki Shimoda', Masato Higashima', Hiroyukl Nakanol, Kenjl Mlyazu', Masahlro Hayashlz, Osamu Tabatat Yoshlfuml Koshino' Downloaded by [University of Sydney Library] at 08:15 15 March 2016 Department of Neuropsychiatry, Kanazawa University School of Medicine, Kanazawa, Ishikawa-ken, Japan Department of Neuropsychiatry, National Sanatorium Hokuriku Hospital, Johana-machi, Toyama-ken, Japan Okanoue Hospital, Kaga, Ishikawa-ken, Japan Introduction Summary We report clinical and neuroimaging findings for Alzheimer's disease (AD) starts with cognitive three patients suffering from Alzheimer's disease disturbance in the absence of any apparent (AD) with focal motor symptoms. These patients neurological deficits. The symptoms and signs initially showed cognitive deficits and subsequently then progress, including disorientation as to featured myoclonus and awkward movements in the time and place, profound memory disturbance, unilateral upper limb while progressing to paresis. lexical anomia, visuospatial disturbance and Paresis was noted in the unilateral upper limb. All constructional apraxia. Pathological substrates patients held the unilateral arm flexed at the wrist for AD are neurofibrillary tangles (NFT) and and elbow, closely adducted to the body and the senile plaques in the cerebral cortex. In neurohand fisted and pronated. No signs of cerebellar pathological terms, Braak and Braak (1991) ataxia, sensory disturbance or long tract signs were established a sequence of AD-related changes in observed, nor any of the initial non-cognitive which NFT start in the entorhinal cortex, then behavioural changes typical of frontotemporal spread to the cornu ammonis and subiculum, dementia. EEGs of these patients showed marked and finally to the cerebral association cortex. slowing of basic activity without epileptic discharges. NIT develop extensively with the progression of MRIs showed progressive brain atrophy in the the illness, so that brain atrophy can be observed contralateral frontoparietal lobes as well as the on MRI or CT in parallel with this pathological hippocampal formation. Cases 2 and 3 featured progression (De Leon et a1 1989, 1993; Lehkricy extensive long T2 lesions on MRI. 99"'Tc-HMPAO- et a1 1995). The symptomatology, pathological SPECT revealed blood flow hypoperfitsion in the findings and clinical course of AD are otherwise corresponding regions. The cerebellum and brain heterogeneous (Schuttleworth 1989; Chui et a1 stem showed neither morphological abnormalities 1985; Mayeux et a1 1985; Klatka et a1 1996). nor blood flow hypoperfusion. On the basis of these Many case studies have described focal sympclinical and neuroimaging observations, the focal toms in individuals with relatively mild cognimotor symptoms were attributed to contralateral tive impairment, which have been designated as frontoparietal cortical atrophy with or without white focal variants of AD (Mayeux et a1 1985). matter lesion. These focal variants of AD include posterior cortical atrophy (Benson et a1 1988; AharonKey words: Alzheimer's disease, myoclonus, Peretz et a1 1999), progressive aphasia (Pogacar et hemiparesis, neuroimaging, SPECT. a1 1984), progressive apraxia (Crystal et a1 1982; Kaida et a1 1998) and progressive hemiparesis Correspondence (Jagust et a1 1990). Jagust et a1 (1990) first Katsuji Kobayashi, M.D. reported a demented patient who initially feaDepartment of Neuropsychiatry tured myoclonus and clumsiness that progressed Kanazawa University School of Medicine to paresis of the left upper limb. Autopsy 13-1, Takara-machi revealed focal accentuation of NFT in the right Kanazawa perirolandic somatosensory cortex and hippoIshikawa-ken campal Alzheimer changes. This case was given 920-8641, Japan the name "focal AD". Subsequently Golaz et a1 Tel: +81 76 265 2000 (1992) reported an autopsied case with focal Fax: +81 76 234 4254 accentuation of NFT in the primary motor cortex. These two cases exhibited unusual localisation of Alzheimer-related changes in the cerebral cortex. It thus appears that AD patients 1 64 Downloaded by [University of Sydney Library] at 08:15 15 March 2016 with focal motor symptoms are extremely rare, Case reports and neuroimaging of focal AD has not been fully Case 1 explored. A 63-year-old, right-handed man noticed forIn the study presented here, we report on the getfulness at age 57. There was no family history clinical features and neuroimaging studies of of psychiatric or neurological illness. His three AD patients who showed initial myoclonus cognitive decline developed insidiously until he and limb apraxia and subsequent paresis of the could no longer pass on any information, and he retired from his work at age 59. Neurological unilateral upper limb. examination disclosed memory disturbance and Patients and methods MRI showed predominant right hemispheric We could examine three AD patients who were cerebral atrophy. Memory disturbance prosubjected to neurological, psychiatric and gressed gradually, and at age 60 he became aware neuropsychological