Dementia and Delirium in 4 Patients with Machado-Joseph Disease

OBSERVATION Dementia and Delirium in 4 Patients With Machado-Joseph Disease

Atsushi Ishikawa, MD, PhD; Mitsunori Yamada, MD, PhD; Kunihiko Makino, MD; Izumi Aida, MD; Jiro Idezuka, MD, PhD; Takeshi Ikeuchi, MD, PhD; Yoshiaki Soma, MD, PhD; Hitoshi Takahashi, MD, PhD; Shoji Tsuji, MD, PhD

Background: Machado-Joseph disease (MJD; spino- compared with the mean repeat length found in pa- cerebellar ataxia type 3) is a hereditary neurodegenera- tients with MJD. On electroencephalographical exami- tive disease caused by mutation of the MJD1 gene. nation, they showed slow background activity, but com- Patients with MJD usually present with cerebellar puted tomography and magnetic resonance imaging scans ataxia, external ophthalmoplegia, pyramidal and extra- showed no cerebrocortical atrophy. Neuropathological pyramidal signs, and muscle wasting. However, it has findings in 2 patients revealed a normal cortical struc- been reported that these patients do not demonstrate ture on conventional morphological examination, but at dementia. immunohistochemical examination, we found abnormal staining by an antipolyglutamine antibody in the ce- Case Description: We noticed symptoms of dementia rebrocortical neuronal nuclei. and delirium in 4 patients with MJD. The symptoms included abnormal behavior, excitation, an uncoopera- Conclusions: Symptoms of dementia and delirium in pa- tive attitude, crying, disorientation, slow thought pro- tients with MJD could occur in the late stages, and they cesses, hallucinations, and delusions. These symptoms might be caused not by loss of cerebrocortical neurons, were observed in patients with a relatively young onset but by their dysfunction. age, and after a long clinical course. In these patients, the CAG repeat length in the MJD1 gene was much longer Arch Neurol. 2002;59:1804-1808

ACHADO-JOSEPH dis- electroencephalography(EEG)findings,and ease (MJD; spinocer- neuropathological findings. ebellar ataxia type 3) is In the affected regions of the MJD the most common form brain, we found intranuclear inclusions,12 of hereditary spinocer- similar to those in other polyglutamine ebellar degeneration in Japan,1 Germany,2 diseases,13-15 that were due to elongated M 3 and the United States. The abnormal ex- CAG repeats in the abnormal gene. Even pansion of CAG repeats in the MJD1 gene in the cerebral cortex, which was reported on chromosome 14q32.1 has been iden- as spared by conventional microscopic tified as the causative mutation.4 The car- examination, immunohistochemical ex- dinal symptoms of MJD are cerebellar amination using antipolyglutamine anti- ataxia, external ophthalmoplegia, pyra- bodies of the MJD brain showed intra- midal signs, dystonia, rigidity, bradykine- nuclear stainings.16 sia, fasciculation, and muscle wasting.5-9 We discuss the relevance of these men- The neuropathological findings of MJD tal symptoms in patients with MJD, and the From the Department of consisted of degenerations in the substan- mechanism causing these symptoms based Neurology, Nishi-Ojiya tia nigra, dentate nucleus, pontine nu- on immunohistochemical examination of National Hospital clei, cranial nerve nuclei, spinal anterior the MJD brain. (Drs Ishikawa, Makino, Aida, horns, Clarke columns, globus pallidus, and Idezuka), the Department and subthalamic nucleus.6,10,11 With re- REPORT OF CASES of Pathology, Brain Research gard to mental activity in patients with CASE 1 Institute, Niigata University MJD, it can be said to be preserved.8,9 (Drs Yamada and Takahashi), We recently examined 4 patients with In 1976, a 26-year-old woman reported ex- the Department of Neurology, MJD revealing similar characteristic symp- periencing ataxic gait and a speech distur- Brain Research Institute, tomsofdementiaanddelirium,and2ofthese bance subsequently developed. In 1988, she Niigata University (Drs Ikeuchi, Soma, and Tsuji), patients had a neuropathological examina- was admitted to Niigata University Hospi- and the Department of tion. Here we describe details of the demen- tal,Kashiwazaki,Japan.Hermentalstatewas Neurology, Niigata National tiaanddeliriumobservedinthepatientswith normal (Wechsler Adult Intelligence Scale Hospital (Dr Ishikawa), MJD,braincomputedtomography(CT)and [WAIS] score: verbal IQ, 93; performance Kashiwazaki, Japan. magneticresonanceimaging(MRI)findings, IQ, 74; and total IQ, 84). Ocular movement

