INTRODUCTION
Wernicke encephalopathy (WE) is a neuropsychiatric disorder caused by a deficiency of thiamine (vitamin B1), which is necessary for oxidative metabolism (Hoyumpa, Reference Hoyumpa1980; Manzo et al., Reference Manzo, Locatelli and Candura1994). This disorder is reversible if properly diagnosed and treated with thiamine supplementation. However, it is often unrecognized (Isenberg-Grzeda et al., Reference Isenberg-Grzeda, Rahane and DeRosa2016b ). The main reason for underdiagnosis is the diversity of its symptoms (Isenberg-Grzeda et al., Reference Isenberg-Grzeda, Kutner and Nicolson2012).
The classical symptoms of WE include delirium, ataxia, and opthalmoplegia; however, these symptoms are not specific to WE, and only 16% of autopsy samples and 11% of clinical cases exhibit these three symptoms; in addition, 19% of autopsy samples show none of the three (Harper et al., Reference Harper, Giles and Finlay-Jones1986; Isenberg-Grzeda et al., Reference Isenberg-Grzeda, Alici and Hatzoglou2016a ). However, if left untreated, it causes severe and irreversible brain damage (Korsakoff syndrome), leading to death.
The best aid for diagnosis of WE, particularly in patients with cancer, is clinical suspicion (Sechi et al., Reference Sechi, Batzu and Agro2016).
Recent studies have revealed that WE patients with cancer are recognized in several situations during cancer progression (Isenberg-Grzeda et al., Reference Isenberg-Grzeda, Alici and Hatzoglou2016a ; Onishi et al., Reference Onishi, Ishida and Toyama2016; Reference Onishi, Kawanishi and Onose2004). Most of the clinical cases of WE are recognized when patients develop delirium, but little is known about the clinical features of WE without delirium.
In this report, we identify cancer patients with WE and without delirium. Correct diagnosis and subsequent parenteral thiamine administration relieved their symptoms and prevented them from developing delirium and irreversible brain damage (Korsakoff syndrome).
CASE REPORTS
Case 1
A 61-year-old woman with non-Hodgkin lymphoma was referred by her hematological oncologist to the psycho-oncology outpatient clinic because of anxiety and depression. She was diagnosed with non-Hodgkin lymphoma 14 months previous and received chemotherapy and radiotherapy; however, her disease progressed. She continued chemotherapy.
On her first psychiatric examination, she exhibited anxiety about her prognosis. She could not accept her situation with respect to the disease. She also sometimes developed emotional incontinence.
She was a retired kindergarten teacher who was very kind to others and had no medical history of psychiatric illness, and she had not abused alcohol or drugs.
Her psychiatric features fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM–V) (American Psychiatric Association, 2013) criteria for adjustment disorder with mixed anxiety and depression.
She was treated mainly with individual and group psychotherapy, which reduced her anxiety and depression. She also received chemotherapy and radiotherapy; however, her disease progressed.
Some 12 months after the first consultation at the psycho-oncology outpatient clinic, she visited our outpatient clinic using a wheelchair because of an unsteady gait. She said that she could not keep her feet firmly on the ground. She had been treated with 1150 mg of gemcitabine and 6.6 mg of dexamethasone 5 days before.
Neurological examination was unremarkable except for unsteadiness of gait. Delirium, headache, vomiting, nausea, and hemiparesis were not recognized.
She was 151 cm in height and weighed 48.8 kg (standard body weight = 50.56 kg).
Chest X-ray demonstrated no significant findings. Laboratory findings revealed that her aspartate aminotransferase, γ-glutamyltransferase, and glucose levels were elevated. She had received blood transfusions the day before. We could not find any laboratory findings to explain her unsteadiness.
A detailed interview with her and her husband revealed that she had developed loss of appetite more than two weeks earlier. Her husband reported that her appetite was 10% of normal for those 10 days and 50% of normal the week before that.
We suspected thiamine deficiency because ingested thiamine is stored in the body for approximately 18 days (MacLean et al., Reference MacLean, Rhode and Shizgal1983). Furthermore, she developed loss of appetite more than 2 weeks previous, and unsteadiness of gait is one of the clinical signs of thiamine deficiency. We administered 100 mg of thiamine intravenously. Two days after thiamine administration, she could walk into the consultation room, and delirium was not observed. Anemia and liver dysfunction remained almost the same after thiamine administration.
