3 RESULTS
The study included six patients who were followed in National Hospital Organization Kikuchi Hospital between July 2012 and December 2019. The three patients provided informed consent for the publication of their medical history, laboratory, imaging, treatment, and follow-up data. They were informed that data that were collected in medical records would be used for research study in accordance with privacy rule.
[Case 1] An 86-year-old man presented with a four-year history of memory disturbance. Cholinesterase inhibitor was prescribed to treat dementia caused by Alzheimer’s disease. The medication of donepezil, which was one of anti-Alzheimer’s disease medicines, started at the age of 82 years and 5mg of donepezil was kept. He scored 23/30 on the Mini Mental State Examination (MMSE) at the age of 83 years, other findings were considered, and was diagnosed as Alzheimer’s disease.37,38 His chest X-ray did not show cardiomegaly. He did not show autonomic nervous disorders of orthostatic hypotension. His cardiothoracic ratio was 42.62%, QT interval on electrocardiogram was 418ms, and brain natriuretic peptide was 41.37pg/mL. His Z-score of the medial temporal lobe in VSRAD, which was performed by 1.0 tesla Magnetic Resonance Imaging (MRI) and version of VSRAD plus, was 1.53.
Chronobiological medication was provided to stabilize awakening-sleep rhythm. 0.25mg of clonazepam at night was added for daytime somnolence and 15 mg of lansoprazole was used for gastric region discomfort. At the age of 85 years, he was admitted to our hospital with disinhibition of anger and face flush. His cardiothoracic ratio was 43.26% and QT interval was 386ms. We used 7.5g of Oren-Gedoku-To, which reduced main psychiatric symptoms, and 7.5g of Choto-San, which made a closure of action. We continued 15mg of lansoprazole to make gastrointestinal movement from morning. We gave 2.5mg of nitrazepam to stabilize his sleep status. After donepezil cancellation, Oren-Gedoku-To was changed to 6g of Ninjin-Yoei-To, which promoted an activity and the use of memory during daytime.
His awakening-sleep rhythm became stable. The patients with dementia met into Murofushi care system in the dementia disease treatment ward and he sat at table of ”family members.” To stabilize awakening and activity of the daytime, he participated in the group occupational therapy.
Two months after, MMSE score became 19/30 from 14/30 and Z-score of the medial temporal lobe in VSRAD became 4.14 from 4.17, which were examined by 1.5 tesla MRI and version of VSRAD advance 2.
[Case 2] A 72-year-old man presented with a three-year history of memory disturbance. He suffered low motivation after his wife’s death at the age of 67 years. At the age of 69 years, he showed memory deterioration and his Z-score of the medial temporal lobe, which was performed by 1.0 tesla Magnetic Resonance Imaging (MRI) and version of VSRAD plus, was 1.49. He scored 26/30 on MMSE. At the age of 70 years, his Z-score by the same VSRAD was 1.67. He was diagnosed as Alzheimer’s disease, and cholinesterase inhibitor, donepezil, was given. However, he scored 25/30 on MMSE and wandered all night. He was admitted to our hospital and donepezil was reduced from 5 to 3mg. The family doctor prescribed 50mg of sitagliptin phosphate hydrate against type II diabetes and we continued to use it. His chest X-ray did not reveal cardiomegaly. He did not show the autonomic nervous disorders of circulatory organ, such as his cardiothoracic ratio was 49.2%, QT interval on electrocardiogram was 413ms, and brain natriuretic peptide was 63.17pg/mL. His systolic blood pressures were 150 to 182mmHg. 5mg of amlodipine besilate and 40mg of valsartan was given for high blood pressure.
We started chronobiological medication, such as 5g of Yokkan-San for construction of awakening-sleep rhythm and 1.25g of Toki-Shakuyaku-San for reduction of cardiac load. 0.25mg of clonazepam was used for REM (rapid eye movement) sleep behavior disorder and 2.5mg of nitrazepam was prescribed to stabilize his sleep status. He scored 19/30 on MMSE. MRI revealed that Z-score of the medial temporal lobe was 2.05, which was performed by 1.5 tesla MRI and version of VSRAD advance 2.
His awakening-sleep rhythm were stable soon and in daytime he participated in the occupational therapy in the inpatient’s ward to strengthen awakening, activity movement. And he left our hospital two months after. His chronobiological medication and reinforcement of the awakening-sleep rhythm were maintained. He stayed the nursing home with day service rehabilitation for six months and after that he lived in his house with his family, continuing day service.
At the age of 72, in about one year and two months, his MMSE score was 23/30. And Z-score by 1.5 tesla Magnetic Resonance Imaging (MRI) and version of VSRAD advance 2 was 1.92. His brain natriuretic peptide was 14.3pg/mL.
