The Neuroradiology Journal 22: 35-40, 2009
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Non-Alcoholic Partially Reversible Marchiafava-Bignami Disease: Review and Relation with Reversible Splenial Lesions A Case Report and Literature Review M. CAULO*, C. BRIGANTI*, F. NOTTURNO**, G. COMMITTERI*, P. A. MATTEI*, A. TARTARO*, M. GALLUCCI***, A. UNCINI** * Department of Clinical Sciences and Bioimaging and ITAB, “G. d’Annunzio” University; Chieti, Italy ** Department of Human Motor Sciences and Neurodegenerative Diseases Unit, Aging Research Centre (CeSI), “G. d’Annunzio” University; Chieti, Italy *** Department of Radiology, University of L’Aquila; L’Aquila, Italy
Key words: non-alcoholic Marchiafava-Bignami disease, MRI, psychotropic drugs, reversible splenial lesions
SUMMARY – Marchiafava-Bignami disease (MBD) is a rare pathological condition characterized by progressive demyelination and necrosis of the corpus callosum (CC). MBD occurs in patients with chronic alcoholism although a few non-alcoholic cases have been reported. We describe a nonalcoholic, depressed patient, who developed MBD after psycho-active drug abuse. Magnetic resonance imaging (MRI) disclosed bilateral, symmetric, hyperintense regions in the genu, body and splenium of the CC associated with increased water diffusivity. Clinical and MRI findings showed a partial recovery after tapering/modification of psycho-active drugs. We reviewed the nine cases of non-alcoholic MBD reported in the literature. We conclude that most cases should have been diagnosed as a reversible isolated splenial lesion (MERS), a recently described condition semiotically similar to MBD but with a specific localization, restricted water diffusivity and reversibility at MRI. In conclusion, MBD is an extremely rare condition in non-alcoholic patients and the use of MRI for distinguishing between MBD and MERS is crucial.
Introduction The corpus callosum (CC) is the selective site of progressive demyelination and necrosis in Marchiafava-Bignami disease (MBD), a rare condition typically occurring in patients with chronic alcoholism 1. The clinical features of MBD are reduced consciousness, psychotic and emotional symptoms, seizures, hemiparesis, ataxia, apraxia and, rarely, symptoms of inter-hemispheric disconnection. In the preimaging era the diagnosis of MBD was based on pathological findings 2. Currently, magnetic resonance imaging (MRI) allows an “in vivo” diagnosis by demonstrating characteristic lesions, generally in the genu and body of the CC 3,4 . MBD was first described in Italian heavy red-wine drinkers 2,5, and subsequently associated with different alcoholic beverages.
We describe a non-alcoholic woman with psycho-active medication abuse who presented MBD with a subsequent partial clinical and neuroradiological recovery after tapering/modification of therapy. We review nine cases in the literature reporting non-alcoholic MBD 6-14. We also discuss the relation and differential aspects of non-alcoholic MBD and the recently described syndrome characterized by reversible splenial lesion of the CC: clinically mild encephalitis/encephalopathy with a reversible isolated splenial lesion (MERS) 15-19. Case Report A 78-year-old depressed woman with a medical history of one-year self-administered diazepam (up to 20 mg day), venlafaxine (up to 35
Non-Alcoholic Partially Reversible Marchiafava-Bignami Disease: Review and Relation with Reversible Splenial Lesion
A
B
C
D
E
F
M. Caulo
Figure 1 A-F) MRI studies at onset (upper row) and 4-month follow-up (lower row). Sagittal A) and axial B) FLAIR with selective spectral attenuation of fat signal (spectral attenuated inversion recovery, SPAIR) images, demonstrating hyperintense regions in the body, genu and splenium of the corpus callosum (arrowheads). Hyperintense signal in the anterior aspect of the splenium of corpus callosum in the ADC map indicating increased diffusivity (C, arrows). Corresponding sagittal D) and axial E) fat saturated FLAIR images showing a reduction of the size of the abnormal signal areas in the corpus callosum, especially in the splenium (arrow heads) where the ADC map shows normalization of water diffusivity (F, arrows).
300 mg day) and trazodone hydrochloride (up to 600 mg day) came to our observation due to aggressive behaviour and because she was no longer self-sufficient. On admission she was alert and oriented, speech was slightly dysarthric, strength/muscle tone and tendon reflexes were normal. Neuropsychological examination revealed depression, apathy and anxiety. The patient was completely unable to read words and sentences but single letters were sometimes readable. A right hemispatial neglect was evident in a spatial-attention task. Signs of inter-hemispheric disconnection were not detected. However, at the Corsi test of spatial short-term memory the patient showed a better performance with the left hand (span=6 36
items) than with the dominant right (span=4 items) 20. Laboratory testing, including serum electrolytes, renal and thyroid function tests, hemochrome and leukocyte count, urine and gas analysis were normal. The patient did not present signs of malnutrition and serum folic acid and B12 were within normal limits. Fluid attenuated inversion recovery (FLAIR) MRI sequences with selective spectral attenuation of fat signal (spectral attenuated inversion recovery, SPAIR) revealed bilateral symmetric hyperintense regions in genu, inferior aspect of the body and splenium of the CC (figure 1A, B). Diffusion weighted imaging (DWI) showed a corresponding region of increased water diffusivity in the splenium of the CC (figure 1C).
