Dr Jun Fukumoto, MD, 1366-1 Kitaaoyagi, Kuki-si, PO Box 346-0024, Saitama-ken, Japan. Email: email@example.com
Since 1903, Marchiafava-Bignami disease has been recognized as a rare syndrome with focal demyelination and necrosis in the corpus callosum, which is usually found in chronic alcoholics. It extends into the neighboring white matter and occasionally as far as the subcortical regions. We report a Japanese patient with Marchiafava-Bignami disease associated with alcohol abuse, who had traveled around Western Europe, North America and China for more than 30 years. As he suffered extreme delirium in the early stages we administered a low dose (10 mg) of mianserin hydrochloride. He was very irritable and uncooperative on admission, after 20 days his delirium had disappeared and his temper had become very calm and mild. After 40 days, his intelligence level increased substantially as measured by various neuropsychological tests.
Marchiafava-Bignami disease (MBD) is a rare complication of chronic alcoholism, even though some cases not related to alcohol abuse are described.1 Since the first case of MBD was reported, approximately 240 cases have been revealed.2
A case of MBD was evaluated with MR imaging and CT at 1 and 2 months after the onset of symptoms. The MR imaging study showed extensive abnormal signal intensity of the corpus callosum with macroscopic changes. MBD was diagnosed and both thiamine and vitamin B-complex therapy of 1000 mg per day was initiated.
Although historically most cases of MBD have not been cured and have been fatal within several months, it seems that the lesion is reversible by such management as high doses of vitamin B or steroids in the early stages when diagnosed using CT, MRI or SPECT.3 Hence it has become a curable disease.
Marchiafava-Bignami disease has specific features of disconnection syndrome, including left hand apraxia, dyslexia, acalculia, crossing neglect of left side, spelling disorder and visual ataxia (this patient is a right-handed man). In this case, the patient had the former three symptoms, which disappeared totally in 60 days.
For many years, the evaluation of neuropsychological aspects of MBD were not respected very much at all. We herein focus on the therapy of its neuropsychological symptoms.
Since the unique aspect of this case was severe delirium continuing after the withdrawal symptoms from alcohol had diminished, we used a low dose of mianserin hydrochloride from day one as the main drug without diazepam.4
Then, we succeeded in decreasing the period of treatment by 30 days, compared with 90 days in the average period of the chronic type of MBD.5
A patient is a right-handed 60-year-old man of 166 cm height and 52 kg weight. The lifetime alcohol intake was a 45-year history of chronic alcohol ingestion of over 500 mL of whisky every day. He has chronic hepatitis B and chronic pancreatitis but no other psychiatric disorders. Suddenly he stopped drinking on 17 July and lost his temper for 2 days. He was transferred to ER, Glasgow Coma Scale was 10 (E4 V2 M4). He had a moderate Korsakoff-like amnesia with poor retention of information, faulty temporal orientation and occasional confabulations, gait disorders, disconnection syndrome of left hand apraxia, changed alimentary habits, diminished social contacts and difficulty in verbal expression, alcoholic polyneuropathy of low deep-tendon reflex and Wernicke’s encephalopathy of ataxia, coma and ocular-motor paralysis.
Physical examination at admission on 27 July revealed blood pressure of 84/60 mmHg, pulse rate of 74 and body temperature of 36.0°C. The heart rate was rhythmic on auscultation, heart and lungs were normal. The abdomen was soft and painless to palpation. Hepatomegaly of 1 cm was discerned. Pupils were equal, with normal reaction to light and ocular-motor functions were intact. No motor deficits were evident but distal muscle atrophy was present in both lower extremities with lesions. All four limbs were hypertonic with hyperactive stretch reflexes. Barre and bilateral Babinski signs were negative. An ECG and EEG were normal and a chest X-ray was unremarkable. An abdominal ultrasonic examination showed moderate hepatomegaly and inflammation of the spleen.
T1-weighted magnetic resonance images (T1WIs, TR = 500/TE30 at 1.5T) in axial slices show hypointensity of the corpus callosum (Fig. 1). Significant cortical atrophy was present with enhancement of gray cortical matter. No other hemispheric, brainstem or cerebellum lesions were detected. T2WIs (TR = 2000/TE30 at 1.5T) indicate that hyperintensity was in the same space as the splenium of the corpus callosum.
Coronal CT showed hypodensity of the corpus callosum anterior to frontal horns of lateral ventricles.
Laboratory analysis showed megalochronic anemia, folic acid and vitamin B1, B12 levels were very low. Vitamin B5 and B6 were within normal limits. LDH, serum Amylase, GTP, AST and ALT were high. NH3 was within normal limits and ChE was low. HBsAg was positive. Tests for HIV and syphilis were negative.
