INTRODUCTION

 

Wernicke’s encephalopathy (WE) is an acute neurological disorder characterized by a clinical triad of mental confusion, ataxia, and ophthalmoplegia/ nystagmus¹. However, this typical presentation is only present in 16-38% of patients², and this may explain in part why this condition is often clinically underdiagnosed³. To improve diagnostic accuracy, certain criteria were proposed by Caine et al. in 1997⁴ that require the presence of two of the following: dietary deficiencies, oculomotor abnormalities, cerbellar dysfunction, and an altered mental state or mild memory impairment. When persistent learning and memory deficits are present, the symptom complex is called Wernicke-Korskoff (WK) syndrome⁵.

The syndrome is caused by thiamine (vitamin B1) deficiency. Thiamine is converted to its active form, thiamine pyrophosphate (TPP), in neural and glial cells, and serves as a cofactor for several enzymes functioning in glucose use in the brain⁶.

 

Though the association between WE and heavy alcohol misuse is a common scenario⁵, yet, it is important to recognise that it can also result from other clinical settings associated with disordered nutrition as hyperemesis gravidarum, malignancy, bariatric surgery, hemodyalisis, AIDS, chronic malnutrition, long term parenteral nutrition and re-feeding after prolonged starvation, where such factors were recorded in to 20% up to 50% of WE cases ^1,2,5,7,8.

Magnetic resonance (MR) imaging is considered the most valuable diagnostic tool with sensibility 0.92±0.10, (CI; 0.95); yet, typical findings are observed in only 58% of patients³. It usually shows symmetric signal intensity alterations in the thalami, mamillary bodies, tectal plate, periaqueductal area, and periventricular regions of third and fourth ventricles ^9,10. Signal intensity alterations in the cerebellum, cerebellar vermis, cranial nerve nuclei, red nuclei, dentate nuclei, caudate nuclei, splenium, and cerebral cortex represent atypical MRI findings^11,12.

The prognosis of WE depends on the stage of disease at presentation and the promptness of therapy¹³. Generally, full recovery of ocular function occurs; nystagmus can persist in up to 60%; approximately 40% recover completely from ataxia and 20% have full recovery from amnestic deficit⁴.

Bearing in mind the strong causal relation between alcoholism and WE, the syndrome is usually under recognized while addressing a case of acute encephalopathy in Egypt, where alcoholism does not represent a major issue.

This study aimed to identify the clinical and neuro-imaging criteria of WE in a group of Egyptian patients and discusses their neurological and radiological outcomes.

 

SUBJECTS AND METHODS

 

Study design: This was a prospective study that enrolled 11 patients (7 women and 4 men) with acute Wernicke’s encephalopathy, who were seen and followed up during the period from September 2005 to December 2009.

Patient's selection and diagnosis confirmation: The clinical diagnosis of Wernicke’s encephalopathy was established according to operational criteria for Wernicke’s encephalopathy adopted by Caine et al.⁴ and this was confirmed by specific MRI findings. Additional features included: (1) presence of documented known predisposing factor, and (2) absence of other attributable causes. We adopted the following exclusionary criteria: (1) patients with known or overt metabolic disorders such as renal and liver cell failure, (2) those with collagen vascular disorders, (3) patients with seizures or papilledema, (4) normal MRI study or that with findings suggestive of other etiologies; such as tumors, encephalitis, vascular disorders, etc., (5) specific EEG pattern denoting encephalitis or other known encephalopathy (as triphasic waves, periodic patterns or epileptic discharges).

 

Methodology

Study design and ethical issues: This was a prospective study that enrolled 11 patients (7 women and 4 men) with WE, who were seen and followed up during the period from September 2005 to December 2009. The relatives of all participants gave an informed written consent approved by Neurology Department Review Board in Cairo University.