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The rest of the brain was unremarkable except for the presence of a few bilateral small white matter lesions, most likely of microvascular origin. Contrast enhancement was not present. Clinical and neuroradiological findings were considered consistent with MBD, possibly secondary to psychoactive drug abuse. Diazepam and Trazodone were tapered and then interrupted. Duloxetine at a dosage of 60 mg/day was introduced. Four months later evaluation confirmed alexia in the entire visual field and right hemi-spatial neglect. The patient’s performance at the Corsi test was now equivalent for both hands (span of five items). MRI follow-up revealed a decrease (visually quantified in approximately 40%) of the hyperintense regions in the CC on SPAIR sequences (figure 1D, E). DWI revealed a complete normalization of diffusivity (figure 1F). Discussion Different pathological conditions may involve the CC: ischemic stroke, diffuse axonal injury, inflammatory demyelination, brain tumors (glioblastoma, gliomatosis cerebri, lymphoma, metastasis, and germinoma), Wernicke encephalopathy and other metabolic diseases, Wallerian degeneration after hemispheric damage, MERS and MBD 2,8,21,22. Ischemic lesions of the CC are rare and usually unilateral (either anterior or posterior depending on the impaired vascular supply). Diffuse axonal injury usually involves the splenium and the genu with a history of major head trauma. Inflammatory demyelinating disease usually presents at MRI with oval or round lesions in the septo-callosal interface and also involves white matter regions other than the CC. Brain tumors generally present a mass effect, MR contrast enhancement and tend to be stable or increase in size. Wernicke encephalopathy has diencephalic and mammillary bodies involvement sometimes associated with CC lesions. Wallerian degeneration of CC is associated with a hemispherical lesion. Metabolic disorders and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) usually affect very young and middle aged people respectively 23. MERS is characterized at MRI by a typically oval, circumscribed lesions selectively involving the central aspect of the splenium of the CC, associated with restricted water diffusivity on DWI. Clinical presentation is non-specific, without evidence of callosal dis-
The Neuroradiology Journal 22: 35-40, 2009
connection syndrome. Lesions completely revert after a variable period 15-19. After we ruled out the other possibilities on the basis of clinical and neuroradiological results, the patient was diagnosed as suffering from MBD. MBD is a primary degeneration of the CC characterized by a symmetrical demyelination and necrosis preferentially of the central layers of the CC 24. The recent clinical and neuroradiological classification of MBD describes two subtypes 1. Type A: acute to subacute onset of consciousness impairment, pyramidal tract signs, limb hypertonia, seizures, hyperintense swelling on T2-weighted MR sequences of the CC and poor prognosis. Type B: normal or slightly impaired level of consciousness, dysarthria, gait disturbance, signs of interhemispheric disconnection and hyperintense lesions on T2-weighted MR sequences partially involving the CC. In the latter the prognosis is favourable and lesions may reverse suggesting an underlying oedema rather than demyelination. Neuro-pathological changes of the white matter of the CC in MBD can be explored using DWI which predicts a poor or favorable outcome with restricted or increased water diffusivity, respectively 25. Although MRI did not show the usual “sandwich-like” appearance in our patient, the CC was diffusely involved. The increased water diffusivity on DWI at the first MR examination, its normalization during follow-up and the favourable clinical outcome lead us to hypothesize the coexistence of extracellular oedema and demyelination in MBD. Due to the “vulnerability” of the CC to different exogenous substances and the partial regression of the disease in our patient after drug tapering/modification, we concluded a toxic effect of psychoactive drugs on the CC as likely 15,19,26 . To our knowledge, only nine cases of non-alcoholic MBD have been described in literature since 1979 (table 1) 6-14. The mean age of these patients was 58.2 years for males (n=5) and 40.5 years for females (n=4). Five patients were Caucasian and four were Asian. Five patients had a history of malnutrition, extremely poor care condition and weight loss 6,8,9,12,14. One patient had a history of hepatic cirrhosis and peritonitis, one patient of stage IV inoperable ovarian cancer and one of schizophrenia, diabetes mellitus and hypertension 10,11,13. At admission eight patients had consciousness impairment 6-8, 10-14. Two patients showed aggressive behaviour and irritability 6,12. Four had language disturbances 37
Non-Alcoholic Partially Reversible Marchiafava-Bignami Disease: Review and Relation with Reversible Splenial Lesion
M. Caulo
Table I Clinical, neuroradiological and autoptical details of 9 cases of non-alcoholic MBD reported in the literature Hystory
Symptoms and Signs
Vomiting and loss of weight
Irritability, monosyllabic replies, confusion, fever, generalized weakness with some increase in muscle tone
Patient 2, 52year-old male [7]
N.A.
Loss of consciousness, dyspnea, cyanosis, fever
Patient 3, 64year-old male [8]
Severe malnutrition, depression, remote alcohol abuse
Stupor, fever, no longer walk alone, no spontaneous speech
Patient 4, 80year-old female [9]
Malnutrition, neglect, maltreatment
Severe exsiccosis, pressure sores and marasmus, contractures of the knee and hip joints
N.A.
