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Keywords:

  • traumatic brain injury;
  • yokukansan (Yi-Gan San)

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CASE REPORT
  5. DISCUSSION
  6. REFERENCES

The Japanese herbal medicine, yokukansan, has been reported to improve behavioral and psychological symptoms of dementia and activities of daily living in patients with dementia. In the present case report, the authors report the effectiveness of yokukansan in treating psychiatric symptoms after traumatic brain injury. An 85-year-old man, who underwent surgery for hepatic portal cholangiocarcinoma, sustained traumatic brain injury after falling from bed as the result of postoperative delirium. He subsequently presented with psychiatric symptoms, showing markedly impulsive and aggressive behavior. Neuroleptics did not alleviate the symptoms. Ultimately, we succeeded in controlling the symptoms, without adverse effects, by giving the patient yokukansan. Yokukansan shows the potential for reducing aggressive and impulsive behavior in dementia as well as in other psychiatric diseases.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CASE REPORT
  5. DISCUSSION
  6. REFERENCES

The Japanese herbal medicine, yokukansan, has been reported to improve behavioral and psychological symptoms of dementia (BPSD) and activities of daily living (ADL) in patients with dementia.

In the present study, we present the case of an elderly man who manifested psychiatric symptoms after brain injury. The patient's behavior was markedly impulsive and aggressive, and hard to manage. Ultimately, we succeeded in controlling these symptoms with the administration of yokukansan.

This is the first report of a case in which yokukansan administration was effective for the alleviation of psychiatric symptoms after traumatic brain injury (TBI).

CASE REPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CASE REPORT
  5. DISCUSSION
  6. REFERENCES

An 85-year-old man admitted to the surgical ward of our hospital for treatment of hepatic portal cholangiocarcinoma underwent left lobectomy of the liver and lymph node dissection.

The patient was a cheerful and outgoing man, but had a short temper. He had successfully operated an import business until the age of 82 years, and had been a widower for approximately 20 years. He was optically-challenged as a result of left tuberculous keratitis and a right cataract. However, he lived a relatively independent life with the aid of home care workers.

From the very day of the surgery, he shouted, spoke nonsense and mimicked a cat. He was diagnosed as having a delirium and haloperidol was given intravenously as necessary. On the morning of postoperative day 5, he was found lying on his back on the floor after presumably falling from bed. Brain computed tomography (CT) showed a right acute subdural hematoma, traumatic subarachnoid hemorrhage and a right temporal bone fracture (Fig. 1). On the recommendations of a brain surgeon, conservative management was started. Thereafter, the patient showed a tendency for daytime sleeping and night-time insomnia, shouting and frequently calling for nurses. He was bedridden and refused to eat. Intravenous haloperidol did not alleviate the symptoms. Despite trying various treatments, this condition remained unchanged for approximately 6 weeks. His refusal to eat required intravenous alimentation. On postoperative day 52, he became excited and swung his fist at a nurse and brandished a cane. At this time, he was referred to the psychiatric clinic in the hospital. His nutritional state was poor (serum albumin was 2.6 g/dL).

image

Figure 1. Brain computed tomography soon after traumatic brain injury. A right traumatic subarachnoid hemorrhage is apparent.

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CT of the brain on postoperative day 58 showed right frontal lobe contusions and subdural hygroma in the left frontal-temporal region (Fig. 2). The patient's undesirable behavior was suspected to be a manifestation of psychiatric symptoms after TBI. Olanzapine (orally disintegrating tablets) at a dose of 5 mg was given. He spat out all other pills. As the effect of olanzapine was limited, intravenous haloperidol and flunitrazepam were required. These medications resulted in drowsiness, dysphagia, articulatory disturbance and urinary retention.

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Figure 2. Brain computed tomography on postoperative day 58 shows right frontal lobe contusions and subdural hygroma in the left frontal-temporal region.

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On postoperative day 70, the patient was moved to a psychiatric ward. He was oriented; however, his emotional condition was unstable. His visual acuity was light perception or better. Electroencephalography showed diffuse θ waves on the background activities of α waves. Olanzapine was continued at the same dose. Discontinuation of intravenous haloperidol and flunitrazepam diminished the dysphagia and urinary retention, but other symptoms continued.