Detailed medical history was obtained from patients’ relatives and recorded in the case-report form that included disease onset, initial presenting features, antecedent events, alcohol intake, drug misuse and any comorbid conditions. A thorough assessment of general condition, conscious state, neurological, ophthalmological and psychiatric status was performed.

Laboratory tests. All patients underwent screening blood tests including complete blood count, ESR, liver and renal function tests, serum electrolytes, blood glucose levels, thyroid function, serum protein electrophoresis, anti ds-DNA and antinuclear antibodies, HIV antibodies and toxicology screening (for suspected cases). CSF analysis was done for 6 patients (normal chemistry and cytology results).

Digital EEG record and Brain MRI were carried out for all patients during the acute stage.

Digital EEG records. EEGs were carried out to all included patients for at least 20 min in each patient using a 32-channel NIHON KOHDEN – Neurofax, EEG–9000 Ver. 05-71 (EEG-9200k, CE). All EEGs were done under standard conditions, using hyperventilation for 3 minutes whenever possible and intermittent photic stimulation for all patients to provoke any existing abnormalities. The EEG records were interpreted based on careful visual analysis by two of the authors (H.H. and H.S.) in the same setting according to definitions of the International Federation of Clinical Neurophysiology¹⁴. EEG traces were inspected as regards frequency, amplitude and symmetry of the background activity, as well as the presence of any abnormalities.

MRI Brain. MRI brain studies were done at National Cancer Institute and Radiology Department in Cairo University. Images were interpreted by same radiologist (N.A.) and they were obtained on a superconducting 1.5 Tesla, MR unit (Signa Horizon, GE medical systems, Milwaukee, Wisconsin, USA).

Imaging sequences included T1 WI (TR, 300-700; TE, 18-25), T2 WI (TR, 3500-5000; TE, 87-110) and fluid-attenuated inversion recovery (FLAIR) (TR, 5000-7000; TE, 100-127). Enhanced scanning by gadolinium contrast was adopted for all patients. All patients underwent their images without anesthesia, and motion artifacts were present in 4/11 patients (36%); however, they were included as the radiologist considered them to have an acceptable diagnostic quality.

Follow up. Patients were followed up clinically during their hospitalization period; monthly after discharge for 6 months; every 3 months for 6 months; and then every 6 months for a period of 1-4 years. Radiological follow up was performed every 6 weeks for 3 months until lesions are no more visible.

 

RESULTS

 

Patients’ demography and medical histories: We identified 11 Egyptian patients with WE; age range was from 24 to 58 years (mean±SD: 40.18 ± 11.45 years). Two patients (18.2 %) in our series had history of chronic alcohol abuse; whereas, the other 9 patients (81.8 %) denied any history of alcohol intake. Table (1) displays basic demography and medical histories.

Initial neurological presentations: Subacute onset of condition (over 3 to 7 days) was reported in 9/11 patients (81.8 %); a more protracted course (over a period of 2 weeks) was recorded in 2/11 patients (18.2%) (patients number 5 and 8). The most frequent presenting neurologic finding was encephalopathy in 7/11 patients (63.6%). Two patients (18.2 %) presented with gait ataxia, and 2 patient (18.2 %) presented with the classic triad of the disease; eventually all other included patients showed the triple-symptom complex of conscious level alteration, ataxia and ocular motility abnormalities.

Clinical features. The most heralding feature was conscious state changes that showed a broad clinical spectrum ranging from mild disorientation to time and persons with short attention span to coma. In all patients, disturbed wake/sleep cycle and mental incontinence were recorded. Coordination deficits were either assessed clinically or reported by relatives in non-cooperative patients. Horizontal nystagmus and sluggish pupillary reflexes were found invariably in all patients. Variable clinical features on neurological examination are shown in Table 2.

EEG findings. All EEG traces showed either normal records (n= 9) or mild generalized (non-lateralized) slowing (n=2).