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 was limited to upward motion, with horizontal gaze nys- He sometimes became excited and cried loudly. Admin- tagmus. Muscle power was normal, but muscle atrophy and istration of 50 mg of chlorpromazine had a mild effect. In fasciculation were noted in her face and tongue. Limb and March 1998, he died of a respiratory infection. truncal ataxia were obvious. She could not walk without Neuropathological examination revealed neuronal assistance. Dystonia was observed in her face and right big degeneration in the globus pallidus that was more se- toe. Her tendon reflexes were exaggerated, and Babinski sign vere in the medial segment, subthalamic nucleus, sub- examination was positive. A brain MRI showed atrophy of stantia nigra, pontine nucleus, reticular formation, lo- the pons and cerebellum. cus ceruleus, and dentate nucleus—all of which are In March 1991, she was admitted to our hospital. comparable with the neuropathological findings in those Her mental state was still normal. Ocular movement was with MJD.10 On immunohistochemical examination us- limited to lateral, in addition to upward directions. She ing a monoclonal antibody (1C2), which recognizes spe- was experiencing dysphagia and bradykinesia. cifically expanded polyglutamine stretches, labeling in During November 1991, the patient cried at night- the neuronal nuclei appeared as small inclusions with oc- time and had nightmares. In April 1993, she was noted on casional staining of the nucleoplasm in a diffuse or finely occasion to reject useful advice from the nurses. In July 1994, granular pattern. Some neuronal nuclei showed only dif- she was noted to speak loudly and become excited in the fuse staining without obvious inclusion formation. hallway at nighttime. At that time, her score on the revised Nuclear labeling was observed in the thalamus and in ce- version of the Hasegawa dementia scale (HDS-R; mental rebrocortical layers V and VI (Figure, A), as well as in examination method commonly used in Japan with a scale the affected central nervous system regions mentioned up to 30) was 29 of 30. In February 1995, she was again above. In the frontal lobe, nuclear pathological abnor- observed speaking loudly, and rejecting advice from the malities appeared in approximately 0.6% of neurons, pre- nurses at nighttime, but the next day, she did not remem- dominantly involving pyramidal cells. The CAG repeats ber anything. From June to August, her psychotic state was of the patient’s MJD1 gene were expanded to 77 and 19. labile. She would sometimes become excited, then cry or CASE 3 speak loudly and aggressively. She also repeatedly experienced delusional episodes. Doses of 100 mg of chlorproma- A 46-year-old woman reported difficulty in standing up at zine had a mild effect on these symptoms. By 1999, her men- age 16 years in 1970, and her gait subsequently became un- tal state had deteriorated, and she could not be examined stable. In May 1993, she was admitted to our hospital. Her using the WAIS. Her HDS-R score was 12 of 30. Back- mental state was normal (HDS-R score, 28/30). She had a ground activity on EEG was 7 Hz. In 2000, her mental ac- limitation of ocular movement in all directions; horizon- tivity decreased, and it was difficult to evaluate her using tal gaze nystagmus; dysphagia; dysarthria; muscle atro- the HDS-R scale. In the daytime, she was sleepy, exhibit- phy and limb weakness; dystonia in the forehead, fingers, ing a slowing of the thought processes, and she sometimes and big toes; ataxia in the limbs and trunk; hyperreflexia; cried. She died in October 2001 of sepsis following pyelo- Babinski sign; and urinary disturbance. A brain MRI showed nephritis. A year before her death, a brain MRI showed no atrophy of the pons and cerebellum. In 1994, her verbal cerebrocortical atrophy. IQ on WAIS was mildly decreased to 67. Her elder sister, younger brother, mother, grandfa- In August 1996, she frequently requested unneces- ther, and great-grandfather had the same disease. Molecu- sary support from the nurses. In October, she sometimes lar analysis of her MJD1 gene revealed that she had an ex- became excited and cried out loudly. In August 1998, she panded allele (79 and 14 repeat units; normal, 14-38). frequently cried, and showed slowing of the thought pro- cess. Chlorpromazine (as much as 375 mg) had a mild effect. CASE 2 She died in February 2000 of a respiratory infection. A 46-year-old man, the younger brother of the patient in Neuropathological findings showed typical neuronal case 1, reported experiencing gait and speech distur- degenerationcompatiblewiththatseeninpatientswithMJD. bance at age 27 years in 1979. In 1987, he was admitted Neuronalintranuclearinclusionsinthecerebralcortex,thala- to Niigata University Hospital. His mental activity was nor- mus, and microscopically affected central nervous system mal (WAIS score: verbal IQ, 97; performance IQ, 72; and regions, were stained with antipolyglutamine antibody. Al- total IQ, 86). He visited our institution with eyelid retrac- though the distribution pattern of polyglutamine accumu- tion, upward gaze palsy, horizontal gaze nystagmus, dys- lation in the neuronal nuclei was similar to that of the pa- arthria, facial weakness, limb atrophy, dystonia in both big tient in case 2, the accumulation appeared (in addition to toes, limb and truncal ataxia, ataxic gait, hyperreflexia, and aggregate form) as a diffuse pattern in the neuronal nuclei Babinski sign. A brain MRI revealed pontine atrophy and (Figure, B), and extended to more neurons (about 4.2% of enlargement of the fourth ventricle. neurons in the frontal lobe), including small neurons in the In August 1990, he was admitted to our hospital. cerebrocortical layers V and VI. He was again experiencing dysphagia, bradykinesia, fas- Her mother, grandmother, 2 uncles, 2 aunts, and 1 ciculation in his face, hypotonia in the upper limbs, spas- cousin had the same disease. The CAG repeats of her MJD1 ticity in the lower limbs, and pollakisuria. gene were expanded to 75 and 14. In October 1996, he reported having persecution de- CASE 4 lusions. In May 1997, he took off his undershirt and played with his stool. He sometimes experienced visual halluci- A 51-year-old man complained of gait disturbance at age nations and exhibited abnormal behavior (eg, stripping 36 years in 1983. Thereafter, he noticed speech distur- himself of his clothes, getting into another patient’s bed). bance, and later, urinary disturbance. In April 1992, he was

