• Sign Up

Marchiafava Bignami Disease


Marchiafava Bignami Disease

Article Author:
Terrence Tian
Article Author:
Marco Pescador Ruschel
Article Author:
Sunhee Park
Article Editor:
John Liang
Updated:
8/24/2020 12:09:01 AM
For CME on this topic:
Marchiafava Bignami Disease CME
PubMed Link:
Marchiafava Bignami Disease

Introduction

Marchiafava-Bignami disease (MBD) is a very rare disorder of demyelination/necrosis of the corpus callosum and the near subcortical white matter that is especially predominant in ill-fed alcoholics[1]. It was discovered in 1903 by Italian pathologists Ettore Marchiafava and Amico Bignami. They described men with alcohol use disorder who died of seizures and coma that presented necrosis of their corpus callosum on autopsy. However, few cases have been described in non-alcoholic patients, suggesting that alcohol is not the sole responsible for these lesions[2].

The disease can be acute, subacute, or chronic. The clinical picture is marked by dementia, dysarthria, spasticity, and walking inability. Also, patients may enter into a coma or a demented condition for many years, and spontaneously recover or die[3][4].

Lesions can appear as hypodense regions of the corpus callosum on tomography, and as areas of diminished T1 signal and increased T2 signal on magnetic resonance. Also, an interhemispheric disconnection syndrome has been found in survivors. Alcoholic patients without hepatic disease, amnesia, or cognitive dysfunction present thinning of the corpus callosum on autopsy and neuroimaging (magnetic resonance) suggesting that alcohol or malnutrition can commonly damage the corpus callosum without the necrotic lesions of MBD. These findings can conclude in the possibility of aggressive nutritional supplementation with a reduction in drinking to prevent the development of MBD in alcoholic patients[5][6][7].

Etiology

The etiology of the disease is still unclear, but it is presumably attributed to the combination of alcohol-induced neurotoxicity (with an uncertain nature) and deficiency of the B-complex vitamins [8]. Other causes can be:

  • Sudden fluctuation in serum osmolality, known as callosal myelinolysis, as a complication of ketoacidosis caused by diabetes mellitus or alcoholism[9].
  • Non-alcoholic malnourishment After Gastric Bypass Surgery[10].
  • It has been related to other non-alcoholic conditions such as carbon monoxide poisoning, sepsis, cerebral malaria, sickle cell disease, and cardiac carcinoma surgery[11][12][13].

Epidemiology

It is most commonly discovered in malnourished patients with chronic alcohol use disorder[14]. However, cases have been described in patients without alcohol use disorder, especially individuals with poorly controlled diabetes mellitus[13][9][15]. Marchiafava-Bignami Disease occurs with no ethnic, racial, or geographic predilection. However, there is a higher incidence in men, probably because of its closer association with alcohol consumption than women[16][17]. The mean age of onset is 45 years[18] It is a very rare condition. In the United States, one study found 250 published cases were reported before 2001, suggesting it is likely many cases have gone undiagnosed[19]. International data is similar, always reminding that the prevalence is underestimated because of the non-autopsied patients[19]. Published in approximately 300 case reports.

Pathophysiology

MBD pathophysiology is unclear. However, there are some explanations for it:

  • Ethanol is an important risk factor for various brain disorders, depending on the amount and frequency of its use. Alcohol-associated hypovitaminosis, mainly B1 (due to gastrointestinal direct effect, liver damage-induced metabolic disturbance, reduced re-absorption by renal tubular cells, increased skeletal and visceral protein catabolism, abnormal lipid metabolism, or dietary deficiency) and oxidative stress may directly damage the corpus callosum producing an initial phase of cytotoxic edema and breakdown of the blood-brain barrier, and a later phase of focal demyelination and necrosis, consequently resulting in atrophy[8][20][8].
  • Alcohol alters neurotransmitter activity, disables neuronal plasticity, interferes with lipid metabolism, and influences the expression of proteins responsible for attaching cytoskeletal elements in the white matter[21]. Ethanol can also be metabolized in the central nervous system through an oxidative process by the aldehyde dehydrogenase (ADH) pathway, especially in the cerebellum and hippocampus, using nicotinamide adenine dinucleotide (NAD+) as a cofactor and, thus, resulting in an oxidative stress disorder[22]. Another conversion pathway is through CYP2E1 which, when increased, promotes increases in concentrations of acetaldehyde and reactive oxygen species which in turn lead to oxidative stress and neuronal damage[23][24][23].
  • B1 vitamin (thiamine) deficiency produces neurological impairment by affecting the carbohydrate metabolism process, reducing the available ATP (adenosine triphosphate), which later induces the inhibition of catechol-O-methyl transferase activity, therefore increasing the activation of catecholamine neurotransmitters such as dopamine, which in turn can result in delirium, hallucinations, and delusions[25][26]. There is also a reduction in the synthesis of other neurotransmitters such as acetylcholine, glutamate, GABA, which all may be linked to inadequate PHD (pyruvate dehydrogenase) functioning, leading to failure in myelin and glutathione synthesis, therefore impairing the neuronal ability of signal conduction and self-defense against oxidative stress[27].
  • Damage of the corpus callosum can be explained because of high myelin content, being the major white matter commissure that connects both of the hemispheres and facilitates the exchange of cognitive, sensory, and motor information[4].