MRI findings. Image characterization. All patients had typical MR findings of acute WE that showed areas of high signal alteration in T2-weighted and/or FLAIR and hypointensities or no abnormalities on T1. Anatomic regions. Images showed symmetrical signal intensity alteration that involved medial thalami (n=11), periventricular region of the third ventricle (n=9), periaqueductal area (n=9), tectal plates (n=11), periventricular gray matter located anterior to the fourth ventricle (n=8) and mamillary bodies (n=9), and capita of caudate (n=2) (Figures 1 and 2). Contrast medium was administered to all included patients; with 7 patients (63.6 %) showed contrast enhancement. The anatomic regions that most frequently enhanced were the mamillary bodies (6 patients), followed by the tectal plate (4 patients), thalamus (4 patients), periaqueductal area (3 patients).

In our case series; majority of patients (9/11) whether alcoholic or non-alcoholic had typical MRI findings of acute WE and the degree of conscious level alteration was related to the lesions load in their MRI images. The only detected difference in the alcoholic patients was the more contrast enhancement of the detected lesions.

Two non-alcoholic patients (18.2%) with deep coma exhibited increased T2-weighted and FLAIR signal intensities, not only in the bilateral medial thalami but also in the capita of the caudate nuclei (Figure 2). No atrophy of the cerebellar vermis or mammillary bodies was observed in any patient.

Treatment strategies and outcome. All patients were subjected to parenteral thiamine (B complex preparation) once diagnosis was established. Intravenous 50 mg / day thiamine was maintained throughout hospitalization period; range (mean ± SD): 7 – 12 days (9.18 ± 1.83). Multivitamin B tablets continued upon discharge. Improvement was detected during hospital course within 3-4 days; the first symptom to improve was ophthalmoplegia, followed briefly by the mental confusion. Incoordination showed relative improvement but minor neurologic residuals were the only signs thereafter mostly in the form of wide base gait and needed minimally assisted walking after having undergone a special physiotherapy program. Clinical improvement showed a plateau by 6 months. Patient no. 8 regained her consciousness but developed signs of Korsakof psychosis. Patient no. 5 died (2 moths later), and her death is mostly attributed to her malignancy. Table 3 shows neurological examination of included patients 6 weeks after initial treatment.

Follow up brain MRI. Patients had their follow up MRI brain 6 weeks after initial diagnosis, in all of them images showed marked resolution of the previously detected lesions as well as its post-contrast enhancement, and lesions disappeared by 3 months,  except case no. 8, with KS, who showed cortical atrophy and persistent damage on the follow-up study.

 

Table 1. Demography and main medical features.

 

No.	Age/Sex	Onset (d)	Medical history
1	32/M	4	HCV +, elevated liver enzymes (double fold), normal synthetic liver functions and no cirrhosis. High serum manganese level.
2	46/M	3	Chronic alcohol abuse. Normal liver status.
3	51/M	2	Chronic alcohol abuse, onset after 2 episodes of heavy drinking. Normal liver status.
4	24/F	3	Hyperemesis gravidarum (10th week). Vomiting for 6 weeks.
5	58/F	10	Cancer pancreas (7 months). Treatment: surgery and chemotherapy. Episodic vomiting for 2 weeks.
6	39/F	5	Bariatric surgery: malabsorptive, 3 months before onset.
7	32/F	7	Hyperemesis Gravidarum (12th week). Vomiting  for 5 weeks.
8	58/F	13	Multiple Myeloma, received Bortezomib with recurrent vomiting (3 weeks)
9	31/F	6	Hyperemesis Gravidarum (14th week). Vomiting for 4 weeks.
10	36/M	6	Bariatric surgery: gastric bypass with repeated vomiting afterward, 2 months before onset.
11	35/F	7	Hyperemesis Gravidarum (11th week). Vomiting for 4 weeks.

Table 2. Variable neuro-ophthalmological manifestations.

