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Infratentorial and supratentorial leukoencephalopathy associated with vitamin B12 deficiency
Case Report
Infratentorial and Supratentorial Leukoencephalopathy Associated With Vitamin B12 Deficiency Shidong Su, MD, PhD, Richard B. Libman, MD, FRCP(C),Alan Diamond, MD, and Sophia Sharfstein, MD
Background: Striking cerebral white matter abnormalities involving supratentorial regions seen on magnetic resonance imaging (MRI) scans have been described in patients with vitamin B12 deficiency. Severe involvement of infratentorial structures with partial reversibility has not been previously documented. Observation: A 54-year-old man experienced severe weight loss, associated with dementia and focal deficits. Laboratory analysis showed a severe vitamin B12 deficiency and elevated serum homocysteine. MRI scans showed a severe and diffuse white matter abnormal signal involving both the supra- and infratentorial compartments. Vitamin B12 supplementation resulted in a mild improvement in cognitive deficits and a marked resolution of imaging abnormalities. Conclusion: Leukoencephalopathy and dementia should raise the suspicion of a vitamin B12 deficiency because vitamin B12 supplementation may result in at least partial clinical improvement. Key Words: Leukoencephalopathy--B12-~Cobalamin.
The clinical and imaging characteristics of patients with vitamin B12 deficiency have been recently described. 1,2 We report an additional patient, who showed striking involvement and partial reversibility of both supratentorial and infratentorial abnormalities.
Case Report A 54-year-old man, returning from an extended visit to Haiti, was noted to be confused, incontinent, and unable to walk because of weakness in his right leg. He could not
From the Departments of Neurology and Radiology (Neuroradiology), Long Island Jewish Medical Center, Long Island Campus for Albert Einstein College of Medicine, New Hyde Park, NY. Received July 23, 1999; accepted October 28,1999. Address reprint requests to Richard B. Libman, MD, The Department of Neurology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, NY 11042. Copyright 9 2000 by National Stroke Association 1052-3057/00/0903-000653.00/0 doi:10.1053/st.2000.5869
136
recall any details of his medical history. According to his wife, who had not seen him for the previous 7 years, he h a d a history of hypertension and a p p e a r e d to have lost about 80 pounds. There was no history of alcohol, tobacco, or drug abuse and no k n o w n family history of stroke or dementia. On examination, the patient appeared cachectic. Neurological evaluation showed abulia, a remarkably blunted affect, bradykinesia, and impaired attention and memory. The patient's Mini-Mental State Examination (MMSE) score was 11. He had moderate dysarthria, but was not aphasic. He had a right h o m o n y m o u s hemianopsia and right hemiparesis with motor strength diffusely, 2 / 5 on Medical Research Council scale. There was moderately increased right u p p e r and lower extremity tone and a right Babinski sign. The patient's sensation and coordination were intact. The patient's vitamin B12 level was 149 p g / m L (normal range, 180 to 914 p g / m L ) , his homocysteine level was 83 ~ m o l / L (normal range, 4 to 17 ~ m o l / L ) , and his methylmalonic acid level was 1248 n m o l / L (normal range, <400 nmol/L). The results of tests for serum hemoglobin,
Journal of Stroke and Cerebrovascular Diseases, Vol. 9, No. 3 (May-June), 2000: pp 136-138
LEUKOENCEPHALOPATHY
AND
B12 D E F I C I E N C Y
hematocrit, mean corpuscular volume, thyroid-stimulating hormone (TSH) electrolytes, antinuclear and anticardiolipin antibodies, human immunodeficiency virus (HIV) antibody, lactate, long chain fatty acids, and cerebrospinal fluid profile were normal or negative. Transcranial and carotid Doppler ultrasonography scans, and magnetic resonance angiograms did not show significant extracranial or intracranial stenosis. An MRI scan of the brain showed mild cerebral atrophy. There was striking confluent T2 hyperintensity in the pons, middle cerebellar peduncles, and left cerebral peduncle. Diffusely abnormal T2 hyperintensity was also noted in the supratentorial periventricular and deep white matter tracts (Fig 1A and C), in addition to an old left occipital infarction. An evolving left anterior cerebral artery territorial infarction was also identified (not shown in figure). The patient was treated with parenteral vitamin B12 and aspirin. He was reevaluated 6 months after his initial treatment. His serum levels of vitamin B12, homocysteine, and methylmalonic acid were then within the normal range. Although his MMSE score showed only minimal improvement (his score was 13), his apathy and attention
137
deficit became less severe. His motor strength remained the same. In contrast with his clinical condition, a follow-up MRI scan of the brain showed impressive reversal of the signal abnormality in the pons and cerebellar peduncles (Fig 1B). There was also reversal of T2 signal abnormality in the left cerebral peduncle and supratentorial periventricular white matter tracts, with residual encephalomalacia in the left occipital lobe (Fig 1D). The left anterior cerebral artery territorial infarction had evolved in the expected fashion (not shown in figure). Discussion
We believe that vitamin B12 deficiency in our patient developed as a result of severe malnutrition, although a detailed medical examination was not performed. Although difficult to prove, a causal relationship between biochemical improvement and imaging improvement is certainly plausible. Recently, striking white matter abnormalities associated with vitamin B12 deficiency seen on MRI scans have been documented. Confluent and focal high intensity in the white matter of both cerebral hemi-
Figure 1. Axial FLAIR images from the initial MRI scan show marked confluent T2 prolongation within the pons and middle cerebellar peduncles (A), left cerebral peduncle, and bilateral periventricular white matter tracts, in addition to a left occipital lobe infarction (C). FLAIR images from the MRI scan performed after 6 months of vitamin B12 therapy show remarkable interval resolution of abnormal T2 signal in the brain stem and cerebellar peduncles (B), and in the left cerebral peduncle and supratentoriaI periventricular white matter tracts, with residual encephalomalacia in the left occipital lobe (D).