Patient 5, 62year-old male [10]
Schizophrenia, diabetes mellitus, hypertension
Reference
Patient 1, 47year-old male [6]
Patient 6, 66year-old male [11]
Patient 7, 21year-old female [12]
Patient 8, 45year-old female [13]
Patient 9, 16year-old female [14]
38
Additionals Comments
Autoptycal Findings
Death
Softening and demyelination of the central portion of the corpus callosum
Death
Symmetric demyelination and necrosis of the entire body of corpus callosum
Death
Symmetric demyelinating focus in the anterior half of the body of the corpus callosum
N.A.
Death
Central necrosis along the length of the corpus callosum
Coma, quadriparesis
T2-hyperintensity in the splenium of the corpus callosum, restricted diffusion on DWI
(30 days) Complete resolution of signal abnormalities on T2-weighted images and DWI
recovered after insulin and antibiotics treatment
N.A.
Hepatic cirrhosis, peritonitis
Acute loss of consciousness, increased tone of the upper extremities and of the mandibular muscle
T2-hyperintensity in the splenium of the corpus callosum
N.A.
recovered after vitamin B supplementation
N.A.
Anxiety, chronic pancreatitis, remote alcohol abuse, malnutrition, laparoscopic cholecystectomy
Fluctuation in level of consciousness, aggressive behavior, visual hallucination, fever, tremor involving all four extremities and increased muscle tone
T2-hyperintensity with mild swelling in the splenium of the corpus callosum, restricted diffusion on DWI
Reduction (11 days) and complete resolution (7 weeks) of signal abnormalities on T2-weighted images and DWI
recovered after multivitamin supplementation
N.A.
IV stage ovarian cancer
Acute loss of consciousness, increased tone of all the extremities, no spontaneous verbal production or repetition
Areas of high T2 signal intensity bilaterally in the corpus callosum
N.A.
Death
N.A.
Coma, increased muscle tone, poverty of speech
T2-hyperintensity in the splenium of the corpus callosum
(45 days) Complete resolution of the signal abnormalities on T2-weighted images
recovered after high-dose intravenous corticosteroid administration
N.A.
Severe malnutrition
Mri Findings
N.A.
N.A.
N.A.
Mri Follow-Up
N.A.
N.A.
N.A.
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(monosyllabic replies, no spontaneous speech) 6,8,13,14 . Only one patient had visual hallucinations 12. Seven patients had hypertonia of the extremities sometimes associated with tremor 6, 9-14 . The electroencephalogram showed moderate generalized slowing and cerebral spinal fluid examination were normal results 8, 10-13. MRI was performed in only five cases. Hyperintense lesions on T2-weighted sequences and mild swelling limited to the splenium of the CC were observed in four patients 10-12,14. Signal changes were observed bilaterally and diffusely in the CC in one patient 13. DWI demonstrated a restricted diffusion in the splenium in two patients 10, 12. Contrast enhancement was never observed. Three patients received MRI followup which showed a complete resolution of the signal abnormalities in the splenium 10,12,14. Four of the patients who did not undergo MRI died shortly after they were admitted and MBD was diagnosed post-mortem 6-9. Of the four patients who survived, two recovered shortly after nutritional and vitamin supplementation 11,12; one recovered after high-dose intravenous corticosteroid administration, and one after insulin and antibiotics treatment 10,14. Our review of the literature shows that four out of the five patients who were diagnosed using imaging as non-alcoholic MBD had a selective involvement of the median aspect of the splenium (two with restricted diffusivity) completely recovered from symptoms after vitamins, corticosteroids, insulin and antibiotics or nutritional implementation. Isolated and reversible splenial MRI signal changes have been recently described as a new entity: MERS, manifesting with seizure, confusion, ataxia, drowsiness, coma, headache and delirium 15-19. Although these features are clinically
The Neuroradiology Journal 22: 35-40, 2009
indistinguishable from MBD, the significant neuroradiological difference is the selective and reversible involvement of the median aspect of the splenium that appears hyperintense on MRI T2-weighted sequences with restricted DWI. Therefore, the four cases with isolated and reversible splenial lesions labelled as nonalcoholic MBD may be reversible splenial lesions. The only patient (case 8) who fulfilled clinical and neuroradiological criteria for nonalcoholic MBD had a history of ovarian cancer and the authors hypothesized that the involvement of the CC might represent a paraneoplastic syndrome 13. Our review of non-alcoholic MBD demonstrated that this condition is even rarer than previously thought because in the neuro-imaging era, it has often been misdiagnosed as MERS. In MBD, the lesions seen in MRI are not confined to the splenium, have variable water diffusivity and are only rarely reversible. By contrast, in MERS, the lesions are circumscribed and located (selectively and exclusively) in the median aspect of the splenium with restricted water diffusivity and are reversible. This change in pathological attribution opens an additional discussion concerning therapeutic strategies. In fact, in the reviewed patients, anatomical and clinical recovery was variably attributed to insulin, antibiotics, vitamins or steroids without any evidence that the specific therapy actually determined a significant clinical improvement. Thus the need for the above-mentioned therapies for the improvement of splenial lesions is questionable. In conclusion, MBD is an extremely rare condition in non-alcoholic patients and the use of MRI for distinguishing between MBD and MERS is crucial because of their different prognosis and therapy.