 

Patient No.	Encephalopathic manifestations	Coordination deficits	Ocular signs	Additional features
1	Confusion, inattention and visual hallucinations	Gait ataxia	Bilateral lid retraction and vertical gaze palsy	Bilateral upgoing plantar response
2	Delirious, agitation, stereotypical visual and tactile hallucinations and delusions of persecution and infidelity	Gait and limbs ataxia	Bilateral partial ophthalmoplegia (asymmetric LR palsy)	Depressed ankle DTJ
3	Delirious, fluctuating aggressive behavior and intense fear, disturbed coherent thoughts and delusional misinterpretation	Gait and limbs ataxia	Bilateral partial ophthalmoplegia (asymmetric LR palsy)	Absent ankle DTJ
4	Confusion, disorientation to time and persons, short attention span, aggressive behavior and lack self hygiene	Gait and limbs ataxia	Bilateral partial 3rd nerve palsy	Bilateral upgoing plantar response
5	Initially: agitation, disorientation and inattention; later on: reduced conscious level and obtunded (GCS: 7)	Gait ataxia (history)	Bilateral partial ophthalmoplegia (asymmetric LR palsy)	Bilateral upgoing plantar response
6	Incoherence, flight of ideas, impaired active attention, distractibility, psychomotor hyperactivity and disinhibition	Limbs ataxia	Rt. partial, Lt. complete LR palsy and ptosis
7	Blurred thinking, disorientation and inappropriate answers	Limbs ataxia	Bilateral LR palsy and ptosis
8	Initially: mental dullness, absent spontaneous speech with abulia-like features; later on: deep coma (GCS: 3)	Gait ataxia (history)	Absent VOR (on time patient was seen). Later ophthalmoparesis (left LR palsy and right ptosis)	Bilateral upgoing plantar response
9	Disorientation, delayed reaction time, poor judgment and infrequent visual hallucinations	Limb ataxia	Bilateral partial ophthalmoplegia (asymmetric LR palsy)
10	Delirious, incoherent speech and visual hallucinations	Limb ataxia	Bilateral partial ophthalmoplegia (asymmetric LR palsy)
11	Mild disorientation and poor judgment	Gait and limb ataxia	Bilateral partial 3rd nerve palsy

DTJ Deep tendon jerk, VOR Vestibuloocular reflex, LR lateral rectus, GCS Glasgow coma scale

                            

.

Figure 1. Axial FLAIR of  Patient no.4 (Twenty four year, female with hyper-emesis gravidarum) showing hyperintensity in quadrigeminal plate (A) and medial thalami (B).

 

Figure 2. Axial T2 WI of Patient no. 5 (Fifty eight year female who had cancer pancreas) showing hyperintensity in tectal plate and periaqueductal gray matter (A) and capita of caudate (B)

 

Table 3. Neurological manifestations 6 weeks after treatment initiation.

 

Patient No.	Encephalopathic manifestations	Coordination deficits	Ocular signs
1	Disinterest and mild inattentiveness. Difficulties in handling finances	Some slurred speech	Left gaze-evoked nystagmus
2	Memory gaps and short attention span	Absent	Normal examination
3	Difficult multitasking, planning and organizing objects. Depressive symptoms	Absent	Normal examination
4	Absent	Mild unsteadiness	Nystagmus
5	Memory distrust, infrequent repetitiveness and misplacement of familiar objects	Mild unsteadiness	Nystagmus
6	Absent	Absent	Normal examination
7	Absent	Mild unsteadiness	Nystagmus
8	Korsakoff’s psychosis: apathetic severe memory loss, confabulation and lacking insight	Unsteady gait	Mild left LR paresis
9	Memory lapses, difficulties in mixing up words and forgetfulness of events’ details. Depressive symptoms	Absent	Normal examination
10	Short attention span and occasional failure of retrieving familiar data	Bilateral mild upper extremities kinetic tremor	Nystagmus
11	Non significant reasoning disturbances and subtle personality changes (rigidity, obsessions and uneasiness)	Mild unsteadiness	Nystagmus

 

DISCUSSION

 

The paucity of diagnosis of WE in Egypt, due to the lack of the issue of alcoholism in the Egyptian society because of the social and religious backgrounds, has made us cautious about selecting patients who were diagnosed according to combined typical clinical and radiological criteria. This contributed to the limited number of patients, who were recruited over a relatively protracted period of time, in our series. More patients could have been included if we considered only the clinical presentation as about 50% of patients with Wernicke's encephalopathy may exhibit normal brain MRI¹⁵.