Histopathology

Histologic diagnosis is performed almost exclusively in a post-mortem autopsy. Diagnostic biopsy in the antemortem patient is rare, and always as a casual finding.

Macroscopic histopathologic features in the corpus callosum (especially in the genu and the body) can consist of necrotizing or cystic lesions. Microscopically there can be white matter necrosis, abundant macrophages (with little inflammatory reaction), foamy histiocyte infiltration (marked by CD68 and CD163), small perivascular lymphocytes (mainly CD3-positive T-cells and incidental CD20-positive B cells), gliosis and prominent demyelination (with relative sparing of the axons) that can extend symmetrically into the centrum semiovale. Oligodendrocytes are reduced in number[28][29][28][28][28].

Other anatomical sites affected by demyelination can be:

  • Anterior and posterior commissures.
  • Optic chiasm.
  • Middle cerebral peduncles.
  • Brachium pontis.
  • Cortex (lesions supposed to be secondary to the callosal damage. May cause frontal-lobe syndromes and dementia).

History and Physical

Although clinical features may be quite variable and nonspecific, MBD should be suspected in patients with chronic alcohol abuse and/or malnutrition who present with certain common neurological symptoms. These symptoms can include psychotic and emotional disorders that can appear somewhat in an acute, subacute, or chronic form[8][30][31][32][28]:

  • Acute presentation is characterized by a sudden onset of loss of consciousness and seizures. Also, other features can be apathy, aggressiveness, confusion, seizures, and psychosis. 
  • Subacute features can be depression, ataxia, apraxia, agraphia, anomia, dysarthria, visual dyslexia. Some of these can be a part of an interhemispheric disconnection syndrome, with a unilateral presentation.
  • Chronic forms can present as progressive severe global dementia, visual hallucinations, auditory delusions, and behavioral abnormalities. Also, there can be signs of interhemispheric disconnection syndrome.

Another pattern of classification, according to clinical status and brain injury detectable by magnetic resonance can be:

  • Type A
    • Great deficit of consciousness, seizures, dysarthria, and hemiparesis.
    • Hyperintense swelling of the corpus callosum can be observed.
    • Associated with a worse prognosis.
  • Type B
    • Presents with dysarthria, gait disturbance, interhemispheric disconnection symptoms, and less impairment in consciousness.
    • Only partial callosal lesions on magnetic resonance.
    • Associated with a better prognosis.

Evaluation

Evaluation relies heavily on imaging findings and correlation with a thorough history and physical exam:

  • Neurological function can be evaluated by the Modified Oxford Handicap Scale (MOHS), and the modified Rankin Scale (mRS).
  • Cognitive function can be assessed by the Abbreviated Mental Test (AMT), the Montreal Cognitive Assessment (MoCA), or the Mini-Mental State Examination (MMSE).
  • Severity of impaired consciousness can be evaluated by the Glasgow Coma Scale (GCS).
  • Evaluation of alcohol consumption can be assessed by the Michigan Alcoholism Screening Test (MAST-C).

Laboratory exam can be useful through the following:

  • Serum electrolytes, to discard electrolytes disorders that can cause coma, consciousness impairment, and seizures.
  • Serum transaminases and bilirubin to assess liver damage.
  • Serum glucose, to discard hypo/hyperglycemia.
  • Complete blood count (suspect alcohol abuse disorder if there are signs of macrocytosis or macrocytic anemia), to determine infectious/inflammatory causes and to assess the hemoglobin and platelet levels.
  • Toxicology screening, to discard abuse of other substances.
  • Serum and spinal fluid infectious serology panel, to determine systemic or central nervous system infections.