References 1 Heinrich A, Runge U, Khaw AV: Clinicoradiologic subtypes of Marchiafava-Bignami disease. J Neurol 251: 1050-1059, 2004. 2 Koeppen AH, Barron KD: Marchiafava-Bignami disease. Neurology 28: 290-294, 1978. 3 Chang KH, Cha SH, Han MH et Al: Marchiafava-Bignami disease: serial changes in corpus callosum on MRI. Neuroradiology 34: 480-482, 1992. 4 Arbelaez A, Pajon, Castillo M: Acute Marchiafava-Bignami disease: MR findings in two patients. Am J Neuroradiol 24: 1955-1957, 2003. 5 Marchiafava E, Bignami A: Sopra una alterazione del corpo calloso osservata in soggetti alcolisti. Riv Pat Nerv Ment 8: 544-549, 1903. 6 Leong ASY: Marchiafava-Bignami Disease in a non-alcoholic Indian male. Pathology 11: 241-249, 1979.
7 Khuo-Chun M, Kuan-Jung C: Primary necrosis of corpus callosum with dystrophic astrogliosis and Rosenthal-like fiber formation. Acta Neuropathol 60: 283-290, 1983. 8 Kosaka K, Aoki M, Kawasaki N et Al: A non-alcoholic Japanese patient with Wernicke’s encephalopathy and Marchiafava-Bignami disease. Clin Neuropathol 3: 231-236, 1984. 9 Rickert CH, Karger B, Varchmin-Schultheiss K et Al: Neglect-associated fatal Marchiafava-Bignami disease in a non-alcoholic woman. Int J Legal Med 115: 90-93, 2001. 10 Hlaihel C, Gonnaud PM, Champin S et Al: Diffusionweighted magnetic resonance imaging in MarchiafavaBignami disease: follow-up studies. Neuroradiology 47: 520-524, 2005.
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Non-Alcoholic Partially Reversible Marchiafava-Bignami Disease: Review and Relation with Reversible Splenial Lesion
11 Más G, González-Caballero G, Martínez-Ortiz MJ et Al: Marchiafava-Bignami disease in a non-alcoholic patient. Rev Neurol 42: 637-638, 2006. 12 Rusche-Skolarus LE, Lucey BP, Vo KD et Al: Transient encephalopathy in a postoperative non-alcoholic female with Marchiafava-Bignami disease. Clin Neurol Neurosurg 109: 713-715, 2007. 13 Celik Y, Temizoz O, Genchellac H et Al: A non-alcoholic patient with acute Marchiafava-Bignami disease associated with gynecologic malignancy: Paraneoplastic Marchiafava-Bignami disease? Clin Neurol Neurosurg 109: 505-508, 2007. 14 Tao H, Kitagawa N, Kako Y et Al: A case of anorexia nervosa with Marchiafava-Bignami disease that responded to high-dose intravenous corticosteroid administration. Psychiatry Res 156: 181-184, 2007. 15 Gallucci M, Limbucci N, Paonessa A et Al: Reversible focal splenial lesions. Neuroradiology 49: 541-544, 2007. 16 Doherty MJ, Jayadev S, Watson NF et Al: Clinical implications of splenium magnetic resonance imaging signal changes. Arch Neurol 62: 433-437, 2005. 17 Tada H, Takanashi J, Barkovich AJ et Al: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology 63: 1854-1858, 2004. 18 Takanashi J, Barkovich AJ, Shiihara T et Al: Widening spectrum of a reversible splenial lesion with transiently reduced diffusion. Am J Neuroradiol 27: 836838, 2006. 19 Da Rocha AJ, Reis F, Gama HP et Al: Focal transient lesion in the splenium of the corpus callosum in three non-epileptic patients. Neuroradiology 48: 731-735, 2006. 20 Farrell Pagulayan K, Busch RM, Medina KL et Al: Developmental normative data for the Corsi Blocktapping task. J Clin Exp Neuropsychol 28: 1043-1052, 2006.
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21 Uchino A, Takase Y, Nomiyama K et Al: Acquired lesions of the corpus callosum: MR imaging. Eur Radiol 16: 905-914, 2006. 22 Guo G, Wu R, Brugge K et Al: Focal lesion in splenium of corpus callosum on FLAIR MRI: common findings in aged patients. The Neuroradiology Journal 19: 301305, 2006. 23 Kalimo H, Ruchoux MM, Viitanen M et Al: CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol 12: 371-384, 2002. 24 Harper C, Butterworth R: Nutritional and metabolic disorders. In: Graham DI, Lantos PL (eds): Greenfield’s Neuropathology, 6th edn. London, Arnold, 1997: 616-617. 25 Ménegon P, Sibon I, Pachai C et Al: Marchiafava-Bignami disease: diffusion-weighted MRI in corpus callosum and cortical lesions. Neurology 65: 475-477, 2005. 26 Prilipko O, Delavelle J, Lazeyras F et Al: Reversible cytotoxic edema in the splenium of the corpus callosum related to antiepileptic treatment: report of two cases and literature review. Epilepsia 46: 1633-1636, 2005.