The mentally established link between WE and alcohol intake renders diagnosis WE in settings other than alcoholism unlikely, though many other medical conditions do predispose to thiamine deficiency⁸. In addition, to chronic alcohol intake, hyperemesis gravidarum, malignancy, bariatric surgery and HCV were encountered in our patients.

Hyperemesis gravidarum was encountered in 4 female patients. Pregnancy itself represents an increased thiamine consumption state¹⁶ and hyperemesis causes increased depletion¹⁷. Several reports have pointed to hyperemesis gravidarum as an underrecognised cause for WE, thus recommending the parentral intake of large doses of thiamine especially prior to dextrose infusion^17-20.

Malignancy was encountered in 2 patients; 1 had cancer head of pancreas, she received dextrose infusion without thiamine; and the other had multiple myeloma and was receiving Bortezomib. Both experienced repeated vomiting for 2-3 weeks.  Generally, thiamine requirements increase during malignancy because of chronic malnutrition (starvation state), chemotherapy-induced nausea and vomiting, and consumption of thiamine by rapidly growing tumors (depletion state)²¹. In addition, administering glucose in a thiamine deficient state exacerbates the process of cell death because of glucose oxidation is a thiamine -intensive process that may drive the insufficient circulating vitamin B1 intracellularly, thereby, precipitating and aggravating neurological injury²².

Two patients have undergone bariatric surgery for morbid obesity (BMI ≥ 40)²³.  Bariatric surgery aims at weight loss which is usually achieved by restrictive surgery, malabsorbitive surgery, or by mixed surgery²⁴. They presented after 2-3 months from surgery. Thiamine deficiency may occur after gastric bypass surgery due to reduced acid production, restriction of food intake, and frequent episodes of vomiting²⁵. In our series, patient with restrictive surgery developed repeated vomiting which persisted for 2 weeks, and received TPN including IV glucose without thiamine.  The body cannot store thiamine and can only store up to 30 mg in its tissues. The half life of thiamine is about 3 weeks ².Thus the occurrence of symptoms 4-12 weeks after surgery would reflect thiamine stores depletion.

In alcohol abuse, thiamine deficiency can result from a combination of factors including malnutrition, poor gastrointestinal absorption due to gastric disease and a loss of liver thiamine stores associated with alcoholic liver disease. In addition, ethanol directly inhibits the transport of thiamine in the gastrointestinal tract. Ethanol also inhibits the phosphorylation of thiamine to its active diphosphate ester, which is required for cellular energy metabolism^1,26. Two patients, in this series, were alcohol consumers.

The last patient in this series was positive for HCV with 2 fold elevation of liver enzymes but no evidence of liver cirrhosis and normal synthetic liver functions. An extensive laboratory work up was done to identify a cause for his condition, and the only positive finding was a high serum manganese level. To our knowledge, a metabolic interrelationship between manganese and vitamin B1 has been reported in experimental rats by Sandberg and associates (1939) who reported that the toxic effects of excess vitamin B1 could be prevented by adding manganese to the diet of rats²⁷. As manganese is primarily cleared by the liver, inadequate elimination of manganese absorbed from the normal diet may lead to manganese overload in patients with liver disease²⁸. Having the clinical triad and typical MRI findings of WE together with the significant improvement after parenteral thiamine would suggest revision of the role of HCV without cirrhosis in WE as well as the relation between manganese and vitamin B1.

