Introduction
Bereavement is life's greatest stressor (Holmes & Rahe, Reference Holmes and Rahe1967) and can influence the psychological, physical, and social aspects of the survivor’ life. For example, in psychological terms, there are increases in the incidence of depression (Zisook & Shuchter, Reference Zisook and Shuchter1991) and suicide rate (Erlangsen et al., Reference Erlangsen, Jeune and Bille-Brahe2004; Kaprio et al., Reference Kaprio, Koskenvuo and Rita1987; Li, Reference Li1995), whereas in physical terms, an increase in the mortality rate from cardiovascular disease (Carey et al., Reference Carey, Shah and DeWilde2014) has been reported.
Based on such findings, we established a “bereavement clinic” at our institution to treat and provide care for bereaved family members, and we have reported various findings related to the medical treatment of the psychological, physical, and social aspects of bereavement (Ishida et al., Reference Ishida, Onishi and Wada2010, Reference Ishida, Onishi and Wada2011, Reference Ishida, Onishi and Wada2012, Reference Ishida, Onishi and Toyama2015, Reference Ishida, Onishi and Morita2018).
Thiamine, in its biologically active form, thiamine pyrophosphate, is an essential coenzyme for oxidative metabolism (Sechi et al., Reference Sechi, Sechi and Fois2016b). However, because it cannot be synthesized in vivo, maintenance of an appropriate level depends on ingestion from outside the body. The stores of thiamine in the body can be depleted in as little as 18 days (MacLean et al., Reference MacLean, Rhode and Shizgal1983), and serum thiamine concentration declines with a reduction in dietary intake lasting two to three weeks (Sechi et al., Reference Sechi, Sechi and Fois2016b).
Thiamine deficiency typically leads to the disease known as Wernicke's encephalopathy (WE). This disease presents with a wide spectrum of signs and symptoms, ranging from cognitive, mood, or behavioral changes, through to ocular, cerebellar, and other neurologic signs. The presentation is quite heterogeneous, and the historical concept of a “triad” of symptoms is no longer recognized as clinically valid. Treatment consists of the administration of thiamine, and if the disease is identified and treated in the early stage it can be resolved without sequelae. However, these symptoms are nonspecific, and less than 20% of cases present with all three symptoms. Further, the disease is often confused with other neuropsychiatric symptoms, and is often overlooked (Isenberg-Grzeda et al., Reference Isenberg-Grzeda, Kutner and Nicolson2012). If overlooked long term, it can progress to Korsakoff syndrome, leading to severe brain-related complications. The subsequent mortality rate is high at 17% (Victor et al., Reference Victor, Adams and Collins1971).
Recent studies have shown that cancer patients can develop thiamine deficiency, with the timing of onset ranging from preoperative to end-stage and presenting a diverse range of symptoms (Onishi et al., Reference Onishi, Ishida and Toyama2016, Reference Onishi, Ishida and Kagamu2018a, Reference Onishi, Ishida and Takahashi2018b, Reference Onishi, Ishida and Tanahashi2018c, Reference Onishi, Ishida and Tanahashi2018d, Reference Onishi, Ishida and Tanahashi2018e, Reference Onishi, Ishida and Uchida2018f; Isenberg-Grzeda et al., Reference Isenberg-Grzeda, Hsu and Hatzoglou2015, Reference Isenberg-Grzeda, Alici and Hatzoglou2016a, Reference Isenberg-Grzeda, Rahane and DeRosa2016b, Reference Isenberg-Grzeda, Shen and Alici2017; Sechi et al., Reference Sechi, Batzu and Agro2016a). Furthermore, thiamine deficiencies have also been recognized in family members caring for cancer patients (Onishi et al., Reference Onishi, Ishida and Uchida2019).
Here we report two cases of thiamine deficiency in the bereaved after cancer-related spousal loss who visited our “bereavement clinic.” In both cases, the onset of WE was prevented by timely treatment.
Case Report
Case 1
A 57-year-old woman visited our “bereavement clinic” for a consultation on the advice of a physician from the Department of Supportive Therapy at our institution.
Her husband had been diagnosed with pancreatic cancer with liver metastasis one year earlier, and despite undergoing chemotherapy and radiation therapy, the disease progressed and he had died one month before her visit.
The bereaved consulted the bereavement clinic because she continued to experience anxiety and regret following her husband's death. Her psychological symptoms at the first visit included depression, anxiety, and decreased appetite. In addition, she felt regret regarding choices made in relation to treatment options and place of care.
No neurological symptoms such as disturbed consciousness, ataxia, or ocular symptoms were observed. No findings of note were observed on her blood and biochemical examinations.
