AUTHOR AND EDITOR INFORMATION

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• Differentials
• Workup
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INTRODUCTION

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Background

In 1903 Marchiafava and Bignami, 2 Italian pathologists, described 3 men with alcoholism who died after having seizures and coma. In each patient, the middle two thirds of the corpus callosum were severely necrotic. Through the years, approximately 250-300 cases of what is now term Marchiafava-Bignami disease (MBD) have been reported in the medical literature. Most patients are men with alcoholism. For years, Italian heritage was thought to be important because Italian pathologists originally described the disease. However, the disease has been found in persons all over the world. Italian ethnicity is now known to not be a factor. In rare cases, the disease has occurred in people without alcoholism.

In some cases, the damage extends to areas such as the nearby subcortical white matter, the anterior commissure, or both. Cases have occurred in association with Wernicke encephalopathy, which nevertheless appears to be a separate problem. Cortical involvement, particularly of the third and forth cortical layers of the lateral frontal cortex, has also been described together with MBD. Whether such cortical pathology is part of MBD or a separate alcohol-related disorder is a matter of controversy. Although nutritional deficiencies have been suspected, the cause of this disease or syndrome is still unknown.

Pathophysiology

Single-photon emission CT (SPECT) scanning has yielded interesting pathophysiologic data related to MBD. In one published case reported by Ferracci et al in 1999, SPECT scanning showed a bilateral reduction in cerebral blood flow. The patient had left hemispatial neglect in addition to the expected left-handed apraxia and agraphia.

In 2006, Nardone et al reported an interesting study on a patient who had partially recovered from MBD who demonstrated impairment of transcallosal inhibition. When performed in the proper way, transcranial magnetic stimulation of the motor cortex elicits excitatory responses in contralateral hand muscles and it also suppresses tonic voluntary activity in ipsilateral muscles. The inhibitory signal is conveyed across the corpus callosum. This inhibition was reduced in the partially recovered patient described by Nardone et al.

Frequency

United States

MBD is a very rare condition. The authors did not find specific published epidemiological data. In 2001, Helenius et al wrote that they had found approximately 250 cases in published reports, although they also suggested that many cases were undiagnosed. In an attempt to check the Helenius conclusions, the authors did a Medline search and found 148 papers published since 1966. Indeed, approximately 250 cases were included among these papers (although occasionally some papers may have duplicated the same patient). Adding 40 or 50 cases mentioned in older textbooks that would not have been included in Pubmed, the number may be a bit higher than 250, but, essentially Helenius et al are accurate. That being stated, the information cannot be converted to accurate epidemiological data.

International

The comments made above for the US cases also apply to the international cases. One additional comment on international cases deserves mention. Some of the old literature on MBD suggests that this condition is more common in Italians. This is solely an artifact of the fact that the initial cases were found in Italy and that for a certain amount of time the Italian physicians appeared to be the only ones interested in finding such cases. It is now firmly believed that no known national, geographic, ethnic, or racial predilection exists. However, with a small number of reports, the numbers of cases reported from each country would not be expected to be exactly in proportion to the population of each country. Numerous factors, including the autopsy rate and, now, the availability of MRI, could influence the rate of diagnosis. Interestingly, the first Polish case to be diagnosed was reported by Staszewski et al in 2006. This case was detected via MRI.

Mortality/Morbidity

The original cases were diagnosed based on pathology findings; therefore, the mortality rate was thought to be extremely high. More recently, MRI has allowed clinicians to detect cases in patients who survived the initial insult. A few patients have had a virtually complete recovery of their intellectual functions; others have only partially improved. Therapy with thiamine and vitamin B complex, including vitamin B-12 and folate, has been used in many patients who have recovered. However, identical therapy has been used in patients who did not recover. In one patient who recovered, corticosteroids were also given, as reported by Nardone et al in 2006. In patients who improved, the CT and MRI findings also showed improvement.

• Reliable numbers are not available because of the few reported cases, but the mortality and morbidity rates are still presumed to be high. However, the mild form is thought to be underdiagnosed. If this is the case, the overall outcome may be better than previously thought.
• As Helenius et al reported in 2001, of the approximately 250 reported patients, 200 have died, 30 remained severely demented or bedridden, and only 20 had a favorable outcome.
• See also the Prognosis section below.