Noticeably, the 2 patients with malignancy had a relatively protracted onset over 10-14 days, whereas the clinical picture usually develops within less than a week¹. Generally, delirious state was the initial symptom ranging from impaired attention, mild confusion and cognitive impairment up to aggressive behavior and psychotic features. Interestingly, patients with malignancy first presented with ataxia before passing to altered consciousness.  Certain clinical features dominated according to various predisposing factors; those with history of alcohol consumption exhibited noticeable agitation together with psychotic features; females with hyperemesis tended to have a hypermotor confusion with evident restlessness and incoherence of ideas; for those with malignancy,   the clinical presentation was dominated initially by striking inattention and later on development of various degrees of coma. Gait ataxia was present in most patients, however, patients with hyperemesis experienced limb incoordination. Ophthalmoplegia was bilateral but asymmetrical reflecting involvement of 6^th nerve nucleus, followed by 3^rd nerve affection, in addition to midbrain vertical gaze centre.

Initially, many differential diagnoses were proposed including encephalitis, lupus cerebritis, hepatic encephalopathy, HIV encephalopathy, and side effects of chemotherapy. These initial diagnoses were excluded based on normal metabolic and immunological work up and on EEG records which showed nonspecific slowing in only 2 patients only indicating non specific pathology. EEG is a non specific measure of clinical state as it shows a limited number of abnormalities in widely varied diseases, on the other hand an abnormal EEG is a sensitive measure of brain function when the patient has clinically symptomatic encephalopathy where the EEG changes are usually proportional to the degree of encephalopathy²⁹.

Eventually, the neuroradiologic findings on MR imaging came to resolve the conflict and verify WE. The main criterion to include was typical findings in MRI of the brain. Our findings showed symmetric hyperintensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images; symmetric hypointensity or no abnormalities on T1-weighted images; and symmetric areas of contrast enhancement after gadolinium injection in the thalamus, periventricular region of the third ventricle, mamillary bodies, periaqueductal area, tectal region, periventricular gray matter of the fourth ventricle (typical findings); these specific brain areas showed bilaterally symmetrical lesions reflecting the systemic pathology of the disorder. These regions have the highest thiamine content and turnover. The defective blood–brain barrier in WE in the periventricular regions, in which there is a high rate of thiamine-related glucose and oxidative metabolism are contributory for these findings, resulting in reversible cytotoxic edema^30,31.

An appealing point was that patients with WE in this series showed relatively good prognosis with a parentral dose of thiamine not exceeding 50 mg/day compared to doses ranging from 200-500 mentioned in literature^32,33. Such striking difference in response to thiamine dose can be attributed to ethnic-genetic variation between Western population and those in the Middle East regarding transketolase (TK) enzyme. There is a difference in binding affinity between TK and its co factor, TPP, found in different racial groups. There is an indication that thiamine deficiency only leads to WK syndrome in those whose TK has a reduced affinity for thiamine³⁴. Those with higher affinity can show a relatively good response to lower thiamine doses³⁵ which seems to be the case in our patients. The disappearance of lesions and absence of enhancement on the follow up reflect restoration of thiamine levels in vulnerable areas.

Conclusion

In Egypt, WE is an underrecognised condition, and is usually diagnosed only in settings of alcoholism, identification problems are attributed to the absence of antecedent alcohol overdrinking in majority of cases. This study verifies that WE should be considered in other situations associated with malnutrition or depletion states, and encourages diagnosis even in the absence of typical clinical triad or MRI findings.

 

[Disclosure: Authors report no conflict of interest]

 

REFERENCES

 

1.        So YT, Simon RP. Deficiency diseases of the nervous system. In: Bradely WG, Daroff RB, Fenichel GM, Jankovic J, editors. Neurology in clinical practice, 4^th ed.. The neurological disorders., Philadelphia: Elsevier; 2008.