138 spheres with a periventricular predominance and some cerebral atrophy on T2-weighted images have been reported. 1,2 In our patient, the increased signal on the fluid attenuated inversion recovery (FLAIR) sequence within more extensive areas, (i.e., the cerebellum, pons, and midbrain, as well as the periventricular and deep white matter tracts in the cerebral hemispheres) was seen. The improvement of the white matter changes in the posterior fossa with vitamin B12 supplementation for 6 months was remarkable. Because reversible myelopathy associated with vitamin B12 deficiency has been reported, 3 it is reasonable that presumed demyelination of the same cause, followed by remyelination, might be observed in infratentorial areas including the cerebellum and the brain stem. These observations suggest that a phase of injury without destruction may occur and may account for the reversibility seen in our patient. In addition to presumed demyelination, our patient also had cerebral atrophy and left anterior and posterior cerebral artery territorial infarctions. Dementia can be associated with a vitamin B12 deficiency,4 but also with cerebrovascular disease, s This might explain w h y our patient had little clinical improvement in cognitive function. Furthermore, recent studies have not shown a reversal of cognitive impairment after replacement of vitamin B12.6 The elevated level of homocysteine might have contributed to our patient's cerebral infarction through a mechanism of accelerated atherosclerosis. 7 Although carotid and transcranial Doppler ultrasound scans were unremarkable, intracranial branch occlusive disease was not eliminated by these studies. Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) may also produce dementia and diffuse white matter changes that can be seen on MRI scans, and family history alone may not be definitive because asymptomatic individuals with imaging findings of leukoencephalopathy have been reported, s Although we did not perform genetic testing or test skin biopsy specimens for CADASIL in our patient, it is unlikely that the arteriopathy (and, therefore, the imaging changes) associated with CADASIL would respond to vitamin B12 replenishment. Our patient had low serum levels of vitamin B12, high serum levels of homocysteine and methylmalonic acid,
S. SU ET AL.
borderline anemia, and normal mean corpuscular volume. Vitamin B12 supplementation corrected serum levels of vitamin B12, homocysteine and methylmalonic acid, and to a significant degree, leukoencephalopathy. It is recognized that neurological symptoms caused by vitamin B12 deficiency may be correlated with serum levels of homocysteine and methylmalonic acid, without anemia or macrocytosis. 9 It remains unclear if the levels of these 2 metabolic products correlate with the extent of leukoencephalopathy. Additional research with the use of animal models may elucidate the toxic effects of this metabolic disorder. In patients with dementia and leukoencephalopathy, a high index of suspicion for a vitamin B12 deficiency is important, because vitamin B12 supplementation may produce at least some degree of improvement.
References 1. Chatterjee A, Yapundich R, Palmer CA, et al. Leukoencephalopathy associated with cobalamin deficiency. Neurology 1996;46:832-834. 2. Stojsavljevic N, Levic Z, Drulovic J, et al. A 44-month clinical-brain MRI follow-up in a patient with B12 deficiency. Neurology 1997;49:878-881. 3. Berger JR, Quencer RM. Reversal myelopathy with pernicious anemia: Clinical and MR correlation. Neurology 1991;41:947-948. 4. Saracaceanu E, Tramoni AV, Henry JM. An association between subcortical dementia and pernicious anemia--a psychiatric mask. Compr Psychiatry 1997;38:349-351. 5. Konno S, Meyer JS, Terayama Y, et al. Classification, diagnosis and treatment of vascular dementia. Drugs Aging 1997;11:361-373. 6. Hutto BR. Folate and Cobalamin in psychiatric illness. Compr Psychiatry 1997;38:305-314. 7. van den Berg M, van der Knaap MS, Boers GHJ, et al. Hyperhomocysteinaemia; with reference to its neuroradiological aspects. Neuroradiology 1995;37:403-411. 8. Ragno M, Tournier-Lasserve E, Fiori MG, et al. An Italian kindred with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Ann Neurol 1995;38:231-236. 9. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1998;26:1720-1728.