Race

No racial predilection is known.

Sex

Most reported cases have been in men.

Age

Most reported cases have occurred in persons older than 45 years.

CLINICAL

Section 3 of 9  

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History

• Most patients have a history of alcoholism and poor nutrition.
• The tempo of onset and the range of clinical symptoms vary.
• • Some patients present to the hospital with sudden onset of stupor or coma, and some present with seizures.
  • Other patients have acute, subacute, or chronic onset of dementia and/or gait problems. Spasticity often complicates the gait disorder.
  • Psychiatric disturbances, incontinence, hemiparesis, aphasia, and apraxia have been described.
• In 2004, Heinrich et al described 2 clinical subtypes based on a review of 50 radiologic cases diagnosed in vivo:
• • Type A had predominant features of coma and stupor. This subtype is associated with a high prevalence of pyramidal-tract symptoms. Radiologic features include involvement of the entire corpus callosum.
  • Type B is characterized by normal or mildly impaired mental status. Radiologic features are partial or focal callosal lesions.

Physical

Although the physical findings are typically nonspecific, good physical examination may offer clues to the diagnosis. Patients with severe alcoholism who have this syndrome frequently have other problems, such as subdural hemorrhage, Wernicke syndrome, and alcoholic liver disease. Therefore, the diagnosis is not often clear.

• General appearance and constitution: Patients later found to have MBD frequently present to an emergency department in a disheveled condition suggestive of chronic problems with alcohol.
• Mental status
• • Patients can be lethargic, stuporous, or even unconscious (coma or seizures).
  • If a patient is sufficiently alert for extensive neuropsychological testing, testing for ideomotor apraxia (ie, inability to perform motor activities that is not explainable by overt motor or sensory loss) may be revealing.
  • Apraxia of the left (or nondominant) hand suggests interhemispheric disconnection (ie, impaired transfer of information from the left hemisphere to the right hemisphere). Damage to the fibers of the corpus callosum is the cause.
  • Inability to retain new information (ie, Korsakoff syndrome) and delirium tremens should suggest alcoholism and prompt the examiner to consider other alcohol-related problems, such as MBD.
  • Dementia and aphasia have been noted in some patients with this disease.
• Cranial nerves: Disconjugate eye movements, together with confusion, may indicate Wernicke-Korsakoff syndrome, which should prompt the examiner to consider MBD.
• Motor function
• • Tremors, weakness, spasticity, and gait abnormalities, although nonspecific, have been seen in patients with MBD.
  • Delirium tremens is another alcohol-induced problem that patients with MBD may have. Currently, no evidence suggests that the presence of one is either positively or negatively correlated with the presence of the other.
• Sensory function: Sensory loss may suggest an alcoholic neuropathy.
• Cerebellar functions: Wide-based gait and truncal ataxia suggest alcoholism.
• Reflexes
• • Alcoholic neuropathy can cause a loss of deep tendon reflexes and therefore prompt the consideration of MBD in some patients.
  • The presence or absence of Babinski signs is not known to be specifically related to MBD.

Causes

• Alcoholism remains the greatest risk factor, although rare cases have occurred in individuals who did not drink alcohol.
• Nutritional factors have been suspected, but no specific nutrient has been identified.
• Electrolyte disturbances (as in central pontine myelinolysis) may be important.
• Cocaine use is not known to cause this condition.

DIFFERENTIALS

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Other Problems to be Considered

The corpus callosum may also be affected in other diseases, such as ischemic stroke, contusion, or lymphoma. However, MBD is distinguished by callosal lesions that are usually symmetrical and located in the anterior portion of the callosum.

WORKUP

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Lab Studies

• Because many patients present with stupor or coma and seizures, the initial laboratory investigations should include measurements of serum electrolyte and glucose levels, a CBC count, and toxicology screening.
• Glucose and intravenous thiamine are frequently given in the emergency department immediately after blood is drawn.
• A spinal tap often is needed and usually performed after findings on a brain CT scan (see Imaging Studies below) have excluded an intracranial mass or hemorrhage.