2.        Sechi G, Serra A. Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol. 2007;6(5):442-55.

3.        Zuccoli G, Gallucci M, Capellades J, Regnicolo L, Tumiati B, Cabada Giadás T, et al. Wernicke encephalopathy: MR findings at clinical presentation in twenty-six alcoholic and nonalcoholic patients. AJNR. 2007; 28:1328-31.

4.        Caine D, Halliday GM, Kril JJ, Harper CG. Operational criteria for the classification of chronic alcoholics: identification of Wernicke's encephalopathy. J Neurol Neurosurg Psychiatry. 1997; 62:51 –60.

5.        Harper C, Fornes P, Duyckaerts C, Lecomte D, Hauw JJ. An international perspective on the prevalence of the Wernicke- Korsakoff syndrome. Metab Brain Dis. 1995;10,17–24.

6.        Cooper JR, Pincus JH. The role of thiamine in nervous tissue. Neurochem Res 1979; 4:223-39.

7.        Chaves LC, Faintuch J, Kahwage S, Alencar FA. A cluster of polyneuropathy and Wernicke-Korsakoff syndrome in bariatric unit. Obes surg. 2002;12:328-34.

8.        Ogershok PR, Rahman A, Nestor S, Brick J. Wernicke encephalopathy in nonalcoholic patients. Am J Med Sci. 2002;323:107–11.

9.        Fei G-q, Zhong C, Jin L, Wang J, Yuhao Zhang, Zheng X, Yuwen, et al. Clinical Characteristics and MR Imaging Features of Nonalcoholic Wernicke Encephalopathy. AJNR. 2008;  164-9.

10.     Zuccoli G, Pipitone N. Neuroimaging Findings in Acute Wernicke's Encephalopathy: Review of the Literature. AJNR. 2009; 192: 501-8.

11.     Zuccoli G, Motti L. Atypical Wernicke's encephalopathy showing lesions in the cranial nerve nuclei and cerebellum. J Neuroimaging. 2008; 18: 194-97.

12.     Kalidass B, Sunnathkal R, Rangashamanna DV, Paraewani R. Atypical Wernicke's Encephalopathy Showing Involvement of Substantia Nigra. J Neuroimaging. 2010 Dec 1. doi: 10.1111/j.1552-6569.2010.00545.x. [Epub ahead of print]

13.     Rufa A, Rosini F, Cerase A, Giannini F, Pretegiani E, Buccoliero R, et al. Wernicke encephalopathy after gastrointestinal surgery for cancer: causes of diagnostic failure or delay. Int J Neurosci. 2011;121(4):201-8.

14.     Noachtar S, Binnie C, Ebersole J, Mauguière F, Sakamoto A, Westmoreland B. A glossary of terms most commonly used by clinical electroencephalographers and proposal for the report form for the EEG findings. The Internationa Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol (Suppl). 1999; 52: 21-41.

15.     Antunez E, Estruch R, Cardenal C, Nicolas JM, Fernandez-Sola J, Urbano-Marquez A. Usefulness of CT and MR imaging in the diagnosis of acute Wernicke's encephalopathy. AJR Am J Roentgenol. 1998;171(4):1131.

16.     Wood P, Murray A, Sinha B, Godley M, Goldsmith HJ.  Wernicke's encephalopathy induced by hyperemesis gravidarum. Case reports. Br J Obstet Gynaecol. 1983; 90: 583–6.

17.     Indraccolo U, Gentile G, Pomili G, Luzi G,  Villani C. Thiamine deficiency and beriberi features in a patient with hyperemesis gravidarum. Nutrition.  2005;21(9):967-8.

18.     Togay-Işikay C, Yiğit A, Mutluer N. Wernicke's encephalopathy due to hyperemesis gravidarum: an under-recognised condition. Aust NZJ Obstet Gynaecol. 2001;41(4):453.

19.     Chiossi G, Neri I, Cavazzuti M, Basso G, Facchinetti F. Hyperemesis gravidarum complicated by Wernicke encephalopathy: background, case report, and review of the literature. Obstet Gynecol Surv. 2006;61(4):255.