Magnetic Resonance Imaging (MRI) is the gold standard imaging study of choice although CT may reveal hypodense lesions in the corpus callosum, especially the central portion[31]. The typical pathognomonic features on MRI are symmetrical lesions on the corpus callosum, usually restricted to the genus, body, or splenium[33]:

  • In the acute stage, the impaired area has cytotoxic edematous changes with or without demyelination: hyperintense T2-weighted/Fluid-attenuated inversion recovery (FLAIR) and diffusion-weighed imaging (DWI) signals in the middle layer of the corpus callosum (sandwich sign)[31][34]. Lesions may also be found in other parts of the brain, including the cerebral lobes, hemispheric white matter, and basal ganglia, which indicates a poorer prognosis.
  • As the acute stage passes, the edema resolves, and hyperintensities on MRI may normalize. If diagnosed and treated early, MRI may demonstrate a complete resolution of the lesions in the corpus callosum[33]. However, in untreated patients (and in those who don't respond to treatment), there will be permanent demyelination and necrosis, and MRI will show thinning and atrophy of the corpus callosum and cystic transformation[14][33].
  • In one study, Estruch et al. compared MRI findings of 28 males with chronic alcohol use disorder with 14 subjects who were non-alcoholic and found statistically significant differences between the group with alcohol use disorder and the control group in the mean of all planimetric brain indices calculated. They found the group with alcohol use disorder had a significant reduction in anterior thickness, middle thickness, posterior thickness, corpus callosum area, corpus callosum percentage, frontal lobe index, and cortical sulci size compared to the control group. Estruch et al. found the mean corpus callosum body area of two-thirds of the subjects in the group with alcohol use disorder were less than two standard deviations of the mean of the subjects in the control group. There was an 18% decrease in genu size, a 16% decrease in truncus size, and a 15% decrease in splenium in the group with alcohol use disorder compared to the control group[14]. Thinning of the corpus callosum can also be seen on autopsy. Furthermore, Estruch et al. were able to show a correlation between increasing lifetime dose of alcohol consumption and reduction of corpus callosum indices[14].

Treatment / Management

There are no management guidelines or specific proven treatment to date. Management is similar to the one for Wernicke-Korsakoff syndrome or alcohol abuse disorder. Most of the case reports of MBD have shown a favorable response to the endovenous administration of thiamine, folate, and vitamin B complexes as well as high-dose corticosteroids[15][18][31][34]. Some case reports show significant improvement with high-dose endovenous thiamine intravenously (500 mg/tid), oral vitamin B complex, amantadine, and folate[18][35]. Management also includes aggressive nutritional supplementation and, undoubtedly, alcohol withdrawal. Treatment can be administered as follows:

  1. Thiamine, in normal saline or 5% dextrose[36][37][38][36]:
    • Alcohol withdrawal syndrome: 100 to 250 mg/QD IV/IM for 3 to 5 days, followed by 100 mg/tid orally for 1 to 2 weeks. Concluding with 100 mg/QD orally. Adding benzodiazepines is almost always necessary in these patients.
    • Properly MBD or Wernicke encephalopathy:
      • Prophylaxis: 100 to 250 mg/QD IV/IM for 3 to 5 days, followed by 100 mg/tid orally for 1 to 2 weeks. Concluding in 100 mg/QD orally.
      • Treatment: 200 to 500 mg/tid IV for 2 to 7 days. If the response is adequate, continue with 250 mg/QD IV/IM for 3 to 5 days (or until there is a maximum clinical improvement) followed by 30 mg/bid orally or 100 mg/tid orally for 1 to 2 weeks, concluding with 100 mg/QD orally.
  2. B Complex pills can be administered as needed.
  3. Amantadine[39][40]: although its mechanism is unknown, and it has not been proven effective through scientific rigorous data, it may probably benefit the patient's symptoms through its dopaminergic effect. The usual dose, in the treatment of extrapyramidal symptoms, is 100 mg/bid orally.
  4. Folic acid can be administered as 1 to 5 mg/QD orally to treat or prevent megaloblastic and macrocytic anemias.

Differential Diagnosis

The following differentials may be considered in all patients with acute delirium or acute ataxia, or structural diseases that overlap in the neuroimaging findings[41][42][43][44][43]:

Nutritional impairments:

  • Wernicke encephalopathy: typically affects the hypothalamus, thalamus, and the periaqueductal grey matter. Diagnosed with 2 of the 4 Caine Criteria.
  • Vitamin B12 and folate deficiencies.