The patient had three remarkable signs of disconnection syndrome on admission, that is, left hand apraxia, acalculia and dyslexia.
We started giving 10 mg of Mianserin hydrochloride, thiamine and vitamin B-complex of 1000 mg per day were initiated.
On day 10, he also had problems recognizing objects manipulated with the left hand but no problem with the right hand, such as his house and garden (Fig. 2). However, he could engage attentively in test sessions of 55 min duration and his performance level was stable with a tendency towards slight improvement during a 2-month observation period. Then, his gait became normal, dysarthria was imperceptible and he could maintain a minimum level of conversation.
Motility was completely recovered with no signs of interhemispheric disconnection. His Mini-Mental State Examination (MMSE) score and its Japanese version of HDS-R, scaling frontal function was 15/30 and 17/30 on 5 August, increasing to 18/30 and 23/30 on 27 August.
On day 40, his left hand apraxia gradually diminished. His WAIS-R, scaling intelligence and memory was 77 (verbal function 89 and performance function 68) and furthermore, his CDR (clinical dementia rating) score was 2–0.5. All parameters had improved substantially:6 auditory verbal learning test (trials 1–5: SD = 11.3–10.7, z = −0.24, P = 0.65, r = −0.05/long delay: SD = 9.1–12.1, z = −0.50, P = 0.49, r = −0.28); controlled oral word association test (score: SD = 10.1–11.5, z = −0.54, P = 0.48, r = 0.02); and finger trapping test (right: SD = 36.3–30.2, z = −1.12, P = 0.04, r = 0.18/Left: SD = 25.8–21.4, z = −2.14, P = 0.02, r = 0.38).7
On day 50, coronal CT showed the space of the low density area in the corpus callosum had become smaller and his left hand acalculia and dyslexia diminished.
On day 60, compared with the former T2WIs, the area of hyperintensity of the corpus callosum had clearly decreased (Fig. 3). MRI on 13 September produced the findings shown in Fig. 4 (FLAIR image, fluid attenuated inversion recovery), Fig. 5 (diffusion weighted image), Fig. 6 (T1WIs enhanced with Gadolinium of sagittal slice) and Fig. 7 (coronal slice). And finally, his disconnection syndrome totally disappeared.
His design of the cube became more correct between 4 August and 5 September (Fig. 8).
Marchiafava-Bignami disease is an acute inflammatory demyelination of the corpus callosum frequently reported in patients with alcohol abuse. It has been linked to a disorder of vitamin B metabolism. In the acute stage there is focal, partially hemorrhagic demyelination of the corpus callosum, often ending up as a cystic defect, although remissions have been reported.8
Typically, a single lesion centrally and symmetrically involves the splenium. Lesions can also be multiple along the corpus callosum and they are symmetrical in the midline in the splenium and do not reach the edge of the corpus callosum.9
There are three types of MBD, that is, acute, subacute and chronic. Acute MBD is characterized by the sudden onset of impaired consciousness and epileptic seizures, with an eventual progression to coma. Neurologic dysfunction, which precedes coma, may include muteness and diffuse muscular hypertonia with dysphagia. The prognosis for acute MBD is poor, and most patients die within several days of onset. Subacute MBD is characterized by the sudden onset of dementia which eventually progresses to a vegetative state. Often, patients with the subacute form present with dysarthria, hypertonia, extension of the neck and facial grimaces. Subacute MBD may steadily progress to death within a few months after onset.10
With recent improvements in radiologic technology, chronic MBD has become more frequently recognized. Although this form of MBD was considered to constitute only 10% of cases with MBD in the past, the majority of recent reports are diagnosed with chronic MBD. Little agreement exists concerning which clinical findings characterize chronic MBD, as most case reports present limited physical findings.11
It is well known that there are several diseases that cause abnormal signs on MRI in the corpus callosum, such as MBD, multiple sclerosis, cerebellar occlusion, glioma or lymphoma, diffuse axonal injury, adrenoleukodystrophy and AIDS dementia complex. Judging from the clinical course and the examination, this case should be diagnosed as MBD with alcoholism. And in this case, the MBD is thought to be a chronic type.