examination. Cognitive of clumsiness of his left upper extremity, which disturbance was evaluated with Mini-mental led to inability to control it, so that he frestatus examination (MMSE). Diagnosis of AD quently bumped his left hand against surwas confirmed by the presence of clinical rounding objects. In conjunction with the features relevant to NINCDS-ADRDA criteria gradual worsening of his motor signs, he (McKhann et a1 1984). Regional cerebral blood sometimes could not recognise his family flow was examined with 99mTc-HMPAO-SPECT members. He was admitted to our clinic at age study, and brain morphology was studied with 63. He was almost totally disorientated and delayed recall was particularly impaired. He MRI and CT. Figure 1 MRI of Case 1 shows atrophy of the cornu ammonis and parahippocampalgyrus with right-sided predominance (1A) and marked atrophy of the parietal lobe (1B). 99mTc-HMPAO-SPECT findings of the horizontal (1C) and coronal (1D) planes show marked blood flow hypoperfusion in the frontal and parietal lobes with right-sided predominance. 165 Downloaded by [University of Sydney Library] at 08:15 15 March 2016 scored 10 on the MMSE and 4 on Hachinski's test. He appeared slightly euphoric and was unaware of his intellectual decline. His left upper extremity manifested arrhythmic myoclonic movements that were provoked easily by stimulation involving hand and elbow joints. He had severe limb apraxia predominantly in his left hand, which appeared slightly paretic. He could not imitate simple finger positions presented by examiners. He showed signs of transcortical sensory aphasia and had difficulty in naming objects. Ocular movements were not impaired but saccades were not smooth. No eyelid apraxia or palatal myoclonus was observed. Deep tendon reflexes were brisk on the left side and his left upper and lower extremities were rigid. Primitive reflexes could be elicited on both sides, but pyramidal tract signs were absent. Sensory disturbance of the limbs was absent, and ataxia was not observed. Cerebral MRI revealed widening of the sylvian fissure, atrophy of the prefrontal and parietal lobe and parahippocampal gyrus (Figure 1A-1B) with right-sided predominance. The ""Tc-HMPAO-SPECT study revealed a marked blood flow reduction in the right frontoparietal lobe (Figure 1C-ID). The apolipoprotein E (APOE) genotype was e3/e3. Case 2 A 70-year-old, left-handed woman had begun to experience mnemonic failure at age 56. She had run a kindergarten until she was 57 years old, at which time she could no longer deal with her business because of her memory disturbance. She consulted a neurologist at age 58. Cerebral CT showed brain atrophy and she was diagnosed as AD. Subsequently she began to complain of inability to control her right hand at age 65, and she was hospitalised at age 67. At admission, arrhythmic myoclonic movements that were easily provoked by any stimuli were observed in her right upper limb. Her mental symptoms progressed with signs of severe aggression, and she frequently uttered strange sounds both during the day and at night. At age 68 she was holding her right arm flexed at the wrist and elbow, closely adducted to her body with the hand fisted and pronated. Muscle atrophy was absent, but right upper limb was spastic, and deep tendon reflexes were brisker on the right side. Babinski's sign could not be elicited. The 99mTc-HMPAO-SPECT study revealed marked blood flow reduction in the left frontoparietal lobe (Figures 2A and 2B), although the cerebellar blood flow remained normal. MRI showed Figure 2 99mTc-HMPAO-SPECTof the coronal (2A)and horizontal (2B) planes showing marked reduction in blood flow in the frontal and parietal lobes with left-sided predominance. MRI of coronal (2C) and horizontal (2D) sections show dilatation of the lateral ventricle with leftsided predominance, severe atrophy of the bilateral hippocampus and extensive T2 hyperintensity covering the cerebral white matter. The left parietal lobe features marked dilatation of the lateral ventricle, which is surrounded by a hyperintensitylesion. 166 complete disorientation. She began to show aggressive tendencies at age 70 and was hospitalised at age 71. At admission she scored 10 on MMSE and was neurologically normal. She showed dysfunction in naming objects and could repeat sentences. But she gradually lost the ability to control her left hand until she could not even hold a spoon. Deft movements of her left hand were impaired and she could not imitate several finger positions. She sometimes became psychotic, showing abnormal emotional Case 3 A 73-year-old woman began to show mnemonic changes and delusions. Her left hand became failure at age 67 and consulted a psychiatrist. She gradually paretic with showing flexor posture at had been in good health and working actively the wrist and elbow joints (Figure 3A). The managing a store together with her husband. interosseous muscles of her hand were slightly Her intellectual ability declined slowly leading to atrophic but the