Her serum thiamine level measured using high-performance liquid chromatography was 19 ng/ml (reference range = 24–66 ng/ml).
From these findings, she was diagnosed with WE without delirium.
Case 2
A 45-year-old woman with breast carcinoma was referred by her oncologist to the psycho-oncology outpatient clinic because of anxiety. She had been diagnosed with breast carcinoma with bone metastasis 3 weeks before.
At the first psychiatric examination, she reported that she was anxious about the treatment and her future life. She had also developed a loss of interest. She had no past medical history of alcohol or drug abuse, and she was usually very kind to others.
Her psychiatric features fulfilled the DSM–V criteria (American Psychiatric Association, 2013) for adjustment disorder with anxiety. She was given psychotherapy, which reduced her anxiety. As for the breast cancer, she was treated with hormonal therapy and chemotherapy.
Five years after the first consultation, she complained of unsteadiness of gait. She stated that she could not walk without the help of a cane. Neurological examination was negative except for unsteadiness of gait. Delirium, headache, and nausea and vomiting were not exhibited.
Two weeks previous, she began taking 120 mg of a TS-1 combination capsule (tegaful, gimeracil, and oteracil potassium) and 2 mg of eribulin.
She was 157 cm in height and her body weight was 64.7 kg (standard body weight = 53.5 kg).
Laboratory findings revealed that her aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase values were elevated, but these could not explain her symptoms. A detailed interview with the patient revealed that she had developed loss of appetite and was eating 30% of normal for the past 2 weeks.
We suspected thiamine deficiency because she had developed loss of appetite for two weeks and body storage of thiamine deficiency is approximately 18 days, and because no other cause for the delirium was evident.
We administered 100 mg of thiamine intravenously. Several days after thiamine administration, she could walk without the help of a cane. Her serum thiamine level as measured using high-performance liquid chromatography was 23 ng/ml (reference range = 24–66 ng/ml). Neuroradiological studies revealed no brain metastasis.
From these findings, she was diagnosed with WE without delirium.
DISCUSSION
We have identified two cases of WE who presented with ataxia as the sole neurological symptom. Although these patients did not develop delirium, clinical suspicion, early detection, and immediate parenteral thiamine administration had prevented development of delirium and Korsakoff syndrome. WE is a medical emergency because the patient can sustain irreversible brain damage, leading to death, if early diagnosis fails. Therefore, clinical suspicion and early detection are particularly important. However, early detection of subclinical thiamine deficiency is a difficult task (Sechi & Serra, Reference Sechi and Serra2007). The clinical course, symptoms, and signs presented for our two cases are useful for clinical suspicion and early detection in other new cases.
There are several reasons why WE without delirium is difficult to recognize. First, delirium is considered as the hallmark of WE. Therefore, most oncologists do not have a clinical suspicion of WE when delirium is not present. Second, all of the clinical symptoms of WE, even the classical triad, are not disease-specific. Chemotherapy-induced peripheral neuropathy is a common side effect of cancer treatment. The resulting sensory and motor dysfunction often leads to such functional impairments as gait or balance disorders (Kneis et al., Reference Kneis, Wehrle and Freyler2016). Unsteadiness is not regarded as a symptom of WE if not accompanied by delirium. This may lead to underrecognition of WE.
The clue to the diagnosis of WE in these two cases was loss of appetite for about 2 weeks. Although the body stores thiamine for 18 days (MacLean et al., Reference MacLean, Rhode and Shizgal1983), a decreased capacity for thiamine storage has been recognized in cancer patients (Onishi et al., Reference Onishi, Sugimasa and Kawanishi2005; Yae et al., Reference Yae, Okuno and Onishi2005). It may be better to check thiamine deficiency in cancer patients, especially in advanced stages, if appetite loss has lasted for at least 2 weeks.
In an autopsy study (Harper et al., Reference Harper, Giles and Finlay-Jones1986), 19% of patients with WE had no documented clinical signs; in fact, only one patient was diagnosed with WE prior to death. Careful clinical observation should be able to reveal WE cases without the classical clinical triad.
In conclusion, we identified two cancer patients with WE without delirium. Careful clinical observation, including level and duration of loss of appetite, will be the key clue to clinical suspicion, early detection, and prevention of thiamine deficiency.