Massimo Caulo, MD, PhD Department of Clinical Sciences and Bioimaging and ITAB “G. d’Annunzio” University Via dei Vestini, 33 66100 Chieti, Italy E-mail: [email protected]
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Non-Alcoholic Partially Reversible Marchiafava-Bignami Disease: Review and Relation with Reversible Splenial Lesions A Case Report and Literature Review M. CAULO*, C. BRIGANTI*, F. NOTTURNO**, G. COMMITTERI*, P. A. MATTEI*, A. TARTARO*, M. GALLUCCI***, A. UNCINI** * Department of Clinical Sciences and Bioimaging and ITAB, “G. d’Annunzio” University; Chieti, Italy ** Department of Human Motor Sciences and Neurodegenerative Diseases Unit, Aging Research Centre (CeSI), “G. d’Annunzio” University; Chieti, Italy *** Department of Radiology, University of L’Aquila; L’Aquila, Italy
Key words: non-alcoholic Marchiafava-Bignami disease, MRI, psychotropic drugs, reversible splenial lesions
SUMMARY – Marchiafava-Bignami disease (MBD) is a rare pathological condition characterized by progressive demyelination and necrosis of the corpus callosum (CC). MBD occurs in patients with chronic alcoholism although a few non-alcoholic cases have been reported. We describe a nonalcoholic, depressed patient, who developed MBD after psycho-active drug abuse. Magnetic resonance imaging (MRI) disclosed bilateral, symmetric, hyperintense regions in the genu, body and splenium of the CC associated with increased water diffusivity. Clinical and MRI findings showed a partial recovery after tapering/modification of psycho-active drugs. We reviewed the nine cases of non-alcoholic MBD reported in the literature. We conclude that most cases should have been diagnosed as a reversible isolated splenial lesion (MERS), a recently described condition semiotically similar to MBD but with a specific localization, restricted water diffusivity and reversibility at MRI. In conclusion, MBD is an extremely rare condition in non-alcoholic patients and the use of MRI for distinguishing between MBD and MERS is crucial.
Introduction The corpus callosum (CC) is the selective site of progressive demyelination and necrosis in Marchiafava-Bignami disease (MBD), a rare condition typically occurring in patients with chronic alcoholism 1. The clinical features of MBD are reduced consciousness, psychotic and emotional symptoms, seizures, hemiparesis, ataxia, apraxia and, rarely, symptoms of inter-hemispheric disconnection. In the preimaging era the diagnosis of MBD was based on pathological findings 2. Currently, magnetic resonance imaging (MRI) allows an “in vivo” diagnosis by demonstrating characteristic lesions, generally in the genu and body of the CC 3,4 . MBD was first described in Italian heavy red-wine drinkers 2,5, and subsequently associated with different alcoholic beverages.
We describe a non-alcoholic woman with psycho-active medication abuse who presented MBD with a subsequent partial clinical and neuroradiological recovery after tapering/modification of therapy. We review nine cases in the literature reporting non-alcoholic MBD 6-14. We also discuss the relation and differential aspects of non-alcoholic MBD and the recently described syndrome characterized by reversible splenial lesion of the CC: clinically mild encephalitis/encephalopathy with a reversible isolated splenial lesion (MERS) 15-19. Case Report A 78-year-old depressed woman with a medical history of one-year self-administered diazepam (up to 20 mg day), venlafaxine (up to 35
Non-Alcoholic Partially Reversible Marchiafava-Bignami Disease: Review and Relation with Reversible Splenial Lesion
A
B
C
D
E
F
M. Caulo
Figure 1 A-F) MRI studies at onset (upper row) and 4-month follow-up (lower row). Sagittal A) and axial B) FLAIR with selective spectral attenuation of fat signal (spectral attenuated inversion recovery, SPAIR) images, demonstrating hyperintense regions in the body, genu and splenium of the corpus callosum (arrowheads). Hyperintense signal in the anterior aspect of the splenium of corpus callosum in the ADC map indicating increased diffusivity (C, arrows). Corresponding sagittal D) and axial E) fat saturated FLAIR images showing a reduction of the size of the abnormal signal areas in the corpus callosum, especially in the splenium (arrow heads) where the ADC map shows normalization of water diffusivity (F, arrows).
300 mg day) and trazodone hydrochloride (up to 600 mg day) came to our observation due to aggressive behaviour and because she was no longer self-sufficient. On admission she was alert and oriented, speech was slightly dysarthric, strength/muscle tone and tendon reflexes were normal. Neuropsychological examination revealed depression, apathy and anxiety. The patient was completely unable to read words and sentences but single letters were sometimes readable. A right hemispatial neglect was evident in a spatial-attention task. Signs of inter-hemispheric disconnection were not detected. However, at the Corsi test of spatial short-term memory the patient showed a better performance with the left hand (span=6 36
items) than with the dominant right (span=4 items) 20. Laboratory testing, including serum electrolytes, renal and thyroid function tests, hemochrome and leukocyte count, urine and gas analysis were normal. The patient did not present signs of malnutrition and serum folic acid and B12 were within normal limits. Fluid attenuated inversion recovery (FLAIR) MRI sequences with selective spectral attenuation of fat signal (spectral attenuated inversion recovery, SPAIR) revealed bilateral symmetric hyperintense regions in genu, inferior aspect of the body and splenium of the CC (figure 1A, B). Diffusion weighted imaging (DWI) showed a corresponding region of increased water diffusivity in the splenium of the CC (figure 1C).