Hemosiderin deposits or collections of lipid-laden macrophages were found by T2WIs. Enhancement of corpus callosum is known to occur in other forms of acute demyelination, but most of these also affect the subependymal white matter and distinguishing them is therefore easy.12
Demyelination of the corpus callosum in association with chronic alcohol ingestion, is a rare disorder with varied symptoms leading to non-specific clinical manifestations.13 Except for alcoholic dementia, all of these diseases exhibit specific neuropathological lesions, which allow their diagnosis at autopsy. Diagnosis of brain lesions in alcoholics is based on clinical features, laboratory analyses and imaging studies.14
More than half of detoxified alcoholics show different degrees of cognitive impairment and approximately 10% exhibit stable and severe cognitive dysfunction ranging from selective amnesia to dementia.15 Pathologic studies confirm that cerebellar atrophy is more prominent in the anterior and superior aspects of the vermis.16 It affects all three layers of the cerebellar cortex, although the Purkinje cell loss is greatest. Purkinje cell depletion is nearly total throughout the folia, and the convexities of the folia are more severely affected than the furrows of the sulci.17
The mechanism of contrast enhancement has been suggested to be a breakdown of the blood–brain barrier, because the enhancement lasts for less than 20 days during the acute phase of the disease. It can be seen within the first two days after disease onset. It has also been suggested to be due to hemorrhages because massive deposits of hemosiderin have been found at autopsy in the walls of the callosal cystic lesion.18 In severe cases, the demyelination of corpus callosum also extends to deep cerebral white matter.19
MRI performed on asymptomatic chronic alcoholics has shown a reduction in the corpus callosum area in two-thirds of cases.20 These findings are similar to those observed in autopsy studies of chronic alcoholics.21 However it remains to be elucidated whether the chronic phase of this disease represents the end-stage of the corpus callosum atrophy observed in a high proportion of heavy drinkers and is only due to the greater sensitivity of some subjects to the effects of ethanol or hitherto unknown factors on white matter.22
Autopsy studies have shown severe chromatolytic changes of pyramidal cells of the cortex, the neurons of the pontine nuclei, vestibular nuclei and anterior horn cells of the spinal cord in these patients.23 Severe chromatolytic change is relatively often associated with Wernicke’s disease and MBD.
In 1959, Adams, Victor and Mancall described a distinctive, previously unrecognized disease characterized primarily by the symmetric destruction of myelin sheaths in the basis of the central pons. Numerous cases of central pontine myelinolysis (CPM) have been reported since then. The cause of CPM is uncertain.24 Most patients with CPM have had documented hyponatremia and serum sodium levels were corrected rapidly to normal or supranormal levels. Many had chronic alcoholism and malnutrition. CPM has been seen, however, in hyponatremic, nonalcoholic patients, including some with dehydration resulting from vomiting, diarrhea or diuretic therapy; with postoperative overhydration; or with compulsive water drinking.25
The lesion may spread into the pontine tegmentum or superiorly into the mesencephalon. Extrapontine myelinolysis may be found in as many as 10% of all cases of CPM. Areas involved include the cerebellum, putamen, thalamus, corpus callosum, subcortical white matter, claustrum, caudate, hypothalamus, lateral geniculate bodies, amygdala, subthalamic nuclei, substantia nigra and medial lemnisci. Within the lesions, myelin sheaths are destroyed, but nerve cells and axon cylinders are relatively preserved. Inflammation does not occur. Microscopically, the lesions resemble those seen in MBD.26
MBD and CPM are not known to have occurred in the same individual; it is not clear if both are the result of the similar etiological process or if they are different nosological entities. The fact that they do not occur together rather favors the hypothesis that they are of different origin.27
Up to the present day, studies of MBD have mainly focused on diagnosis with CT, MRI or SPECT and the therapy of vitamin B-complex or steroid. Therefore the mental symptoms of MBD are not considered so much. Progressive dementia, changed personality, hallucination and depressive mood are to be seen in MBD.28 Our clinical course demonstrates that mianserin hydrochloride can be applicable to the treatment or care for those mental or neuropsychological symptoms in the due process.
Functional neuroimaging showed widespread cortical involvement in a patient with MBD, which would account for the patient’s cognitive deficits.29
Principally, mianserin hydrochloride is used as an antidepressant drug, which has especially the effect of blocking the receptor of two neurons.30 On the other hand, it has also an antihistamine effect and is well known to be effective for decreasing delirium of organic changes or senile dementia.31
Therefore in this case, we dare not to use diazepam which may lower the level of consciousness and worsen the delirium. We can recognize that MBD with delirium or depressive mood or confabulation would be eased by a low dose of mianserin hydrochloride.
Now the early diagnosis using MRI for MBD has been almost established. In the future, the treatment for MBD not only on the physical side but also on the mental side should be constructed systematically, starting from the early stages.
We thank Dr Yuka Kiuchi of Internal Medicine, Saitama-Saiseikai-Kurihashi Hospital and radiology service of Hasuda Hospital. And last of all, this paper totally depends on the support of many coworkers in Kuki-Suzunoki Hospital.