Imaging Studies

• Findings on the initial CT scan may confirm the diagnosis.
• • If callosal damage is mild, it may go unnoticed until the radiologist carefully reviews the CT scan.
  • In some cases, the lesions may not be visible on a CT scan.
• MRI is currently the most sensitive diagnostic tool.
• • Fast spin-echo T2-weighted MRIs show hyperintensity of the lesions due to both edema and myelin damage.
  • Hypointensity on T1-weighted images (see Image 1) is mainly related to a total loss of myelin with replacement of the region by a cyst. Neurons can also be lost, in a situation similar to that of multiple sclerosis. As reported by Sair et al in 2006, diffusion tensor imaging and the associated technique of fiber tracking can further increase the sensitivity of the MRI.
  • Acute or subacute lesions are characterized by edema and early myelin damage more than other changes. As lesions become chronic, cystic lesions are likely to develop. Cystic lesions are generally hyperintense around the rim on T2-weighted MRIs and hypointense in the actual cavity on T1-weighted MRIs.
  • Fluid-attenuated inversion recovery (FLAIR) images may be even more sensitive than those described above. Hyperintense rims and hypointense cores on FLAIR images probably represent damage to the myelin at the rim with a central necrotic area. Uniformly hyperintense lesions may contain a mixture of demyelination and edema. In acute lesions, the area of edema seen is frequently larger than the area of permanent damage.
  • Pathology may also be seen on diffusion-weighted imaging. Unlike stroke, however, in MBD, Hlaihel et al reported in 2005 that it is not uncommon for areas of restricted diffusion to resolve completely without apparent permanent damage.
• In a 2004 review of acute and chronic cases, Heinrich et al separated most cases into 2 groups, which they labeled A and B.
• • Group A included the worst cases in which patients presented with coma or other severe impairment of consciousness. On MRIs, their lesions typically involved all or almost all of the corpus callosum. For example, in the acute phase, the entire corpus callosum was commonly hyperintense on T2-weighted MRIs. As the lesions evolved, considerable necrosis occurred, and cystic areas of necrosis were present in most or many regions of the corpus callosum. The death rate for patients with such presentations was high (21%), and those who lived frequently had severe deficits.
  • In group B, patients had little or no impairment of consciousness. Their deficits were subtle: various cognitive difficulties and signs of impaired interhemispheric information transfer, gait disturbances, dysarthria, limb hypotonia, and rare seizures or upper motor neuron signs. Initial hyperintense lesions on T2-weighted MRIs were limited to a few areas of the corpus callosum. Some cystic necrotic areas developed over time, but they were fewer and smaller than those in type A. No deaths occurred in this group, and patients frequently had good recoveries.
  • The authors did not attempt to correlate the severity of the cases with the presumed causes. Patients with the most severe alcoholism might have been in group A, but this is speculation. In both groups, the amount of early callosal edema in the acute phase often markedly exceeded the areas of ultimate cystic necrosis.
• Other radiologic studies have been reported in the literature.
• • In 2003, Gambini et al used magnetic resonance spectroscopy to suggest that an inflammatory reaction accompanies demyelination and necrosis.
  • SPECT scans have yielded interesting pathophysiologic data in persons with MBD. In one published case, SPECT scanning showed a bilateral reduction in cerebral blood flow. The patient had left hemispatial neglect in addition to the expected left-handed apraxia and agraphia
  • Although the callosal lesions are the hallmark of the disease, for years some cases of MBD were known to be associated with cortical damage in addition to damage to the white matter tracts of the corpus callosum. Generally, the cortical damage was in the lateral frontal and the temporal lobes mainly in the third (although sometimes also in the fourth) cortical layer. In these areas, the neurons degenerated and were replaced by glial cells. In 1939, Morel described this as "cortical laminar sclerosis." Subsequently, this has been called Morel cortical laminar sclerosis.
  • Although Morel did not report an association of cortical laminar sclerosis with MBD, many subsequent authors did, including Jequier and Wildi in 1956 and Delay et al in 1959. Indeed, Roper et al stated in 2005 in Adams and Victor's Principles of Neurology that Jequier and Adams (in an otherwise unpublished review) reexamined Morel's slides and found evidence of MBD in all of those cases. Thus, the prevailing view has generally been that Morel cortical laminar sclerosis is secondary to MBD. Nevertheless, in 1978, Naeije et al reported a case of Morel cortical laminar sclerosis in an alcoholic woman who did not have MBD. In addition, Okeda et al reported 3 cases of cortical laminar sclerosis in 1986 in patients who had various combinations of pontine and extrapontine myelinolysis but who did not have MBD. One of these patients had alcoholic cirrhosis and 2 had malignancies.
  • Prior to the MRI era, neuroradiological findings had little impact on the detection of cortical laminar sclerosis. Indeed, a prior version of this article stated that "Such lesions are rarely found with in vivo imaging" although a functional MRI demonstration by Ishii et al in 1999 was described as showing perfusion and metabolic effects on the cerebrum in a case of MBD. A 1996 article by Logak et al, which was not referenced in the previous version of this article, described cortical positron emission tomographic findings in a case of MBD.
  • In 2005, Johkura et al reported 2 cases in which lateral and frontal cortical lesions, in addition to corpus callosal lesions, were seen on FLAIR imaging. In 2006, Menegon et al reported 6 MBD patients in whom (1) the entire corpus callosum appeared to be affected by a reduced apparent diffusion coefficient as seen on diffusion-weighted imaging studies and (2) lateral and frontal cortical lesions were also detected by diffusion-weighted imaging. Menegon et al suggested, on the basis of the outcomes of their patients, that such a combination of findings was a harbinger of a poor outcome both for survival and for cognitive recovery. However, as pointed out by Khaw et al in 2006, the older literature, such as that by Brion from 1977, does not support a correlation between laminar sclerosis and bad outcome. In addition, recent studies such as that by Hlaihel et al from 2006 do not support a correlation between reduced apparent diffusion coefficient and poor prognosis or even with irreversibility of thelesion.
  • Finally, they note that cortical MRI findings have not been definitively correlated with the specific pathology of Morel cortical laminar sclerosis. However, if indeed they represent laminar sclerosis, the fact that this is present in the acute or subacute stages of MBD may force a reevaluation of the thought that the laminar sclerosis is a secondary consequence of the MBD.