Drugs and toxins:

  • Medications (eg. opioids, sedatives, benzodiazepines)
  • Heroin and hallucinogens.
  • Methanol, carbon monoxide, cyanide, hydrogen sulfide.

Infections:

  • Sepsis.
  • Fever delirium.
  • Meningitis and encephalitis.

Metabolic impairments:

  • Endocrin disturbances: thyroid and parathyroid hormones, pituitary, and adrenal glands.
  • Electrolyte disturbances: sodium, calcium, magnesium, phosphate.
  • Hypercarbia and hypoxemia.
  • Glycemia changes.
  • Osmolarity changes.
  • Inborn metabolism disorders (eg. porphyria, Wilson's).

Central Nervous System disorders:

  • Epileptic seizures.
  • Contusion.
  • Hypertensive encephalopathy.
  • Intracranial hypertension.
  • Psychosis and dementia.
  • Multiple Sclerosis.
  • Morel laminar sclerosis (usually found in MBD patients).
  • Central pontine myelinolysis.
  • Local tumors.

Systemic disorders:

  • Heart Failure.
  • Thrombocytosis, leukemic blast cell crisis, polycythemia.
  • Acute/chronic liver failure (especially hepatic encephalopathy).
  • Acute/chronic renal failure.
  • Acute/chronic respiratory failure.

Prognosis

Disease severity is variable. A patient may survive for years with presenting symptoms, recover fully, or deteriorate into comatose state and decease. It is hypothesized that incomplete lesions with relative sparing of the superior commissure fibers are associated with better prognosis when compared with lesions extending into the convolution white matter. Extracallosal lesions, cerebral lobe impairment, severe disturbance of consciousness, and heavy alcohol consumption are associated with poor prognosis and/or severe dementia. Early diagnosis and effective treatment are therefore important to the patient’s recovery, and serial MRI has demonstrated some cases of complete disappearance of lesions with early diagnosis and treatment[33].

Pearls and Other Issues

  • MBD is a rare disorder characterized by demyelination and necrosis of the corpus callosum, especially seen in patients with alcohol abuse disorder.
  • The corpus callosum is affected in almost a pathognomonic way.
  • Clinical presentation is based on cognitive impairment, gait disturbance, seizures, and coma.
  • Diagnosis is made in a patient with alcohol abuse disorder and an MRI showing hyperintensity of the corpus callosum on T2WI and T2-FLAIR.
  • The main differentials are:
    • Wernicke encephalopathy.
    • Epileptic seizures.
    • Acute encephalitis.
    • Stroke.
    • Other demyelinating diseases.
  • There is no specific proven treatment, but parenteral thiamine is usually administered.

Enhancing Healthcare Team Outcomes

MBD is a very rare disorder that is not only difficult to diagnose but very complex to manage. With very few cases reported, it is best managed by an interprofessional team that includes internists, neurologists, nurses, therapists, and dietitians.