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10 µm

Immunohistochemistry for expanded polyglutamine stretches in the cerebral cortices of patients with Machado-Joseph disease. Immunopositive intranuclear inclusion (A) and diffuse staining of nucleoplasm (B) are present in neurons of the cerebral cortical layer V of patients 2 and 3, respectively.

admitted to our hospital. His mental state was normal (HDS been published. In a review of MJD in 1993, Sequeiros and score; 32.5/32.5). He had upward gaze limitation, hori- Coutinho11 noted 2 patients with memory disturbance, and zontal gaze nystagmus, dysphagia, and dysarthria. Fascicu- many patients with sleep disturbance, which was some- lation was found in his face. His muscle tone was hypo- times associated with nocturnal crying, agitation, and night- tonic. Limb and truncal ataxia was found, and walking was mares. In 1993, Fukutani et al17 reported 3 patients expe- possible only with assistance. Deep tendon reflexes were riencing delirium. They noted nocturnal delirium and a exaggerated, and examination for Babinski sign was posi- slowing of background activity on EEG. They speculated tive bilaterally. that brainstem lesions (eg, reticular formation, raphe nu- In August 1996, he was readmitted to our hospital. clei, and locus ceruleus) induced a delirious state from the His mental activity was still normal (HDS-R score; 29/30). neuropathological findings of 2 patients. In 1997, Ma- Ocular movement was limited in all directions. He de- ruyama et al18 reported cases of 10 patients with demen- veloped bradykinesia, dystonia in his face and in both tia among 108 patients with MJD. In 1998, Loxkkegaard et big toes, and urinary disturbance. He was unable to walk. al19 reported 3 patients with dementia among 23 patients A brain MRI revealed atrophic findings in the brainstem with MJD. One had disturbance of memorizing, storing, and cerebellum. and evoking verbal materials. As for examination of cog- In November 1996, he began to feel disoriented in nitive function, Maruff et al20 reported specific cognitive his room at night, and on another occasion at night, he deficit in visual attentional function in the MJD patients. left the hospital. The next day, he did not remember what They insisted that this symptom occurred without the pres- had happened. The following month, he insisted that he ence of dementia. had to visit a family member in another hospital at night- The molecular diagnosis of MJD was confirmed for time. In January 1997, he set off a foam extinguisher in a all of our patients by analyzing CAG repeats of the MJD1 ward, also at nighttime. In February, he insisted “I must gene. The common features of our 4 patients were rela- go on an airplane” and “I must go to work on the presi- tively young onset age (16-36 years), long latency to the dent’s instructions” at night. He also repeatedly turned lights occurrence of dementia and delirium (13-25 years), and on and off and stripped himself of his clothes at night. Af- much longer CAG repeat lengths (74-79) (Table 1). They ter being discharged from our hospital, he died in a nurs- all had normal mental activity in the early stages. Their ing home in November 1998 of a respiratory infection. dementia and delirium began after age 40 years. Initial His younger brother, father, and 1 uncle had the same abnormal episodes in daily living included crying in 2 disease. The CAG repeats of his MJD1 gene were ex- patients, and delusion and disorientation in 1 patient. In panded to 74 and 25. all patients, abnormal episodes often occurred during as short a time as a few hours or half of a day, especially at COMMENT night. After these symptoms disappeared, their mental and consciousness levels returned to normal, suggest- In reports describing the clinical symptoms of MJD, the ing a delirious state. In a short time, disturbance of men- mental state has been considered normal, and dementia tal activity developed, including slowness of thought, and has not been mentioned.8,9 Recently, a few reports sug- mental test scores began to decrease. Interestingly, the gesting the presence of dementia in patients with MJD have symptoms of dementia and delirium in our 4 patients were