Other Tests

• EEG is frequently performed to evaluate seizures. No specific or characteristic EEG findings are indicative of MBD.
• If the patient eventually recovers a reasonable level of consciousness, neuropsychological testing can demonstrate difficulties with information transfer between the right side of the brain and the left. Other aspects of the patient's dementia may also be elucidated.

Histologic Findings

In MBD, the middle portion (middle lamina) of the myelinated fiber tracts of the corpus callosum degenerates. The degeneration is frequently but not necessarily uniform. Degeneration of the corpus callosum is a cardinal feature. In some cases, the anterior portion is preferentially involved, with the most severe degeneration in the center of the lesion. The anterior and posterior commissures, the centrum semiovale, and the other white-matter tracts (eg, the long association fibers and the middle cerebral peduncles) may also be affected. However, the internal capsule and corona radiata, as well as the shorter arcuate subgyral association fibers, are typically spared. If the splenium of the corpus callosum is affected, the greatest degeneration most commonly occurs in the lateral portions of the middle segment.

With the advent of CT and MRI, more cases have been recognized than before. Analyses of such cases have revealed several patterns, including scattered lesions or cysts observed at intervals from the front to the back of the callosum. Nearby areas (eg, anterior commissure, posterior commissure, brachium pontis, other white-matter tracts) and the centrum semiovale are frequently involved.

Histopathologic studies reveal abundant macrophages in the areas of lesions. Otherwise, little inflammatory reaction is noted. Axons are demyelinated in the involved areas, but the axon cylinders are relatively spared, particularly in the peripheral portions of the lesions. Deep in the lesion, cavitation or cyst formation may be seen and corresponds to complete necrosis of all neural and glial elements.

Patients with MBD do not usually have midline lesions, which are typical in patients with Wernicke encephalopathy (of the medial thalamus or mamillary bodies).