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The rest of the brain was unremarkable except for the presence of a few bilateral small white matter lesions, most likely of microvascular origin. Contrast enhancement was not present. Clinical and neuroradiological findings were considered consistent with MBD, possibly secondary to psychoactive drug abuse. Diazepam and Trazodone were tapered and then interrupted. Duloxetine at a dosage of 60 mg/day was introduced. Four months later evaluation confirmed alexia in the entire visual field and right hemi-spatial neglect. The patient’s performance at the Corsi test was now equivalent for both hands (span of five items). MRI follow-up revealed a decrease (visually quantified in approximately 40%) of the hyperintense regions in the CC on SPAIR sequences (figure 1D, E). DWI revealed a complete normalization of diffusivity (figure 1F). Discussion Different pathological conditions may involve the CC: ischemic stroke, diffuse axonal injury, inflammatory demyelination, brain tumors (glioblastoma, gliomatosis cerebri, lymphoma, metastasis, and germinoma), Wernicke encephalopathy and other metabolic diseases, Wallerian degeneration after hemispheric damage, MERS and MBD 2,8,21,22. Ischemic lesions of the CC are rare and usually unilateral (either anterior or posterior depending on the impaired vascular supply). Diffuse axonal injury usually involves the splenium and the genu with a history of major head trauma. Inflammatory demyelinating disease usually presents at MRI with oval or round lesions in the septo-callosal interface and also involves white matter regions other than the CC. Brain tumors generally present a mass effect, MR contrast enhancement and tend to be stable or increase in size. Wernicke encephalopathy has diencephalic and mammillary bodies involvement sometimes associated with CC lesions. Wallerian degeneration of CC is associated with a hemispherical lesion. Metabolic disorders and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) usually affect very young and middle aged people respectively 23. MERS is characterized at MRI by a typically oval, circumscribed lesions selectively involving the central aspect of the splenium of the CC, associated with restricted water diffusivity on DWI. Clinical presentation is non-specific, without evidence of callosal dis-
The Neuroradiology Journal 22: 35-40, 2009
connection syndrome. Lesions completely revert after a variable period 15-19. After we ruled out the other possibilities on the basis of clinical and neuroradiological results, the patient was diagnosed as suffering from MBD. MBD is a primary degeneration of the CC characterized by a symmetrical demyelination and necrosis preferentially of the central layers of the CC 24. The recent clinical and neuroradiological classification of MBD describes two subtypes 1. Type A: acute to subacute onset of consciousness impairment, pyramidal tract signs, limb hypertonia, seizures, hyperintense swelling on T2-weighted MR sequences of the CC and poor prognosis. Type B: normal or slightly impaired level of consciousness, dysarthria, gait disturbance, signs of interhemispheric disconnection and hyperintense lesions on T2-weighted MR sequences partially involving the CC. In the latter the prognosis is favourable and lesions may reverse suggesting an underlying oedema rather than demyelination. Neuro-pathological changes of the white matter of the CC in MBD can be explored using DWI which predicts a poor or favorable outcome with restricted or increased water diffusivity, respectively 25. Although MRI did not show the usual “sandwich-like” appearance in our patient, the CC was diffusely involved. The increased water diffusivity on DWI at the first MR examination, its normalization during follow-up and the favourable clinical outcome lead us to hypothesize the coexistence of extracellular oedema and demyelination in MBD. Due to the “vulnerability” of the CC to different exogenous substances and the partial regression of the disease in our patient after drug tapering/modification, we concluded a toxic effect of psychoactive drugs on the CC as likely 15,19,26 . To our knowledge, only nine cases of non-alcoholic MBD have been described in literature since 1979 (table 1) 6-14. The mean age of these patients was 58.2 years for males (n=5) and 40.5 years for females (n=4). Five patients were Caucasian and four were Asian. Five patients had a history of malnutrition, extremely poor care condition and weight loss 6,8,9,12,14. One patient had a history of hepatic cirrhosis and peritonitis, one patient of stage IV inoperable ovarian cancer and one of schizophrenia, diabetes mellitus and hypertension 10,11,13. At admission eight patients had consciousness impairment 6-8, 10-14. Two patients showed aggressive behaviour and irritability 6,12. Four had language disturbances 37
Non-Alcoholic Partially Reversible Marchiafava-Bignami Disease: Review and Relation with Reversible Splenial Lesion
M. Caulo
Table I Clinical, neuroradiological and autoptical details of 9 cases of non-alcoholic MBD reported in the literature Hystory
Symptoms and Signs
Vomiting and loss of weight
Irritability, monosyllabic replies, confusion, fever, generalized weakness with some increase in muscle tone
Patient 2, 52year-old male [7]
N.A.
Loss of consciousness, dyspnea, cyanosis, fever
Patient 3, 64year-old male [8]
Severe malnutrition, depression, remote alcohol abuse
Stupor, fever, no longer walk alone, no spontaneous speech
Patient 4, 80year-old female [9]
Malnutrition, neglect, maltreatment
Severe exsiccosis, pressure sores and marasmus, contractures of the knee and hip joints
N.A.