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Patient No.

Characteristics 123 4 Age, y/sex 51/F 46/M 46/F 51/M Age at onset, y 26 27 16 36 Duration to occurrence of dementia and delirium, y 14 16 25 13 Age at occurrence of dementia and delirium, y 40 43 41 49 HDS-R score (year administered) First administration 29/30 (1994) . . . 28/30 (1994) 29/30 (1996) Second administration 12/30 (1999) . . . 19/30 (1999) . . . Brain CT/MRI Atrophy of pons and cerebellum + + + + Atrophy of cortex − − − − Background activity in EEG, Hz (year reported) Initial EEG 9-10 (1991) 11 (1996) 10 (1993) 12 (1992) Second EEG 7 (1998) 8 (1998) 8 (1999) 10 (1995) CAG repeat length in MJD1† 79/14 77/19 75/14 74/25 Neuropathologic examination − + + − Antipolyglutamine antibody in cerebral cortical neuronal nuclei . . . + + . . .

*HDS-R indicates Hasegawa Dementia Scale—Revised; CT, computed tomography; MRI, magnetic resonance imaging; EEG, electroencephalography; pluses and minuses, the presence or absence, respectively, of a given characteristic; and ellipses, not applicable. †Abnormal repeat length, 56-84.

very similar (eg, abnormal behavior, excitation, uncooperative attitude, crying, disorientation, slow thought Table 2. Details of Delirium and Dementia in 4 Patients* processes, hallucinations, and delusions) (Table 2). For the treatment of delirium in these MJD patients, low doses Patient No. of chlorpromazine proved mildly effective. Characteristic/Behavior 1234 Hitherto, neuroradiological examinations such as CT Abnormal behaviors and MRI scans did not elucidate cerebrocortical atro- Undressing oneself ++−+ 10,21 phy in patients with MJD. None of our 4 patients Leaving hospital +−−+ showed cerebrocortical atrophy on CT or MRI scans even Playing with stool −+−− after the appearance of dementia and delirium symp- Excitation ++++ toms. On the other hand, Kitamura et al22 noted frontal Uncooperative attitude +−+− cortical atrophy, and Murata et al23 showed frontal and Crying +−+− Disorientation −+−+ temporal cortical atrophy in the patients with MJD. Slowness of thought +−+− 24 Using single-photon emission CT, Etchebehere et al Hallucination −+−− showed low perfusion in the frontal lobe, in the lateral Delusion ++−+ portion of the temporal lobe, and in the parietal lobe. Re- cently, by means of a positron emission tomography study, *Pluses and minuses indicate the presence or absence, respectively, Soong et al25 revealed hypometabolism in the occipital of a given characteristic or behavior. cortex, and Taniwaki et al26 showed diffuse hypometabolism of the cerebral cortices in patients with MJD. Slow of the cerebral cortex, thalamus, the nucleus basalis of background activity on EEG was reported in patients with Meynert, and autonomic ganglia that had been reported MJD having dementia and delirium,17 and it was also ob- as usually spared by conventional microscopic exami- served in all 4 of our patients (Table 1). These reports nation. Conventional microscopic examination did not suggest dysfunction of the cerebral cortices and the pos- reveal cortical neuronal loss or gliosis in these patients. sibility of cerebrocortical atrophy in patients with ad- Abnormal staining by antipolyglutamine antibody showed vanced MJD. intranuclear inclusions, and sometimes intranuclear fine On the other hand, neuropathological examination granular or diffuse staining. Neuronal intranuclear in- did not suggest atrophy or neuronal loss in the cerebral clusions stained by antipolyglutamine antibody were cortex,10,11 even in patients with dementia.17,19 In2ofour shown in pyramidal neurons in the frontal, temporal, pa- patients, the cortical structures also showed normal find- rietal, and occipital cortices of cortical layers III, V, and ings by macroscopic and