20.     Santos AC,   Tavares LL, Da Graça MM,  Joaquina MM, Pezzi PL, Scarabôtolo GG, et al. Non-alcoholic Wernicke's encephalopathy: broadening the clinicoradiological spectrum. Br J Radiol. 2010; 83(989): 437-46.

21.     Guo-Hui S, Yun-Sheng Y, Qing-Sen L, Liu-Fang C, Xu-Sheng H. Pancreatic encephalopathy and Wernicke encephalopathy in association with acute pancreatitis: A clinical study. World J Gastroenterol. 2006;14;12(26):4224-7.

22.     Plum F, Posner JB. Diagnosis of Stupor and Coma, 3^rd ed. Philadelphia: FA Davis Co.; 1980.

23.     World Health Organization. 2000, p.9.

24.     Malcolm K.R. Editorial, Surgical treatment of obesity -- weighing the facts, N Engl J Med. 2009 July 30;361:520.

25.     Aesheim ET. Wernicke encephalopathy after bariatric surgery: a systematic review. Ann Surg. 2008;248(5):714-20.

26.     Butterworth R.  Thiamine deficiency and brain disorders. Nutr Res rev. 2003; 16:277-83.

27.     Sandberg M, Perla D, Holly M. Interdependence of vitamin B1 and manganese. Manganese, copper, iron metabolism in B1 deficient rats. Ibid., 42:368. Cited in: Anderson BM, Parker HE. The effects of dietary manganese and thiamine levels on growth rate and manganese concentration in tissues of rats1-2. J Nutr. 1955 Sep 10;57(1):55-9.

28.     Hauser R, Zesiewicz T, Rosemurgy A, Martinez C, Olanow C. Manganese intoxication and chronic liver failure. Ann Neurol. 1994;36(6):871-5.

29.     Geller E. Generalized disturbances of brain function: encephalopathies, coma, degenerative diseases, and brain death. In: Levin KH, Luders HO, eds. Comprehensive Clinical Neurophysiology. Philadelphia, Pa: WB Saunders; 2000. pp.438-55.

30.     Suzuki S, Ichijo M, Fujii H, Matsuoka Y, Ogawa Y. Acute Wernicke's encephalopathy: comparison of magnetic resonance images and autopsy findings. Intern Med. 1996;35 : 831–4.

31.     Harper C, Butterworth RF. Nutritional and metabolic disorders. In: Graham DI, Lantos PL, editorss. Greenfield's neuropathology, 6th ed., volume 1 London, UK: Hodder Arnold, 1997: 601-52.

32.     Thomson A, Cook C, Touquet R, Henry J. The royal college of physicians report on alcohol: guidelines for managing wernicke’s encephalopathy in the accident and emergency department Alcohol Alcoholism. 2002;37(6): 513 – 521.

33.     Thomas P, Elias T, Dimitris K, Anastasios K,  Ioannis L. Complete recovery from undertreated HYPERLINK "http://www.biomedexperts.com/Abstract.bme/20364001/Complete_recovery_from_undertreated_Wernicke-Korsakoff_syndrome_following_aggressive_thiamine_treatment"Wernicke-KorsakoffHYPERLINK "http://www.biomedexperts.com/Abstract.bme/20364001/Complete_recovery_from_undertreated_Wernicke-Korsakoff_syndrome_following_aggressive_thiamine_treatment" syndrome following aggressive thiamine treatment. In vivo (Athens, Greece). 2010; 24(2): 231-3.

34.     Blass JP , Gibson, G.E. Abnormality of a thiamine-requiring enzyme in patients with Wernicke-Korsakoff syndrome. The New England Journal of Medicine 297(25):1367-1370, 1977.

35.     Cox M, Nelson D, Lehninger A. Lehninger principles of biochemestry. San Fransisco: Freeman WH; 2005.