[Case 3] A 65-year-old woman presented with a three-year history of memory disturbance. She suffered bipolar disorder since she was 58 years old. The doctor in charge prescribed 4 mg of risperidone and 400 mg of sodium valproate to stabilize her mood. At the age of 62 years, she was not able to do money management, because of her memory decline. At the age of 63 years, she often complained that she was spoken ill and was admitted to our hospital. She did not show her chest X-ray findings. As her cardiothoracic ratio was 51.26% and QT interval on electrocardiogram was 423ms, she did not show autonomic nervous disorders of circulatory organ. She scored 17/30 on MMSE and showed that Z-score of the medial temporal lobe was 1.48, which was performed by 1.0 tesla Magnetic Resonance Imaging (MRI) and version of VSRAD plus. At the age of 70 years, his Z-score by the same VSRAD was 1.67. She was diagnosed as Alzheimer’s disease.
Her chronobiological medication were started. 7.5 g of Bohu-Tsusho-San, which was used for irritability and itchy status, was added to the mood stabilizers. This Japanese Kampo medicine also provides the stabilization of the awakening. 2.5mg of nitrazepam was used as a sleep-inducing drug. Two months after hospitalization, 0.25mg of clonazepam was added for the reduction of REM (rapid eye movement) sleep and the stabilization of awakening and sleep rhythm.
She participated in daily occupational therapy to strengthen awakening, activity movement. She left our hospital in nine months and attended the occupational therapy in outpatient unit. When she was not able to have breakfast because of her appetite loss, 15mg of lansoprazole in the morning was added to make the rhythm of receptive relaxation of stomach.
At the age of 64, dizziness in daytime and many dreams in sleep were recognized. 2.5g of Yokkan-San-Ka-Chinpi-Hange was added to stabilize awakening-sleep rhythm. She scored 19/30 on MMSE and showed that the Z-score, which was examined by 1.5 tesla MRI and version of VSRAD advance 2, was 0.93 at the age of 65.
[Case 4] A 93-year-old woman presented with a 7-year history of fluctuating cognition and memory disturbance. She often talked to towards the photographs and wall. She became to have visual hallucination of a person at the age of 87 years. The medication of 3mg of donepezil was started at the age of 93. However, she was seized with a delusion state, taken to the psychiatry, and diagnosed as dementia with Lewy bodies.39,40 She scored 10/30 on MMSE at the age of 93 years. Antipsychotics, such as 25mg of quetiapine fumarate or 5mg of olanzapine, were given, but her hallucination and delusion status rather turned worse. She was introduced to our hospital for admission. Her chest X-ray showed 51.35% of cardiothoracic ratio. QT interval on electrocardiogram was 447ms and brain natriuretic peptide was 275.4pg/mL. Her autonomic nervous system disorders were the QT interval prolongation and chronic heart failure.
We started chronobiological medication and canceled donepezil. 0.25 mg of clonazepam in the night were used for the reduction of REM (rapid eye movement sleep) behavior disorder. 2.5mg of amlodipine besilate, 80mg of valsartan, and 20mg of furosemide were given for high blood pressure. Valsaltan was one of angiotensin II receptor blockers, which was used against the instability of blood pressure caused by cardiac autonomic nervous disorders. Furosemide for urination in the morning was one of diuretics. 15 mg lansoprazole was used to make receptive relaxation of stomach in the morning. 75 mg of tiapride, which was the small amount of antipsychotic, was prescribed against her hallucination and delusion. 5 g of Oren-Gedoku-To was added to get rid of irritation and to make falling sleep. 5 g of Choto-San was provided to make the decreases of the awakening in the night.
The patients with dementia met into Murofushi care system in the dementia disease treatment ward. She sat at table of ”family members” and participated in the group occupational therapy in the daytime. On the 52nd day after hospitalization, she suffered parkinsonism and motor apraxia. Both Japanese Kampo Medicines were changed to 7.5g of Yokkan-San-Ka-Chinpi-Hange and 2.5g of Hochu-Ekki-To, which stabilized awakening-sleep rhythm and reduced parkinsonism and promoted the motivation. Because of hypokalemia, furosemide was changed to 25 mg of spironolactone, which was one of diuretics and promoted the action of bladder in the morning.
In two months, the severity of Neuropsychiatric Inventory-Questionnaire became 9/36 from 20/36 and her Z-score of the medial temporal lobe in 1.5 tesla Magnetic Resonance Imaging (MRI) and version of VSRAD advance 2 became 2.33 from 2.37
[Case 5] A 95-year-old woman presented with a 15-year history of memory disturbance. She showed delusion of being stolen from since she was 80 years old. 1.0 tesla MRI and version of VSRAD plus were performed at the age of 86. Her Z-score of the medial temporal lobe in VSRAD was 3.43 and She scored 27/30 on MMSE. 7.5g Yokkan-San was prescribed against her irritability and fluctuating cognition. In the same year 3mg of donepezil, which was one of cholinesterase inhibitors, was started for her fluctuating cognition. However, her cognitive function deteriorated progressively. The irritability was reduced, and only 3mg of donepezil was continued at the age of 91. She suffered syncope and vertigo at the age of 94 years. She was absentminded in the daytime and showed REM (rapid eye movement) sleep behavior disorder by night. She was admitted to our hospital for the treatment of BPSD (behavioral and psychological symptoms of dementia) and the peristaltic gastrointestinal tract disorder. Her chest X-ray showed 48.33% of cardiothoracic ratio. QT interval on electrocardiogram was 424ms and brain natriuretic peptide was 26.76pg/mL. However, the instability of systolic blood pressure was shown in the range of 76 to 155mmHg. Her cardiac autonomic nervous disorder was considered. She was diagnosed as dementia with Lewy bodies.
