Rare case of Marchiafava-Bignami disease due to thiamine deficiency and malnutrition

Abstract

Marchiafava-Bignami disease (MBD) is a rare, toxic demyelinating disorder of the central nervous system associated with chronic alcoholism and malnutrition. The clinical presentation is varied and non-specific, including symptoms of acute dementia, impaired consciousness, dysarthria, hemiparesis, pyramidal tract signs, seizure activity, ataxia and signs of interhemispheric disconnection. The differential diagnosis of MBD may include Wernicke’s encephalopathy, multiple sclerosis, encephalitis, infectious or paraneoplastic leucoencephalopathy, infarction, Alzheimer’s disease, multi-infarct dementia and frontotemporal lobar degeneration (Pick) disease. The diagnosis of MBD is dependent on MRI findings of hyperintensity of the corpus callosum on T2 and fluid-attenuated inversion recovery T2 sequences, with or without extracallosal lesions. The use of MRI in diagnosis has allowed for early initiation of treatment with parenteral thiamine, and improved the prognosis of MBD from frequently fatal to a mortality of less than 8%. Administration of thiamine within 14 days of symptom onset has demonstrated statistically better outcomes over delayed treatment. We present a case report of MBD diagnosed in a 72-year-old woman who presented with ataxia and slurred speech, in an effort to highlight the importance of obtaining MRI in patients presenting with behavioural disturbance and neurological findings, as well as discuss the relationship between thiamine supplementation and demyelinating diseases in the central nervous system.

Background

Marchiafava-Bignami disease (MBD) is a rare, toxic demyelinating disorder of the central nervous system associated with chronic alcoholism and malnutrition.¹ In 2001, a study estimated that approximately 250 cases have been reported worldwide.² MBD most commonly affects Caucasian men aged 40–60 years with chronic alcoholism, but has also been reported in cases of severe malnutrition, paraneoplastic processes and uncontrolled diabetes.^3–5 MBD was previously classified based on clinical presentation as acute, subacute or chronic. Acute MBD can present with coma, pyramidal tract signs and seizure activity. Subacute MBD can present with acute dementia, dysarthria, ataxia and signs of interhemispheric disconnection. Chronic MBD can present with progressive dementia over the course of years.^{6 7} While the acute, subacute and chronic classification are still used, more recent case reports have adopted the classification of MBD into Type A or B based on clinical and radiology findings, and use acute, subacute and chronic terminology to describe stages of disease.⁸ The use of MRI in diagnosis has allowed for early initiation of treatment with parenteral thiamine, and improved the prognosis of MBD from frequently fatal to a mortality of less than 8%.^{9 10} There exists no specific treatment regimen approved for MBD but initiation of vitamin B complex supplementation, regardless of serum levels, within 2 weeks of symptom onset has been shown to have improved outcomes.⁴

Effective treatment regimens for MBD are studied by reviewing available published data, as randomised controlled trials are not practical to study the treatment of this rare disease. We present a case report of MBD diagnosed in a 72-year-old woman who presented with ataxia and slurred speech. The purpose of this study is to demonstrate clinical and radiographical findings of MBD in an effort to highlight the importance of MRI in the evaluation of patients presenting with behavioural disturbance and neurological findings, with discussion of thiamine treatment as it relates to the pathophysiology of disease.

Case report

A 72-year-old African-American woman with a medical history of hypertension, iron deficiency anaemia and malnutrition presented to the emergency department with a 2-day history of progressive slurred speech. The patient had acute-onset confusion and balance difficulty that started on the day of presentation. Prior to this presentation, the patient did not have any previous episodes of altered mental status. She admitted to a 30 pack-year smoking history, frequent alcohol use of up to 750 mL of wine per week for the past 6 years, with poor oral intake and nutrition. At her baseline, the patient lived alone, ambulated with a walker or cane, and was otherwise independent. She was afebrile, normotensive and was not hypoxic. She appeared comfortable, but chronically ill and malnourished. Her extraocular movements were intact, with horizontal nystagmus. She had dry mucous membranes, and white plaques in her oral mucosa, consistent with candida. Her cardiac, respiratory, gastrointestinal and integumentary examinations were unremarkable. She had symmetric, full range of motion of all of her extremities, but with generalised weakness. The neurological examination was significant for disorientation to the date, dysarthria, slow response to commands and generalised weakness. Her gait was unable to be assessed due to generalised weakness. Otherwise, her neurological examination, including motor, sensory and cranial nerve evaluation, was unremarkable.

