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. 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.
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.
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.
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 . Other causes can be:
- Sudden fluctuation in serum osmolality, known as callosal myelinolysis, as a complication of ketoacidosis caused by diabetes mellitus or alcoholism.
- Non-alcoholic malnourishment After Gastric Bypass Surgery.
It is most commonly discovered in malnourished patients with chronic alcohol use disorder. However, cases have been described in patients without alcohol use disorder, especially individuals with poorly controlled diabetes mellitus. 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 to alcohol consumption than women. The mean age of onset is 45 years 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. International data is similar, always reminding that the prevalence is underestimated because of the non-autopsied patients. Published in approximately 300 case reports
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.
- 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. 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. 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.
- 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. 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.
- 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.
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.
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).
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:
- 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
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).
- Cognitive function can be assessed by the Abbreviated Mental Test (AMT).
- 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, 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. The typical pathognomonic features on MRI are symmetrical lesions on the corpus callosum, usually restricted to the genus, body, or splenium:
- 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). 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. 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.
- 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. 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.
There are no management guidelines to date. Most of the case reports of MBD have shown a favorable response to endovenous administration of thiamine, folate, and vitamin B complexes as well as high-dose corticosteroids.,,, One case reported significant improvement of symptoms within 7 days of symptom onset after a 5-day course of high-dose thiamine intravenously (500 mg, 3 times/day) and vitamin B complex orally. Another case reported improvement after giving amantadine together with thiamine, vitamin B12, and folate. Management also includes aggressive nutritional supplementation. Reducing alcohol abuse may help prevent the development of Marchiafava-Bignami disease in those with alcohol use disorder.
Based on MRI findings, clinical presentation, and history, differential diagnosis may include the following:
Marchiafava-Bignami disease may be categorized into acute and chronic stages. The acute stage may be subdivided into Type A and Type B based on symptom presentation. [See History and Physical section]
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. Eextracallosal 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 patient’s recovery, and serial MRI has demonstrated complete disappearance of lesions with early diagnosis and treatment. 
MBD is a very rare disorder that is not only difficult to diagnose but complex to manage. With very few cases reported, it is best managed by an interprofessional team that includes nurses, therapists, and dietitians. Without any guidelines, the treatment is empirical. Anecdotal reports suggest supplements of vitamins may help but no long term data are available. The prognosis for these patients is poor.
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