Continuing Education Activity

Marchiafava-Bignami disease (MBD) is a very rare disorder characterized by demyelination and necrosis of the corpus callosum. The adjacent subcortical white matter may also be involved. This activity describes the pathophysiology, etiology, presentation, and management of MBD. Although clinical features may be quite variable and nonspecific, Marchiafava-Bignami Disease should be considered in patients with chronic alcohol use or malnutrition who present with certain neurological symptoms. These symptoms include dementia, altered mental status, spasticity, dysarthria, ataxia, gait abnormalities, and seizures. Other reported clinical findings include desynchronization of bilateral symmetric movements and unilateral signs of agraphia, apraxia, dyspraxia, and anomia. This activity illustrates the evaluation and management of Marchiafava-Bignami Disease and reviews the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Describe the causes of Marchiafava-Bignami disease.

• Describe the presentation of Marchiafava-Bignami disease.

• Summarize the treatment options and prognosis for Marchiafava-Bignami disease.

• Explain the importance of enhancing care coordination amongst interprofessional team members to improve outcomes for patients affected by 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 patients with alcohol use disorder[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-drinking 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. Patients with alcohol use disorder 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 the possibility of aggressive nutritional supplementation with a reduction in drinking to prevent the development of MBD in patients who use alcohol.[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, is a complication of ketoacidosis caused by diabetes mellitus or alcoholism[9].
• Non-alcohol-related malnourishment after gastric bypass surgery[10].
• It has been related to other non-alcohol-related 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 that many cases likely have gone undiagnosed[19]. International data is similar, indicating 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. 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[23][24]. There is also a reduction in the synthesis of other neurotransmitters such as acetylcholine, glutamate, and 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[25].
• Damage to the corpus callosum can be explained by its high myelin content. Myelin is the major white matter commissure that connects both 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[26][27].

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 use 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][28][29][30][26]:

• 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).
• The 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 exams can be useful through the following:

• Serum electrolytes, to exclude electrolyte 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 use 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 exclude the use 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[29]. The typical pathognomonic features on MRI are symmetrical lesions on the corpus callosum, usually restricted to the genus, body, or splenium[31]:

• 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)[29][32]. 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[31]. 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][31].
• In one study, Estruch et al. compared MRI findings of 28 males with chronic alcohol use disorder with 14 subjects who did not have this condition 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 was 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 treatments to date. Management is similar to the one for Wernicke-Korsakoff syndrome or alcohol use disorder. Some of the case reports of MBD have shown a favorable response to the intravenous administration of thiamine, folate, and vitamin B complexes as well as high-dose corticosteroids[15][18][29][32]. Some case reports show significant improvement with high-dose intravenous thiamine intravenously (500 mg/tid), oral vitamin B complex, amantadine, and folate[18][33]. Management also includes aggressive nutritional supplementation and, undoubtedly, alcohol withdrawal. Treatment can be administered as follows:

1. Thiamine, in normal saline or 5% dextrose[34][35][36][34]:
   • 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, ending with 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[37][38]: Although its mechanism is unknown and has not been proven effective through scientifically rigorous data, its dopaminergic effect may probably benefit the patient's symptoms. The usual dose for treating 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[39][40][41][42]:

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:

• Endocrine 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)

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 a comatose state and die. 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[31].

Pearls and Other Issues

• MBD is a rare disorder characterized by demyelination and necrosis of the corpus callosum, especially seen in patients with alcohol use 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 use disorder, and an MRI shows 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.