Patient 5, 62year-old male [10]
Schizophrenia, diabetes mellitus, hypertension
Reference
Patient 1, 47year-old male [6]
Patient 6, 66year-old male [11]
Patient 7, 21year-old female [12]
Patient 8, 45year-old female [13]
Patient 9, 16year-old female [14]
38
Additionals Comments
Autoptycal Findings
Death
Softening and demyelination of the central portion of the corpus callosum
Death
Symmetric demyelination and necrosis of the entire body of corpus callosum
Death
Symmetric demyelinating focus in the anterior half of the body of the corpus callosum
N.A.
Death
Central necrosis along the length of the corpus callosum
Coma, quadriparesis
T2-hyperintensity in the splenium of the corpus callosum, restricted diffusion on DWI
(30 days) Complete resolution of signal abnormalities on T2-weighted images and DWI
recovered after insulin and antibiotics treatment
N.A.
Hepatic cirrhosis, peritonitis
Acute loss of consciousness, increased tone of the upper extremities and of the mandibular muscle
T2-hyperintensity in the splenium of the corpus callosum
N.A.
recovered after vitamin B supplementation
N.A.
Anxiety, chronic pancreatitis, remote alcohol abuse, malnutrition, laparoscopic cholecystectomy
Fluctuation in level of consciousness, aggressive behavior, visual hallucination, fever, tremor involving all four extremities and increased muscle tone
T2-hyperintensity with mild swelling in the splenium of the corpus callosum, restricted diffusion on DWI
Reduction (11 days) and complete resolution (7 weeks) of signal abnormalities on T2-weighted images and DWI
recovered after multivitamin supplementation
N.A.
IV stage ovarian cancer
Acute loss of consciousness, increased tone of all the extremities, no spontaneous verbal production or repetition
Areas of high T2 signal intensity bilaterally in the corpus callosum
N.A.
Death
N.A.
Coma, increased muscle tone, poverty of speech
T2-hyperintensity in the splenium of the corpus callosum
(45 days) Complete resolution of the signal abnormalities on T2-weighted images
recovered after high-dose intravenous corticosteroid administration
N.A.
Severe malnutrition
Mri Findings
N.A.
N.A.
N.A.
Mri Follow-Up
N.A.
N.A.
N.A.
www. centauro. it
(monosyllabic replies, no spontaneous speech) 6,8,13,14 . Only one patient had visual hallucinations 12. Seven patients had hypertonia of the extremities sometimes associated with tremor 6, 9-14 . The electroencephalogram showed moderate generalized slowing and cerebral spinal fluid examination were normal results 8, 10-13. MRI was performed in only five cases. Hyperintense lesions on T2-weighted sequences and mild swelling limited to the splenium of the CC were observed in four patients 10-12,14. Signal changes were observed bilaterally and diffusely in the CC in one patient 13. DWI demonstrated a restricted diffusion in the splenium in two patients 10, 12. Contrast enhancement was never observed. Three patients received MRI followup which showed a complete resolution of the signal abnormalities in the splenium 10,12,14. Four of the patients who did not undergo MRI died shortly after they were admitted and MBD was diagnosed post-mortem 6-9. Of the four patients who survived, two recovered shortly after nutritional and vitamin supplementation 11,12; one recovered after high-dose intravenous corticosteroid administration, and one after insulin and antibiotics treatment 10,14. Our review of the literature shows that four out of the five patients who were diagnosed using imaging as non-alcoholic MBD had a selective involvement of the median aspect of the splenium (two with restricted diffusivity) completely recovered from symptoms after vitamins, corticosteroids, insulin and antibiotics or nutritional implementation. Isolated and reversible splenial MRI signal changes have been recently described as a new entity: MERS, manifesting with seizure, confusion, ataxia, drowsiness, coma, headache and delirium 15-19. Although these features are clinically
The Neuroradiology Journal 22: 35-40, 2009
indistinguishable from MBD, the significant neuroradiological difference is the selective and reversible involvement of the median aspect of the splenium that appears hyperintense on MRI T2-weighted sequences with restricted DWI. Therefore, the four cases with isolated and reversible splenial lesions labelled as nonalcoholic MBD may be reversible splenial lesions. The only patient (case 8) who fulfilled clinical and neuroradiological criteria for nonalcoholic MBD had a history of ovarian cancer and the authors hypothesized that the involvement of the CC might represent a paraneoplastic syndrome 13. Our review of non-alcoholic MBD demonstrated that this condition is even rarer than previously thought because in the neuro-imaging era, it has often been misdiagnosed as MERS. In MBD, the lesions seen in MRI are not confined to the splenium, have variable water diffusivity and are only rarely reversible. By contrast, in MERS, the lesions are circumscribed and located (selectively and exclusively) in the median aspect of the splenium with restricted water diffusivity and are reversible. This change in pathological attribution opens an additional discussion concerning therapeutic strategies. In fact, in the reviewed patients, anatomical and clinical recovery was variably attributed to insulin, antibiotics, vitamins or steroids without any evidence that the specific therapy actually determined a significant clinical improvement. Thus the need for the above-mentioned therapies for the improvement of splenial lesions is questionable. In conclusion, MBD is an extremely rare condition in non-alcoholic patients and the use of MRI for distinguishing between MBD and MERS is crucial because of their different prognosis and therapy.