From postoperative day 98, nutrition was provided through a percutaneous endoscopic gastrostomy (PEG) tube because the patient continued to refuse to eat and drink. Through the PEG tube, 100 mg daily of sodium valproate was given, which was subsequently increased to 600 mg daily. 10 mg daily of mianserin and 1 mg daily of flunitrazepam were given together. Sodium valproate seemed to reduce his violent behavior somewhat; however, administration was discontinued because of oversedation and pancytopenia. Olanzapine was replaced with quetiapine and then tiapride, but both drugs caused dysphagia.

On postoperative day 109, the patient was started on yokukansan, at a dose of 5 g daily. Twelve days later, the patient began to eat again and he appeared more emotionally stable. During the night, he often became excitable, expressing his wish to return home. However, low-dose risperidone was able to calm his excitement. Yokukansan dosage was increased to 7.5 g daily on postoperative day 132. At this point, his nutritional state had not improved (serum albumin was 2.7 g/dL). Despite use of mianserin and flunitrazepam, his daytime sleeping and night-time insomnia had not been altered. Brain CT on postoperative day 145 showed the reduction of subdural hygroma in the left frontal-temporal region and no change of frontal lobe contusions.

On postoperative day 154, the patient was moved to a rehabilitation hospital. At that time, he was taking 7.5 g yokukansan, 10 mg mianserin and 1 mg flunitrazepam. The clinical course is schematized in Figure 3. After 80 days of hospitalization in the rehabilitation hospital, the patient could walk holding a handrail and was discharged to home.

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Figure 3. Clinical course from the day of the traumatic brain injury to the day of discharge and medication doses. Yokukansan improved psychiatric symptoms and food intake without extrapyramidal symptoms and oversedation. EPS, extrapyramidal symptoms; PEG, percutaneous endoscopic gastrostomy.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CASE REPORT
  5. DISCUSSION
  6. REFERENCES

Traumatic brain injury, defined as damage to the brain resulting from an external mechanical force, causes both neurological and psychiatric disabilities.1 While neurological sequelae usually stabilize with time, psychiatric symptoms often persist. Mood and behavioral problems after TBI can interfere with rehabilitation and cause adverse outcomes, such as repeated hospitalizations, legal problems and alienation from family and friends. The psychiatric symptoms of TBI are classified into acute and chronic sequelae. An acute psychiatric sequela is loss of consciousness, which might be brief or protracted. After recovering from loss of consciousness, the patient subsequently develops confusion, agitation, disorientation and delirium. Although some symptoms fade in time, others can persist as chronic psychiatric sequelae, such as memory problems, behavioral and emotional control problems and mood disorders.1

The correlation between damage to a certain part of the brain and the manifestation of psychiatric symptoms is as follows.2 Damage to the orbitofrontal region manifests as disinhibition, antisocial behavior, affective lability, hyperactivity, sexual preoccupation, impulsiveness, distractibility, and poor insight. Damage to the frontal convexity manifests as apathy, indifference, lack of spontaneity, psychomotor retardation, inflexibility, impersistence and perseveration. Damage to the medial frontal portion manifests as akinesia, sparse verbal output and incontinence. In terms of the patient discussed in the present case report, the damage was localized to the right orbitofrontal region; such damage can cause aggression and impulsiveness.

Physical and verbal aggression, and impulsiveness are particularly difficult for medical staff and family members to manage. The administration of antipsychotics, anticonvulsants, beta-blockers and benzodiazepines are recommended for the treatment of such symptoms.1,2 However, especially in the elderly, these drugs carry a risk of adverse effects, such as extrapyramidal symptoms, oversedation and cardiovascular complications, which might subsequently cause aspiration pneumonia, bone fracture as a result of a fall, or sudden death.

Yokukansan, originally used for the treatment of neuroses, insomnia and night terrors as well as neuroasthenia in childhood, has been recognized as a useful drug for BPSD, which improves ADL in patients with dementia.3–8 In addition, some reports show that yokukansan effectively controls aggressive and impulsive behavior in patients with borderline personality disorder.9 Similarly, yokukansan is expected to be effective for alleviating symptoms of aggression and impulsiveness, not only in Alzheimer disease and dementia of Lewy bodies, but also in other psychiatric diseases. We started our patient on yokukansan because his symptoms resembled BPSD. However, a further consideration is that yokukansan has neuroprotective effects10,11 and is efficacious for the alleviation of aggression and impulsiveness.12

Because the alleviation of the psychiatric symptoms occurred soon after the administration of yokukansan, we concluded that yokukansan was the most important factor for the improvement of the patient's state. However, other factors should be considered. The symptoms might have resolved as part of the natural course of the TBI recovery. This factor can't be excluded fully. The nutritional state and the sleep and wakefulness rhythm of the patient were almost unchanged throughout the clinical course, despite the improvement of eating behavior and the use of medications (e.g. mianserin, flunitrazepam). Therefore, these factors can't be significant.