Finally, as previously mentioned, cortical lesions are sometimes found on postmortem neuropathological studies. In these cases, neuronal degeneration of the third and fourth layers of the frontal and temporal cortices occurs, with replacement of the neuron by gliosis (ie, Morel cortical laminar sclerosis). As noted, controversy now exists regarding whether cortical MRI findings in MBD actual correlate with such pathological findings and whether they might have implications for prognosis. Whether the cortical findings are secondary to the callosal damage, whether both are caused by a similar process, or whether they are coincidental findings either of which may occur separately particularly in severe alcoholism, malnutrition, and/or other severely impairments remains unclear.

TREATMENT

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Medical Care

Various treatments similar to those commonly administered Wernicke-Korsakoff syndrome, or for alcoholism in general, have been given to patients with MBD. Some have improved and some have not. The most common treatments are thiamine and other B vitamins (especially vitamin B-12 and folate, which is not a B vitamin but which is commonly given with B-12). With regard to more unusual treatments, one case report by Staszewski et al from 2006 described amantadine given together with thiamine, vitamin B-12, and folate; the patient improved. In another case reported by Kikkawa et al from 2000, administration of high-dose corticosteroids was said to precede clinical improvement. In patients who improved, the CT and MRI findings also improved, at least somewhat.

• No specific proven treatment is available.
• Seizures and coma are treated as described in the various eMedicine articles on these topics (eg, see Seizures in the Emergency Department).
• Thiamine is administered for Wernicke-Korsakoff syndrome, although no significant evidence suggests that thiamine is a specific treatment for MBD. Vitamin B-12, folate, and other B vitamins (and sometimes multivitamins) are also frequently given to sick alcoholic patients admitted to the hospital; the authors deem administering the same protocol of vitamin therapy that would be given to patients with possible Wernicke-Korsakoff syndrome justified.
• The fact that the brain pathology can now be observed repeatedly via serial MRI scans raises the question of whether to try other treatments mentioned in the literature and then monitor the appearance of the brain. A course of high-dose intravenous corticosteroids (eg, 250 mg methylprednisolone q6h) could be tried if the attending physician believes the possible benefits outweigh the risks. Likewise, a standard dose of amantadine (100 mg bid) could be considered if the patient can safely take it orally or through a tube. However, remember that no method exists to calculate a risk-to-reward ratio from isolated case reports and the improvement seen in the small number of individual patients who received such treatments may have occurred anyway with the passage of time.
• Patients who survive should receive rehabilitation and, if appropriate, alcohol and nutritional counseling.
• Patients are usually admitted because they present with stupor, coma, and, frequently, seizures.

Consultations

• Depending on the specific presentation and course, the patient may require consultation with a neurologist for seizure control, a critical care specialist for coma management, a neuropsychologist for workup of the dementia, a neurorehabilitation specialist, and a psychiatrist or psychologist for treatment of the alcoholism.

FOLLOW-UP

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Prognosis

• No systematic study has been conducted to assess the prognosis of patients with MBD. In the pre-CT era, almost all patients were discovered at autopsy. They usually died from the effects of alcoholism and typically had severe neuropsychological deficits before death.
• Modern CT scanning and MRI allow the detection of mild cases, and some patients have recovered with minimal deficits.
• If the underlying cause is alcoholism, the prognosis is poor unless the patient adheres to an alcohol treatment program.
• Recent data suggest an improved overall prognosis, which is correlated with the subtype, as follows:
• • Type A has a long-term disability rate of 86% and a mortality rate of 21%.
  • Type B has a long-term disability rate of 19% and a mortality rate of 0%.
• As Helenius et al reported in 2004, of the approximately 250 reported patients, 200 died, 30 remained severely demented or bedridden, and only 20 had a favorable outcome.
• • Alcohol abuse is such a common problem that underdiagnosis of MBD seems likely.
  • Many cases may be diagnosed but not reported, and autopsies are largely not performed.
  • Hence, the disease may be more common than thought, and the overall outcome may be better than previously believed.

MULTIMEDIA

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Media file 1:  Callosal damage in Marchiafava-Bignami disease. Sagittal nonenhanced T1-weighted image (repetition time (milliseconds)/echo time (milliseconds), 500/16) demonstrates a small, well-defined, and hypointense lesion in the genu of the corpus callosum.
	View Full Size Image
Media type:  MRI

REFERENCES

Section 9 of 9

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Article Last Updated: Feb 1, 2007