References

[1] Hillbom M,Saloheimo P,Fujioka S,Wszolek ZK,Juvela S,Leone MA, Diagnosis and management of Marchiafava-Bignami disease: a review of CT/MRI confirmed cases. Journal of neurology, neurosurgery, and psychiatry. 2014 Feb     [PubMed PMID: 23978380]
[2] Wenz H,Eisele P,Artemis D,Förster A,Brockmann MA, Acute Marchiafava-Bignami disease with extensive diffusion restriction and early recovery: case report and review of the literature. Journal of neuroimaging : official journal of the American Society of Neuroimaging. 2014 Jul-Aug     [PubMed PMID: 23253188]
[3] Matsuura H,Shindo K, Marchiafava-Bignami disease. QJM : monthly journal of the Association of Physicians. 2018 Oct 1     [PubMed PMID: 29788472]
[4] Hoshino Y,Ueno Y,Shimura H,Miyamoto N,Watanabe M,Hattori N,Urabe T, Marchiafava-Bignami disease mimics motor neuron disease: case report. BMC neurology. 2013 Dec 21     [PubMed PMID: 24359465]
[5] Hampel H,Teipel SJ,Alexander GE,Horwitz B,Teichberg D,Schapiro MB,Rapoport SI, Corpus callosum atrophy is a possible indicator of region- and cell type-specific neuronal degeneration in Alzheimer disease: a magnetic resonance imaging analysis. Archives of neurology. 1998 Feb     [PubMed PMID: 9482361]
[6] Wiegmann C,Mick I,Brandl EJ,Heinz A,Gutwinski S, Alcohol and Dementia - What is the Link? A Systematic Review. Neuropsychiatric disease and treatment. 2020     [PubMed PMID: 32021202]
[7] Kapogiannis D,Kisser J,Davatzikos C,Ferrucci L,Metter J,Resnick SM, Alcohol consumption and premotor corpus callosum in older adults. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2012 Oct     [PubMed PMID: 22401959]
[8] Fernandes LMP,Bezerra FR,Monteiro MC,Silva ML,de Oliveira FR,Lima RR,Fontes-Júnior EA,Maia CSF, Thiamine deficiency, oxidative metabolic pathways and ethanol-induced neurotoxicity: how poor nutrition contributes to the alcoholic syndrome, as Marchiafava-Bignami disease. European journal of clinical nutrition. 2017 May     [PubMed PMID: 28225048]
[9] Suzuki Y,Oishi M,Ogawa K,Kamei S, A patient with Marchiafava-Bignami disease as a complication of diabetes mellitus treated effectively with corticosteroid. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2012 May     [PubMed PMID: 22325074]
[10] Bachar M,Fatakhov E,Banerjee C,Todnem N, Rapidly Resolving Nonalcoholic Marchiafava-Bignami Disease in the Setting of Malnourishment After Gastric Bypass Surgery. Journal of investigative medicine high impact case reports. 2018 Jan-Dec     [PubMed PMID: 30083556]
[11] Boutboul D,Lidove O,Aguilar C,Klein I,Papo T, Marchiafava-Bignami disease complicating SC hemoglobin disease and Plasmodium falciparum infection. Presse medicale (Paris, France : 1983). 2010 Sep     [PubMed PMID: 20537852]
[12] Cui Y,Zheng L,Wang X,Zhang W,Yuan D,Wei Y, Marchiafava-Bignami disease with rare etiology: A case report. Experimental and therapeutic medicine. 2015 Apr     [PubMed PMID: 25780461]
[13] Pérez Álvarez AI,Ramón Carbajo C,Morís de la Tassa G,Pascual Gómez J, Marchiafava-Bignami disease triggered by poorly controlled diabetes mellitus. Neurologia (Barcelona, Spain). 2016 Sep     [PubMed PMID: 25728951]
[14] Estruch R,Nicolás JM,Salamero M,Aragón C,Sacanella E,Fernández-Solà J,Urbano-Márquez A, Atrophy of the corpus callosum in chronic alcoholism. Journal of the neurological sciences. 1997 Mar 10     [PubMed PMID: 9077511]
[15] Yadala S,Luo JJ, Marchiafava-bignami disease in a nonalcoholic diabetic patient. Case reports in neurological medicine. 2013     [PubMed PMID: 23710388]
[16] Ceylan-Isik AF,McBride SM,Ren J, Sex difference in alcoholism: who is at a greater risk for development of alcoholic complication? Life sciences. 2010 Jul 31     [PubMed PMID: 20598716]
[17] Khan S,Okuda M,Hasin DS,Secades-Villa R,Keyes K,Lin KH,Grant B,Blanco C, Gender differences in lifetime alcohol dependence: results from the national epidemiologic survey on alcohol and related conditions. Alcoholism, clinical and experimental research. 2013 Oct     [PubMed PMID: 23763329]
[18] Garcia-Santibanez R, Marchiafava-Bignami disease presenting as acute dysarthria and ataxia. Alcohol and alcoholism (Oxford, Oxfordshire). 2015 Mar     [PubMed PMID: 25534932]