She had no medical history of psychiatric illness or alcohol or drug abuse. Her psychiatric features fulfilled the criteria set out in The Diagnostic and Statistical Manual of Mental Disorders 5th edition (American Psychiatric Association, 2013) for uncomplicated bereavement.
More detailed examination revealed a decrease in appetite to about 30% of normal that had continued from approximately one week before her husband had died. Because thiamine is stored in the body for as little as 18 days, we considered the possibility of thiamine deficiency and 100 mg of thiamine was intravenously injected after collection of a blood sample to test her blood thiamine level. After five days, it was revealed that her blood thiamine level had decreased to 23 ng/mL (reference range: 24–66 ng/mL). However, there was no onset of WE.
Case 2
A 73-year-old male was brought for a consultation at our “bereavement clinic” by his daughter.
His wife had suffered from hypopharyngeal cancer for five years. Despite treatment, her symptoms progressed and she died one month before his visit.
He had shown a lack of energy for the month preceding his wife's death, but because there was no improvement after her death his family became concerned and recommended he seek consultation.
Psychiatric consultation at the initial visit revealed depression, decreased motivation, decreased appetite, sleep disturbance, inhibition, and difficulty concentrating. Neurological examination showed no disturbance of consciousness, ataxia, or ocular symptoms.
Normal blood and biochemical examinations did not show any notable abnormalities, and computed tomography scans of the head did not reveal anything of note. He had no medical history of psychiatric illness, or alcohol or drug abuse. His psychiatric features fulfilled the criteria set out in The Diagnostic and Statistical Manual of Mental Disorders 5th edition (American Psychiatric Association, 2013) for major depressive disorder, and mianserin (10 mg) was prescribed for his depression.
With regard to other findings, because his dietary intake had been decreased for more than two weeks and the storage of vitamin B1 in the body is known to be approximately 18 days (MacLean et al., Reference MacLean, Rhode and Shizgal1983), thiamine deficiency was suspected and blood samples showed the concentration of vitamin B1 to have fallen to 20 ng/mL (reference range: 24–66 ng/mL).
The patient was treated with oral vitamin B1 administration (75 mg/day) and no onset of WE was observed. His depression was resolved after six months because of the continuation of drug therapy and psychotherapy, and no recurrence has been observed to date.
Discussion
We identified thiamine deficiency in the bereaved who had lost their spouses to cancer. Surviving family members present with various physical symptoms depending on the stress levels; however, to the best of our knowledge there have been no reports of thiamine deficiency to date. Thus, these case studies can be said to present new information for further consideration. The patients in these cases did not present with any of the classical symptoms of WE: disturbed consciousness, ataxia, and ocular symptoms. Previous studies have shown that these symptoms show low sensitivity, and cases without any of the three symptoms have been reported (Isenberg-Grzeda et al., Reference Isenberg-Grzeda, Shen and Alici2017; Onishi et al., Reference Onishi, Ishida and Tanahashi2018d).
The key to the diagnosis of thiamine deficiency was the decrease in appetite lasting more than two weeks. Thiamine deficiency can occur any time nutrition is unbalanced for a period of two to three weeks (Sechi et al., Reference Sechi, Sechi and Fois2016b) because thiamine is only stored in the body for about 18 days (MacLean et al., Reference MacLean, Rhode and Shizgal1983).
A reduction in dietary intake is regarded as the major cause of WE onset, although malabsorption of thiamine resulting from old age may also be involved (Chen et al., Reference Chen, Chen and Gold1996; Nichols & Basu, Reference Nichols and Basu1994; Vir & Love, Reference Vir and Love1977).
In case 2, we administered thiamine orally. Intravenous thiamine administration of >200 mg/day is recommended for the treatment of WE (Galvin et al., Reference Galvin, Brathen and Ivashynka2010; Isenberg-Grzeda et al., Reference Isenberg-Grzeda, Kutner and Nicolson2012). In elderly patients, oral thiamine (10 mg/day) was reported to improve the quality of life compared with a placebo (Wilkinson et al., Reference Wilkinson, Hanger and Elmslie1997). We think that the ability to absorb thiamine via the small intestine remained intact in this case.
In case 2, symptoms of depression appeared foremost, with no symptoms indicative of thiamine deficiency, other than decreased appetite, observed. Because the death of a spouse is the greatest risk factor for the development of depression in the elderly (Cole & Dendukuri, Reference Cole and Dendukuri2003), it is important to keep depression in mind during medical treatment. However, physical symptoms other than depression, such as those observed in the present case, should also be noted.
In conclusion, although the diagnosis and treatment of mental illness as well as the provision of grief care are important for survivor care, it is also vital to pay close attention to physical problems such as thiamine deficiency.