Laboratory evaluation was unremarkable, including a complete metabolic panel, complete blood count, coagulation studies and troponin level. An ECG and chest X-ray were also unremarkable. CT scan of her head demonstrated new, low density within the splenium area of the corpus callosum, and subtle blurring of the grey–white junction of the parasagittal posterior left frontal lobe. MRI of her brain demonstrated hyperintensity on T2 and fluid-attenuated inversion recovery (FLAIR) T2 sequences in the corpus callosum and the cerebral cortex of the bilateral frontal lobes (figure 1). Diffusion-weighted images also showed hyperintensity in these regions with relatively decreased apparent diffusion coefficient (ADC) values. These findings were new when compared with a prior MRI brain examination from 2018. Magnetic resonance arteriogram of her brain was unremarkable.

Figure 1.

Fluid-attenuated inversion recovery images demonstrating hyperintensity of the corpus callosum (left) and the frontal cortex (right).

The patient was admitted for further evaluation of her acute encephalopathy. She was evaluated by a neurologist, who initially suspected a paraneoplastic, infectious or inflammatory process. Laboratory evaluation for vasculitis, autoimmune disorders and infectious processes, including syphilis and HIV testing, cerebrospinal fluid analysis, urinalysis and thyroid-stimulating hormone level, were unremarkable. Inflammatory markers were elevated, including a sedimentation rate of 51 mm/hour (reference level 0–30 mm/hour) and C reactive protein level of 3.4 mg/dL (reference level 0.000–1.000 mg/dL). Thiamine level was decreased at 34.7 nmol/L (reference level 66.5–200.0 nmol/L), cyanocobalamin level was elevated at 1149 pg/mL (reference level 180–914 pg/mL) and her folate level was normal. Speech pathologists evaluated her swallowing ability on her first hospital day, and recommended against oral feeding due to impaired swallowing function. After minimal improvement for 3 days, the patient and her family agreed to placement of a nasogastric (NG) tube for nutritional support, and tube feedings were initiated.

The diagnosis of MBD was made by the medical team, after discussing her clinical presentation, evaluation and radiographic images with the neurologist and radiologist. Six days after the onset of her symptoms and 4 days after her admission, parenteral thiamine supplementation was initiated with 500 mg three times per day. A second MRI of her brain was performed 3 days after initial imaging, and demonstrated progression of FLAIR T2 and T2 hyperintensity within the corpus callosum and grey matter cortex of the bilateral frontal lobes (figure 2). Sagittal CUBE FLAIR sequence demonstrated preferential involvement of the central layers of the corpus callosum. Atrophy of the body of the corpus callosum had also developed from remote prior examination. Diffusion-weighted images also showed persistent hyperintensity in these regions with relatively decreased ADC values.

Figure 2.

Diffusion-weighted images demonstrating hyperintensity in the corpus callosum (left) and the frontal cortex (right).

Treatment

We began parenteral thiamine supplementation with 500 mg three times per day. Her swallowing function remained impaired, and the NG tube remained in place. After a third swallowing evaluation, she was able to begin eating on her own, and was started on a clear liquid diet. She was discharged to a skilled nursing facility on her tenth hospital day, where she continued her rehabilitation, and intravenous thiamine replacement for four more days, totalling 7 days of parenteral thiamine treatment. After completion of parenteral thiamine supplementation, she continued oral thiamine supplementation of 100 mg per day indefinitely.

Her confusion, aphasia, weakness, gait and mental status continued to improve over the following 3 weeks. She was discharged from inpatient rehabilitation after 3 weeks to the care of her children and with home healthcare services.

Outcome and follow-up

The patient was discharged to a rehab facility where she continued to receive high-dose parenteral thiamine. Her confusion, aphasia, weakness, gait, dysphagia and mental status slowly improved and continued to improve over the following 3 weeks.