[19] Helenius J,Tatlisumak T,Soinne L,Valanne L,Kaste M, Marchiafava-Bignami disease: two cases with favourable outcome. European journal of neurology. 2001 May     [PubMed PMID: 11328337]
[20] He X,Sullivan EV,Stankovic RK,Harper CG,Pfefferbaum A, Interaction of thiamine deficiency and voluntary alcohol consumption disrupts rat corpus callosum ultrastructure. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2007 Oct     [PubMed PMID: 17299515]
[21] Warden AS,Mayfield RD, Gene expression profiling in the human alcoholic brain. Neuropharmacology. 2017 Aug 1     [PubMed PMID: 28254370]
[22] Manzo-Avalos S,Saavedra-Molina A, Cellular and mitochondrial effects of alcohol consumption. International journal of environmental research and public health. 2010 Dec     [PubMed PMID: 21318009]
[23] Haorah J,Ramirez SH,Floreani N,Gorantla S,Morsey B,Persidsky Y, Mechanism of alcohol-induced oxidative stress and neuronal injury. Free radical biology & medicine. 2008 Dec 1     [PubMed PMID: 18845238]
[24] Kumar A,LaVoie HA,DiPette DJ,Singh US, Ethanol neurotoxicity in the developing cerebellum: underlying mechanisms and implications. Brain sciences. 2013 Jun 14     [PubMed PMID: 24961432]
[25] Spector R, Thiamin homeostasis in the central nervous system. Annals of the New York Academy of Sciences. 1982     [PubMed PMID: 7044228]
[26] Osiezagha K,Ali S,Freeman C,Barker NC,Jabeen S,Maitra S,Olagbemiro Y,Richie W,Bailey RK, Thiamine deficiency and delirium. Innovations in clinical neuroscience. 2013 Apr     [PubMed PMID: 23696956]
[27] Singleton CK,Martin PR, Molecular mechanisms of thiamine utilization. Current molecular medicine. 2001 May     [PubMed PMID: 11899071]
[28] Al-Witri A,Vialatte AL,Tan KL,Dexter MAJ, Antemortem histopathology and imaging findings in a case of Marchiafava-Bignami disease. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2019 Aug     [PubMed PMID: 31178304]
[29] Weis S,Büttner A, Alcohol-related diseases. Handbook of clinical neurology. 2017     [PubMed PMID: 28987168]
[30] Heinrich A,Runge U,Khaw AV, Clinicoradiologic subtypes of Marchiafava-Bignami disease. Journal of neurology. 2004 Sep     [PubMed PMID: 15372245]
[31] Rosa A,Demiati M,Cartz L,Mizon JP, Marchiafava-Bignami disease, syndrome of interhemispheric disconnection, and right-handed agraphia in a left-hander. Archives of neurology. 1991 Sep     [PubMed PMID: 1953424]
[32] Ménégon P,Sibon I,Pachai C,Orgogozo JM,Dousset V, Marchiafava-Bignami disease: diffusion-weighted MRI in corpus callosum and cortical lesions. Neurology. 2005 Aug 9     [PubMed PMID: 16087921]
[33] Dong X,Bai C,Nao J, Clinical and radiological features of Marchiafava-Bignami disease. Medicine. 2018 Feb     [PubMed PMID: 29384842]
[34] Parmanand H T, Marchiafava-Bignami disease in chronic alcoholic patient. Radiology case reports. 2016 Sep     [PubMed PMID: 27594956]
[35] Staszewski J,Macek K,Stepień A, [Reversible demyelinisation of corpus callosum in the course of Marchiafava-Bignami disease]. Neurologia i neurochirurgia polska. 2006 Mar-Apr     [PubMed PMID: 16628513]
[36] Latt N,Dore G, Thiamine in the treatment of Wernicke encephalopathy in patients with alcohol use disorders. Internal medicine journal. 2014 Sep;     [PubMed PMID: 25201422]
[37] Cook CC,Hallwood PM,Thomson AD, B Vitamin deficiency and neuropsychiatric syndromes in alcohol misuse. Alcohol and alcoholism (Oxford, Oxfordshire). 1998 Jul-Aug;     [PubMed PMID: 9719389]
[38] Sechi G,Serra A, Wernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management. The Lancet. Neurology. 2007 May;     [PubMed PMID: 17434099]
[39] Carrilho PE,Santos MB,Piasecki L,Jorge AC, Marchiafava-Bignami disease: a rare entity with a poor outcome. Revista Brasileira de terapia intensiva. 2013 Mar     [PubMed PMID: 23887763]
[40] Pinter G,Borbely K,Peter L, [Marchiafava-Bignami disease (Case-report)]. Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology. 2016 Jun     [PubMed PMID: 27390208]
[41] O'Keeffe ST,Tormey WP,Glasgow R,Lavan JN, Thiamine deficiency in hospitalized elderly patients. Gerontology. 1994     [PubMed PMID: 8034199]
[42]     [PubMed PMID: 18779434]
[43]     [PubMed PMID: 20642790]
[44]     [PubMed PMID: 30881711]