Chronobiological medication was provided to stabilize awakening sleep rhythm. 0.125mg of clonazepam at night was added to stabilize the sleep status and 15 mg lansoprazole was given to make the receptive relaxation of stomach in the morning. She took 5 mg of mosapride citrate hydrate three times a day against dysperistalsis. 2.5g of Yokkan-San-Ka-Chinpi-Hange was started for construction of awakening-sleep rhythm and intestinal peristalsis. One week later, 660mg of magnesium oxide was added for constipation. However, the loss of appetite continued. She scored 14/30 on MMSE on the 30th day after the hospitalization. The gradual decrease of donepezil was started on the 49th day, and donepezil was canceled on the 77th days. We started 5 g of Keishi-Ka-Shakuyaku-To, which promoted motion of intestine. She recovered her appetite and entered ”family members” in the unit and participated in the group occupational therapy to stabilize awakening and activity of the daytime.
The severity of Neuropsychiatric Inventory-Questionnaire changed from 21/36 of the first day to 2/36 about 170 days after the hospitalization. And her Z-score of the medial temporal lobe in 1.5 tesla Magnetic Resonance Imaging (MRI) and version of VSRAD advance 2 became 5.58 from 5.7.
[Case 6] A 73-year-old woman presented with a five-year history of fluctuating cognition (FC). She showed insomnia at the age of 63, but did not take the medicine. She visited our hospital for amnesia at the age of 68. Her basic activity of 11Hz alpha waves were mixed by theta train on EEG, that is, fluctuating cognition was detected. Her chest X-ray showed 47.71% of cardiothoracic ratio. QT interval on electrocardiogram was 424ms and brain natriuretic peptide was 39.29pg/mL. Her blood pressure was high, such as the systolic blood pressure was 168mmHg and diastolic pressure was 110mmHg. Her Z-score, which was performed by 1.0 tesla Magnetic Resonance Imaging (MRI) and version of VSRAD plus, was 1.50. Her falling asleep was bad and there was somniloquy in the night. She was hard to get up and had no appetite in the morning, and her body came to be active after lunch. Her total score of MMSE was 22/30 and the recall was 1/3. She was diagnosed as dementia with Lewy bodies.
Chronobiological medication was started to reconstruct awakening-sleep rhythm. 15 mg of lansoprazole in the morning was used for gastric region discomfort and appetite loss. 2.5mg of amlodipine besilate were given for high blood pressure. 10mg of furosemide for urination in the morning was one of diuretics. 0.5mg of clonazepam was used for REM (rapid eye movement) sleep behavior disorder and 2.5mg of nitrazepam was prescribed to stabilize his sleep status. 50mg of tiapride hydrochloride and 10mg of mianserin hydrochloride were prescribed for the stabilization of mood and the reduction of depressive state. In addition, we started 4.5mg of rivastigmine patch to treat the dementia with Lewy bodies. She participated in our occupational therapy twice a week in outpatient section. Because the activity in the daytime was provided when she participated in our occupational therapy, her awakening sleep rhythm was improved. On other days of a week, her awakening-sleep rhythm remained unstable. By the inspection after one year and five months, although her MMSE score was improved to 25/30 and the recall was 2/3, Z-score, which was performed by 1.0 tesla Magnetic Resonance Imaging (MRI) and version of VSRAD plus, turned worse to 2.31, and QT interval in the electrocardiography extended to 434ms.
When she was 73 years old, her husband suffered from his cognitive deterioration and he showed violence to her. She began to fail the management of drugs and her fluctuating cognition became worse again. Then, she was admitted into our hospital to resume the reconstruction of the awakening-sleep rhythm. 1.5 tesla Magnetic Resonance Imaging (MRI) revealed her medial temporal lobar atrophy and her Z-score of medial temporal lobe in version of VSRAD advance 2 was 2.74. Her total score of MMSE was 25/30 and the recall was 2/3. We gave her 7.5 g of Yokkan-San to reconstruct her awakening sleep rhythm. We prompted her to participate in occupational therapy to improve her activity of the daytime. Her MMSE score was 29/30 and the recall was 3/3 on the 34th day after hospitalization. The Z-score was 1.46 on the 82th day.