Brain SPECT Findings at the Acute Stage of Disease in Patients with Wernicke Encephalopathy

Background: We aimed to objectively examine regional cerebral blood flow at the acute stage of disease in patients with Wernicke encephalopathy. Methods: We performed single photon emission computed tomography (SPECT) with 99mTc ethylcysteinate dimer in 5 patients with Wernicke encephalopathy, and 15 ageand sex-matched control subjects. SPECT data were analyzed by statistical parametric mapping 8 (SPM8). Results: SPM8 revealed relative hypoperfusion in the bilateral anterior cingulate gyri and the left inferior frontal gyrus compared to controls. Conclusion: Our findings suggest that Wernicke encephalopathy affects brain function mainly in the frontal lobe, similar to Korsakoff syndrome.


Introduction
Wernicke's encephalopathy (WE) is an acute neurologic syndrome that results from thiamine deficiency [1]. Chronic alcohol abuse is the most common cause of thiamine deficiency [2]. WE classically presents as a triad of symptoms: altered consciousness, oculomotor abnormalities, and ataxia. Brain imaging techniques, particularly magnetic resonance imaging (MRI) are important and useful in the diagnosis of WE [2][3][4]. Moreover, functional imaging studies (e.g., positron emission tomography (PET) and single-photon emission computed tomography (SPECT) provide indirect markers of the function and dysfunction of the neuronal networks involved in WE and Korsakoff syndrome. While many PET and SPECT studies are reported in patients with Korsakoff syndrome [5][6][7][8][9][10], only one SPECT study has examined brain perfusion in patient with WE [11]. We performed a SPECT study with 99m Tc ethylcysteinate dimer ( 99m Tc-ECD SPECT) in patients with WE at the acute stage of disease to evaluate alterations in regional cerebral blood flow (rCBF) using statistical parametric mapping 8 (SPM8) analyses.

Subjects
We included five patients with WE (2 men, 3 women; age, 43-67 years; mean age, 56.6) who admitted to the department of neurology, Oita University between 2007 and 2016. Both brain MRI and brain 99m Tc-ECD SPECT studies were performed within 30 days of clinical onset of the symptoms. WE was diagnosed based on clinical features, including malnutrition, oculomotor abnormalities, cerebellar dysfunction, an altered mental state, and a good response to thiamine replacement [12]. Information regarding age, sex, drinking history, past surgical history, neurologic symptoms, laboratory tests, and cerebrospinal fluid analysis findings was obtained from the medical records. All patients were treated with 100 mg per day intravenous administration of thiamine for 5-15 days. Fifteen age-matched subjects (mean age 56.9 ± 3.1 years; age range 53-62 years) without neurologic disorders were also included as controls for SPECT image analysis. Fully informed consent was received, and all patients or their closest relative agreed to participate in this study.

SPECT image analysis using SPM8
We used the noninvasive Patlak plot method with the fully automated region of interest technique to measure rCBF. Differences in the rCBF between WE patients and the control group were determined by voxel-by-voxel group analysis with SPM8 (Welcome Trust Centre for Neuroimaging, University College, London, UK), running on MATLAB version R2009b (MathWorks, Inc., Natick, MA) according to previous studies [13]. The SPM {t} maps were obtained at a height threshold of P<0.005 (uncorrected) and an extent threshold of 50 voxels. Finally, the Montreal Neurological Institute atlas coordinates were converted to Talairach brain coordinates.

Results
The clinical and demographic characteristics of the patients with WE are provided in Table 1. Four patients were chronic alcoholics and one patient had undergone gastrointestinal surgical procedures. Two of the five patients presented with the classical triad signs of WE, i.e., altered consciousness, oculomotor abnormalities, and ataxia. Two patients had two signs and one patient had only mild consciousness disturbance. Brain MRI showed high signal intensities on T2-and FLAIR images in the periaqueductal gray matter and bilateral paramedian thalami in patient 1 ( Figure 1A and 1B) and in the cerebellum in patient 2 ( Figure 1C and 1D). The other three patients had normal MRI findings. SPM8 analysis revealed relatively decreased rCBF in the bilateral anterior cingulate gyri and in the left inferior frontal gyrus in the WE patients compared with the controls (Figure 2 and Table 2

Discussion
Brain perfusion images at the acute stage of disease in patients with WE were evaluated using SPM8. Previous SPECT studies of Korsacoff's syndrome used 99m Tc-hexamethyl propyleneamine oxime ( 99m Tc-HMPAO) or 123 I-isopropylamphetamine ( 123 I-IMP) [5,6]. Our SPECT study used 99m Tc-ECD, which can evaluate not only brain perfusion, but also the reduction of the enzymatic process due to neuronal dysfunction [13,14]. Patients with WE exhibited significantly decreased rCBF in the bilateral anterior cingulate gyri and in the left inferior frontal gyrus. Figure 2: SPM brain map of the group. Group comparison of cerebral blood flow between patients with Wernicke encephalopathy and controls. Wernicke encephalopathy exhibited decreased regional cerebral blood flow in the bilateral anterior cingulate gyri and left inferior frontal gyrus compared with controls.
There have been several PET or SPECT studies in patients with Korsakoff syndrome. PET studies reported a metabolic reduction in the thalamus, anterior cingulate gyrus, and medial temporal lobe [7][8][9]. Matsuda et al. [10] reported bilateral decreases in the rCBF or regional cerebral metabolic ratio of oxygen in the frontotemporal areas and left thalamus, suggesting that the cognitive impairments observed in Korsakoff syndrome are due to abnormalities in the frontal-thalamic neural network or Papez circuit. A previous 99m Tc-HMPAO SPECT study reported decreased rCBF in the frontal lobe [5], whereas an 123 I-  Locations and peaks of decreased regional cerebral blood flow in patients with Wernicke encephalopathy compared with controls.
Our SPECT findings at the acute stage of disease in patients with WE revealed decreased rCBF in the bilateral anterior cingulate gyri and in the left inferior frontal gyrus, similar to the PET findings of Korsakoff syndrome. We suggest that the decreased rCBF observed predominantly in the limbic system might be due to secondary changes resulting from degeneration of the frontal-thalamic neural network or Papez circuit.
The present study has several limitations. We diagnosed the patients based solely on clinical findings and did not obtain pathologic confirmation. Due to the small number of patients, the present results should be considered preliminary and should be confirmed by additional studies with more subjects.