Yokukansan was also favorable for our patient because extrapyramidal symptoms and oversedation did not result. The mechanism of action of yokukansan for BPSD can be explained as follows: (i) partial agonistic effects for 5-HT 1A receptors, (ii) antagonistic effects for 5-HT 2A receptors, and (iii) protective effects against the glutamate-induced excitatory neurotoxicity by amelioration of astrocyte dysfunction.10,13,14 The direct effects of yokukansan on the dopaminergic neuron system are not as yet known, but this might be the reason for it having fewer adverse effects than neuroleptics.

In today's unprecedented aged society, the number of surgical operations for aged patients is increasing. Accordingly, managing postoperative delirium is an urgent problem. Recently, yokukansan has been used for the prevention of postoperative delirium in some hospitals in Japan,15 Therefore, yokukansan might be effective, with few adverse effects, not only for the treatment of but also for the prevention of problems in aged patients. This traditional Japanese medicine might provide us with new and various applications.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CASE REPORT
  5. DISCUSSION
  6. REFERENCES
  • 1
    Rao V. Traumatic brain injury. In: LyketsosCG, RabinPV, LipseyJR et al., eds. Psychiatric Aspects of Neurologic Diseases. New York: Oxford University Press, 2008; 84100.
  • 2
    Sudarsanan BS, Chaudhary LCS, Pawar SCAA et al. Psychiatric effects of traumatic brain injury. Med J Armed Forces India 2006; 62: 259263.
  • 3
    Iwasaki K, Maruyama M, Tomita N et al. Effects of the traditional Chinese herbal medicine Yi-Gan San for cholinesterase inhibitor-resistant visual hallucinations and neuropsychiatric symptoms in patients with dementia with Lewy bodies. J Clin Psychiatry 2005; 66: 16121613.
  • 4
    Iwasaki K, Satoh-Nakagawa T, Maruyama M et al. A randomized, observer-blind, controlled trial of the traditional Chinese medicine Yi-Gan San for improvement of behavioral and psychological symptoms and activities of daily living in dementia patients. J Clin Psychiatry 2005; 66: 248252.
  • 5
    Mizukami K, Asada T, Kinoshita T et al. A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia. Int J Neuropsychopharmacol 2009; 12: 191199.
  • 6
    Shinno H, Utani E, Okazaki S et al. Successful treatment with Yi-Gan San for psychosis and sleep disturbance in a patient with dementia with Lewy bodies. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 15431545.
  • 7
    Shinno H, Inami Y, Inagaki T et al. Effect of Yi-Gan San on psychiatric symptoms and sleep structure at patients with behavioral and psychological symptoms of dementia. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 881885.
  • 8
    Monji A, Takita M, Samejima T et al. Effect of yokukansan on the behavioral and psychological symptoms of dementia in elderly patients with Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 308311.
  • 9
    Miyaoka T, Furuya M, Yasuda H et al. Yi-gan san for the treatment of borderline personality disorder: an open-label study. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 150154.
  • 10
    Kawakami Z, Kanno H, Ueki T et al. Neuroprotective effects of yokukansan, a traditional Japanese medicine, on glutamate-mediated excitotoxicity in cultured cells. Neuroscience 2009; 159: 13971407.
  • 11
    Tateno M, Ukai W, Ono T et al. Neuroprotective effects of Yi-Gan San against beta amyloid-induced cytotoxicity on rat cortical neurons. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 17041707.
  • 12
    Sekiguchi K, Yamaguchi T, Tabuchi M et al. Effects of yokukansan, a traditional Japanese medicine, on aggressiveness induced by intracerebroventricular injection of amyloid beta protein into mice. Phytother Res 2009; 23: 11751181.
  • 13
    Egashira N, Iwasaki K, Ishibashi A et al. Repeated administration of yokukansan inhibits DOI-induced head-twitch response and decreases expression of 5-hydroxytryptamine (5-HT) 2A receptors in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 15161520.
  • 14
    Igarashi Y. Elucidation of the pharmacological mechanism of yokukansan. Geriatr Med 2008; 46: 255261 (in Japanese).
  • 15
    Mukai N, Kurauchi N, Suzuki S et al. Trial of yokukansan for postoperative delirium. Hokkaido Gerka Zasshi 2008; 53: 9091 (in Japanese).