References 1 Heinrich A, Runge U, Khaw AV: Clinicoradiologic subtypes of Marchiafava-Bignami disease. J Neurol 251: 1050-1059, 2004. 2 Koeppen AH, Barron KD: Marchiafava-Bignami disease. Neurology 28: 290-294, 1978. 3 Chang KH, Cha SH, Han MH et Al: Marchiafava-Bignami disease: serial changes in corpus callosum on MRI. Neuroradiology 34: 480-482, 1992. 4 Arbelaez A, Pajon, Castillo M: Acute Marchiafava-Bignami disease: MR findings in two patients. Am J Neuroradiol 24: 1955-1957, 2003. 5 Marchiafava E, Bignami A: Sopra una alterazione del corpo calloso osservata in soggetti alcolisti. Riv Pat Nerv Ment 8: 544-549, 1903. 6 Leong ASY: Marchiafava-Bignami Disease in a non-alcoholic Indian male. Pathology 11: 241-249, 1979.
7 Khuo-Chun M, Kuan-Jung C: Primary necrosis of corpus callosum with dystrophic astrogliosis and Rosenthal-like fiber formation. Acta Neuropathol 60: 283-290, 1983. 8 Kosaka K, Aoki M, Kawasaki N et Al: A non-alcoholic Japanese patient with Wernicke’s encephalopathy and Marchiafava-Bignami disease. Clin Neuropathol 3: 231-236, 1984. 9 Rickert CH, Karger B, Varchmin-Schultheiss K et Al: Neglect-associated fatal Marchiafava-Bignami disease in a non-alcoholic woman. Int J Legal Med 115: 90-93, 2001. 10 Hlaihel C, Gonnaud PM, Champin S et Al: Diffusionweighted magnetic resonance imaging in MarchiafavaBignami disease: follow-up studies. Neuroradiology 47: 520-524, 2005.
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Non-Alcoholic Partially Reversible Marchiafava-Bignami Disease: Review and Relation with Reversible Splenial Lesion
11 Más G, González-Caballero G, Martínez-Ortiz MJ et Al: Marchiafava-Bignami disease in a non-alcoholic patient. Rev Neurol 42: 637-638, 2006. 12 Rusche-Skolarus LE, Lucey BP, Vo KD et Al: Transient encephalopathy in a postoperative non-alcoholic female with Marchiafava-Bignami disease. Clin Neurol Neurosurg 109: 713-715, 2007. 13 Celik Y, Temizoz O, Genchellac H et Al: A non-alcoholic patient with acute Marchiafava-Bignami disease associated with gynecologic malignancy: Paraneoplastic Marchiafava-Bignami disease? Clin Neurol Neurosurg 109: 505-508, 2007. 14 Tao H, Kitagawa N, Kako Y et Al: A case of anorexia nervosa with Marchiafava-Bignami disease that responded to high-dose intravenous corticosteroid administration. Psychiatry Res 156: 181-184, 2007. 15 Gallucci M, Limbucci N, Paonessa A et Al: Reversible focal splenial lesions. Neuroradiology 49: 541-544, 2007. 16 Doherty MJ, Jayadev S, Watson NF et Al: Clinical implications of splenium magnetic resonance imaging signal changes. Arch Neurol 62: 433-437, 2005. 17 Tada H, Takanashi J, Barkovich AJ et Al: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology 63: 1854-1858, 2004. 18 Takanashi J, Barkovich AJ, Shiihara T et Al: Widening spectrum of a reversible splenial lesion with transiently reduced diffusion. Am J Neuroradiol 27: 836838, 2006. 19 Da Rocha AJ, Reis F, Gama HP et Al: Focal transient lesion in the splenium of the corpus callosum in three non-epileptic patients. Neuroradiology 48: 731-735, 2006. 20 Farrell Pagulayan K, Busch RM, Medina KL et Al: Developmental normative data for the Corsi Blocktapping task. J Clin Exp Neuropsychol 28: 1043-1052, 2006.
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21 Uchino A, Takase Y, Nomiyama K et Al: Acquired lesions of the corpus callosum: MR imaging. Eur Radiol 16: 905-914, 2006. 22 Guo G, Wu R, Brugge K et Al: Focal lesion in splenium of corpus callosum on FLAIR MRI: common findings in aged patients. The Neuroradiology Journal 19: 301305, 2006. 23 Kalimo H, Ruchoux MM, Viitanen M et Al: CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol 12: 371-384, 2002. 24 Harper C, Butterworth R: Nutritional and metabolic disorders. In: Graham DI, Lantos PL (eds): Greenfield’s Neuropathology, 6th edn. London, Arnold, 1997: 616-617. 25 Ménegon P, Sibon I, Pachai C et Al: Marchiafava-Bignami disease: diffusion-weighted MRI in corpus callosum and cortical lesions. Neurology 65: 475-477, 2005. 26 Prilipko O, Delavelle J, Lazeyras F et Al: Reversible cytotoxic edema in the splenium of the corpus callosum related to antiepileptic treatment: report of two cases and literature review. Epilepsia 46: 1633-1636, 2005.
Massimo Caulo, MD, PhD Department of Clinical Sciences and Bioimaging and ITAB “G. d’Annunzio” University Via dei Vestini, 33 66100 Chieti, Italy E-mail: [email protected]