nerve conduction velocity was normal. Cerebral CT showed atrophy of the hippocampal formation with right-sided predominance (Figure 3B) and T2-weighted MRI disclosed hyperintensity areas covering the white matter of the frontoparietal lobe. Downloaded by [University of Sydney Library] at 08:15 15 March 2016 progressive cerebral atrophy, especially in the left frontal and parietal lobes and bilateral hippocampal formation. On T2-weighted images, high intensity areas were seen to cover all of the cerebral white matter particularly of the left frontoparietal lobes (Figures 2C and 2D). The APOE genotype was e4le4. She was treated with oral risperidone administration that was effective to her behavioural changes. Figure 3 The left upper limb indicated by arrow, showing flexor posture at the wrist and elbow joints (3A). Horizontal section of the CT (38) showing hippocampal atrophy marked on the right side accompanied by periventricular low density. Discussion We described three rare cases of AD with initial cognitive impairment followed by focal motor signs, including myoclonus, apraxia and paresis of the unilateral upper extremity. The diagnosis of these patients meets the criteria for "probable AD" as set forth in NINCDSIADRDA (McKhann et a1 1984) and DSM-IV (American Psychiatric Association 1994) because progressive cognitive and neuropsychological deficits are compatible with AD. Klatka et a1 (1996) reported signs and symptoms incompatible with a diagnosis of early AD. They include tremors at rest, cogwheel muscle rigidity, long tract signs at the initial stage, ocular movement disturbance, cerebellar signs and initial non-cognitive behavioural change. Our cases lacked these clinical features, and MRI or CT revealed the progressive atrophy of the hippocampal formation related to AD (De Leon et a1 1989, 1993; Fox et a1 1996; Golebiowski et a1 1999). Cerebral white matter lesions were noted in periventricular and deep white matter in Case 2 and 3, but they were not white matter lacunae. These white matter changes raise a possibility of cerebral infarcts combined with AD. Extensive white matter lesions have been frequently reported in AD patients with severe symptomatology (O'Brien et a1 1996). These white matter lesions histologically consist of a cluster of perivascular small infarcts and/or secondary degeneration from cortical Alzheimer changes (Englund et a1 1988; Englund 1998). Particularly, localised edema due to cerebrospinal fluid infiltration into the white matter is causative of periventricular white matter changes (Tomimoto et a1 1997). Therefore, white matter lesions in our cases may be partly of vascular origin. Massive cerebral infarcts cannot account for the insidiously and gradually developed motor deficits and clinical features in our cases did not fit well with diagnostic criteria of vascular dementia (Roman et a1 1993). The SPECT study showed hypoperfusion 167 CASE REPORT/CASE SERIES b Downloaded by [University of Sydney Library] at 08:15 15 March 2016 of these atrophied lesions, which is contradictory to evidence that vascular dementia tends to show frontal lobe hypoperfusion (Ransmayr 1998). The EEGs showed generalised slowing of background activities without focal slowing. Predominant focal motor signs characterise corticobasal degeneration (CBD), and dementia has been recently recognised in CBD, but it usually occurs late in the clinical course and the pathological substrate for the dementia remains unclear. In fact, even macroscopic hippocampal atrophy could not be identified in a demented CBD patient (Kobayashi et a1 1999). For these reasons, our cases do not fit a diagnosis of CBD. A combination of dementia and myoclonus raises the possibility of Creutzfeldt-Jakob disease (CJD), but our cases show long-term degeneration and an absence of periodic synchronous discharge. These features are not compatible with CJD. Occurrence of myoclonus prior to limb paresis and monoplegic manifestation was a characteristic finding in our cases. Monoplegia without muscle atrophy is due to cerebral cortical lesion (Adams and Victor 1993), while monoplegia caused by a localised cortical lesion, particularly of the upper motor neuron, is usually accompanied by spasticity, hyperreflexia and an extensor plantar reflex. The position of the unilateral upper limb observed in our patients may be helpful for the diagnosis because myoclonus has been generally regarded as a late clinical feature in AD and several studies describe myoclonic AD as a distinct subtype (Chen et a1 1991; Chui et a1 1985; Rise et a1 1990; Clark et a1 1991). The neuropathological correlates of myoclonus have not been precisely determined, however aminergic neuronal cell loss in the dorsal raphe nucleus (Ebinger et a1 1987; Kaye et a1 1988), high density of NFT (Feldman et a1 1963; Duffy et a1 1988) and imbalance of neuronal population in the dentate nucleus (Fukutani et a1 1999) have all been speculatively identified as loci of myoclonus. 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