Discussion

MBD is a rare complication of chronic alcoholism and malnutrition. The clinical presentation is varied, and may be misdiagnosed as other neurocognitive disorders, causing delayed diagnosis and treatment.² We considered differential diagnoses, including Wernicke’s encephalopathy, hypoglycemic encephalopathy, multiple sclerosis, infectious or paraneoplastic leucoencephalopathy, infarction, Alzheimer’s disease and vascular dementia. MBD can be differentiated from these diagnoses by laboratory evaluation and MRI diffusion restriction patterns. Parainfectious, paraneoplastic and hypoglycemic encephalopathies were excluded by laboratory evaluation, demonstrating unremarkable cerebrospinal fluid, autoimmune and vasculitis findings. Multiple sclerosis and Alzheimer’s disease were excluded on the basis of MRI findings demonstrating the presence of bisymmetric corpus callosal lesions and the absence of pronounced temporal atrophy.^{1 11} Wernicke’s encephalopathy may be differentiated from MBD by MRI demonstrating abnormal signal intensity in the mammillary bodies, periaqueductal region and the walls of the third ventricle.¹⁰ Our patient presented with dysarthria and ataxia, with hyperintensity throughout the entire corpus callosum and extracallosal lesions noted in the frontal lobes on MRI; these findings are consistent with Type A MBD. The diagnosis of MBD is dependent on MRI findings, because the clinical presentation is non-specific.¹¹ Type A MBD typically presents with impaired consciousness, seizures, dysarthria and hemiparesis with hyperintensity on T2 and FLAIR T2 MRI sequences throughout the corpus callosum and presence of extracallosal lesions. Type B typically presents with less disturbance of consciousness, partial involvement of the corpus callosum on T2 and FLAIR T2 MRI sequences, and has a better prognosis than Type A.⁸ A distinguishing feature in our case was the presence of diffuse signal abnormalities in the cerebral cortices. Given the associated symmetric corpus callosal involvement, and the absence of midline abnormalities typically seen in Wernicke’s encephalopathy, our patient’s cortical lesions are felt to represent Morel’s laminar sclerosis.^{1 11}The presence of Morel’s laminar sclerosis in MBD may correlate with poor prognosis, though this is controversial.^{8 10} MBD has been reported to co-exist with cortical lesions consistent with Morel’s laminar sclerosis in up to 30% of patients.^{4 11}

The pathophysiology of MBD is uncertain; however, the role of thiamine deficiency has consistently been demonstrated in published case reports as a contributing factor to the development of disease.¹² Chronic alcoholism has a detrimental effect on thiamine deficiency, and is associated with a poor prognosis in MBD.⁴ The aetiology of thiamine deficiency in the setting of chronic alcoholism is multifactorial, and includes decreased dietary intake, intestinal malabsorption, altered hepatic uptake and metabolism, reduced renal tubular reabsorption, increased skeletal and visceral protein catabolism, and abnormal lipid metabolism. These processes that lead to thiamine deficiency within the tissues also cause impaired metabolism of sugar molecules, which impairs myelin synthesis in the brain.³ Neuroimaging studies have demonstrated decreased glucose metabolism in the brain on positron emission tomography in patients diagnosed with MBD.⁵ Impaired glucose metabolism in the brain decreases ATP production and myelin synthesis, while thiamine deficiency also directly affects thiamine-cofactor dependent enzymes increasing oxidative stress.³ Decreased ATP production increases dopamine and decreases acetylcholine, glutamate, aspartate and gamma-aminobutyric acid, all of which contribute to neurocognitive findings that have been misdiagnosed as schizophrenia.¹³ Increased oxidative stress through the production of reactive oxygen species causes lipid peroxidation, protein oxidation and neuronal damage that is evidenced by the characteristic MRI findings of MBD.³ This proposed biochemical pathophysiology is supported by histopathological findings in post-mortem autopsy as well as in vivo biopsy findings of cystic white matter necrosis, foamy histiocyte infiltration, demyelination and gliosis.¹⁴ Applying this proposed pathophysiology to therapeutic approaches reinforces the importance of thiamine supplementation, suggests a potential role for antidepressants and provides an explanation as to the questionable benefit of steroid treatment.

Serum thiamine levels do not directly correlate with tissue levels, therefore, thiamine supplementation should be initiated in patients suspected of having any alcoholic encephalopathy regardless of serum thiamine levels.³ There are no guidelines on the recommended regimen of thiamine supplementation, but good outcomes have been reported with treatment regimens similar to those used in Wernicke’s encephalopathy.⁹ Administration of thiamine within 14 days of symptom onset has demonstrated statistically better outcomes over delayed treatment.⁴ We initiated thiamine supplementation 4 days after symptom onset with 1500 mg per day, and improvement was noted in the patient’s speech and ambulation after 2 days of therapy. Intestinal malabsorption and impaired hepatic uptake of thiamine in the setting of chronic alcoholism support the preference of parenteral administration of thiamine for a minimum of 5 days’ duration in the treatment of MBD.¹⁵

This case demonstrates unique features from what is known of MBD. MBD is most commonly reported in Caucasian men aged 40–60 years, with an estimated 80% of cases diagnosed in this patient population, and a mean age at onset of 48 years.⁴ However, this case was diagnosed in an elderly woman who was aged 72 years at presentation. This case demonstrates that without MRI, the diagnosis of MBD may be mistaken for dementia, causing delay in treatment initiation and poor prognosis, and highlights the importance of obtaining MRI in patients presenting with behavioural disturbance and with neurological findings.^{4 15}

Learning points.

• Marchiafava-Bignami disease is a rare, toxic demyelinating disorder of the central nervous system associated with chronic alcoholism and malnutrition.

• As this is a rare disease, it is important to have a broad differential diagnosis when evaluating and treating a patient with neurological changes.

• Communication and learning from different specialists in an inpatient setting is critical for patient care as well as treating complex cases.