microscopic examination. VI. There were no significant differences in the distribu- Recently, similar to other polyglutamine diseases tion pattern and frequency of the staining between these caused by elongated CAG repeats in abnormal genes,13-15 cortices. Patients with longer CAG repeats tended to have neuronal intranuclear inclusions in the affected regions higher numbers of labeled neurons. of the MJD patients were reported.12 By immunohisto- In this study, patients with longer CAG repeats in the chemical examination using an antipolyglutamine anti- MJD1 gene manifested a tendency toward dementia and body in patients with MJD (including our patient 2), Ya- delirium, and immunohistochemical studies of patient mada et al16 identified abnormal staining in many neurons brains with longer CAG repeats showed many more neu-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 ronal nuclei stained by antipolyglutamine antibody.16 Schill- Corresponding author: Atsushi Ishikawa, MD, Depart- ingetal27 showed that transgenic mice of a dentatorubural- ment of Neurology, Niigata National Hospital, Akasaka pallidoluysian atrophy model having neuronal intranuclear 3-52, Kashiwazaki 945-8585, Japan (e-mail: isikawaa inclusions and stainings similar to those of the patients @niigata.hosp.go.jp). with MJD without neuronal degeneration developed the neurological phenotype of dentatorubural-pallidol- REFERENCES uysian atrophy, suggesting dysfunction of the cortical neu- 1. Takano H, Cancel G, Ikeuchi T, et al. Close associations between prevalences of rons in mice with dentatorubural-pallidoluysian atro- dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and fre- phy. 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A new family with Joseph disease in Japan: homovanillic acid, magnetic resonance, and sleep ap- mada); drafting of the manuscript (Drs Ishikawa and Tsuji); nea studies. Arch Neurol. 1989;46:425-428. critical revision of the manuscript for important intellec- 23. Murata Y, Yamaguchi S, Kawakami H, et al. Characteristic magnetic resonance tual content (Dr Tsuji); statistical expertise (Dr Tsuji); ob- imaging findings in Machado-Joseph disease. Arch Neurol. 1998;55:33-37. 24. Etchebehere ECSC, Cendes F, Lopes-Cendes I, et al. Brain single-photon emis- tained funding (Drs Ishikawa, Yamada, and Takahashi); sion computed tomography and magnetic resonance imaging in Machado- administrative, technical, and material support (Drs Ya- Joseph disease. Arch Neurol. 2001;58:1257-1263. mada and Takahashi); study supervision (Drs Ishikawa, 25. Soong B, Cheng C, Liu R, Shan D. Machado-Joseph disease: clinical, molecular, and metabolic characterization in Chinese kindreds. Ann Neurol. 1997;41:446-452. Yamada, Soma, Takahashi, and Tsuji). 26. Taniwaki T, Sakai T, Kobayashi T, et al. Positron emission tomography (PET) in This study was partly supported by grant 12A-1 for Machado-Joseph disease. J Neurol Sci. 1997;145:63-67. 27. Schilling G, Wood JD, Duan K, et al. Nuclear accumulation of truncated atrophin-1 Nervous and Mental Disorders and a grant for the Re- fragments in a transgenic mouse model of DRPLA. Neuron. 1999;24:275-286. search Committee for Ataxic Diseases from the Ministry of 28. Gibb WRG, Esiri MM, Lees AJ. Clinical and pathological features of diffuse cor- Health, Labor and Welfare, Tokyo, Japan, and a Grant-in- tical Lewy body disease (Lewy body dementia). Brain. 1985;110:1131-1153. 29. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and Aid for Scientific Research from the Ministry of Education, pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consor- Culture, Sports, Science and Technology, Tokyo. tium on DLB international workshop. Neurology. 1996;47:1113-1124.

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