Infratentorial and Supratentorial Leukoencephalopathy Associated With Vitamin B12 Deficiency Shidong Su, MD, PhD, Richard B. Libman, MD, FRCP(C),Alan Diamond, MD, and Sophia Sharfstein, MD
Background: Striking cerebral white matter abnormalities involving supratentorial regions seen on magnetic resonance imaging (MRI) scans have been described in patients with vitamin B12 deficiency. Severe involvement of infratentorial structures with partial reversibility has not been previously documented. Observation: A 54-year-old man experienced severe weight loss, associated with dementia and focal deficits. Laboratory analysis showed a severe vitamin B12 deficiency and elevated serum homocysteine. MRI scans showed a severe and diffuse white matter abnormal signal involving both the supra- and infratentorial compartments. Vitamin B12 supplementation resulted in a mild improvement in cognitive deficits and a marked resolution of imaging abnormalities. Conclusion: Leukoencephalopathy and dementia should raise the suspicion of a vitamin B12 deficiency because vitamin B12 supplementation may result in at least partial clinical improvement. Key Words: Leukoencephalopathy--B12-~Cobalamin.
The clinical and imaging characteristics of patients with vitamin B12 deficiency have been recently described. 1,2 We report an additional patient, who showed striking involvement and partial reversibility of both supratentorial and infratentorial abnormalities.
Case Report A 54-year-old man, returning from an extended visit to Haiti, was noted to be confused, incontinent, and unable to walk because of weakness in his right leg. He could not
From the Departments of Neurology and Radiology (Neuroradiology), Long Island Jewish Medical Center, Long Island Campus for Albert Einstein College of Medicine, New Hyde Park, NY. Received July 23, 1999; accepted October 28,1999. Address reprint requests to Richard B. Libman, MD, The Department of Neurology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, NY 11042. Copyright 9 2000 by National Stroke Association 1052-3057/00/0903-000653.00/0 doi:10.1053/st.2000.5869
136
recall any details of his medical history. According to his wife, who had not seen him for the previous 7 years, he h a d a history of hypertension and a p p e a r e d to have lost about 80 pounds. There was no history of alcohol, tobacco, or drug abuse and no k n o w n family history of stroke or dementia. On examination, the patient appeared cachectic. Neurological evaluation showed abulia, a remarkably blunted affect, bradykinesia, and impaired attention and memory. The patient's Mini-Mental State Examination (MMSE) score was 11. He had moderate dysarthria, but was not aphasic. He had a right h o m o n y m o u s hemianopsia and right hemiparesis with motor strength diffusely, 2 / 5 on Medical Research Council scale. There was moderately increased right u p p e r and lower extremity tone and a right Babinski sign. The patient's sensation and coordination were intact. The patient's vitamin B12 level was 149 p g / m L (normal range, 180 to 914 p g / m L ) , his homocysteine level was 83 ~ m o l / L (normal range, 4 to 17 ~ m o l / L ) , and his methylmalonic acid level was 1248 n m o l / L (normal range, <400 nmol/L). The results of tests for serum hemoglobin,
Journal of Stroke and Cerebrovascular Diseases, Vol. 9, No. 3 (May-June), 2000: pp 136-138
LEUKOENCEPHALOPATHY
AND
B12 D E F I C I E N C Y
hematocrit, mean corpuscular volume, thyroid-stimulating hormone (TSH) electrolytes, antinuclear and anticardiolipin antibodies, human immunodeficiency virus (HIV) antibody, lactate, long chain fatty acids, and cerebrospinal fluid profile were normal or negative. Transcranial and carotid Doppler ultrasonography scans, and magnetic resonance angiograms did not show significant extracranial or intracranial stenosis. An MRI scan of the brain showed mild cerebral atrophy. There was striking confluent T2 hyperintensity in the pons, middle cerebellar peduncles, and left cerebral peduncle. Diffusely abnormal T2 hyperintensity was also noted in the supratentorial periventricular and deep white matter tracts (Fig 1A and C), in addition to an old left occipital infarction. An evolving left anterior cerebral artery territorial infarction was also identified (not shown in figure). The patient was treated with parenteral vitamin B12 and aspirin. He was reevaluated 6 months after his initial treatment. His serum levels of vitamin B12, homocysteine, and methylmalonic acid were then within the normal range. Although his MMSE score showed only minimal improvement (his score was 13), his apathy and attention
137
deficit became less severe. His motor strength remained the same. In contrast with his clinical condition, a follow-up MRI scan of the brain showed impressive reversal of the signal abnormality in the pons and cerebellar peduncles (Fig 1B). There was also reversal of T2 signal abnormality in the left cerebral peduncle and supratentorial periventricular white matter tracts, with residual encephalomalacia in the left occipital lobe (Fig 1D). The left anterior cerebral artery territorial infarction had evolved in the expected fashion (not shown in figure). Discussion
We believe that vitamin B12 deficiency in our patient developed as a result of severe malnutrition, although a detailed medical examination was not performed. Although difficult to prove, a causal relationship between biochemical improvement and imaging improvement is certainly plausible. Recently, striking white matter abnormalities associated with vitamin B12 deficiency seen on MRI scans have been documented. Confluent and focal high intensity in the white matter of both cerebral hemi-
Figure 1. Axial FLAIR images from the initial MRI scan show marked confluent T2 prolongation within the pons and middle cerebellar peduncles (A), left cerebral peduncle, and bilateral periventricular white matter tracts, in addition to a left occipital lobe infarction (C). FLAIR images from the MRI scan performed after 6 months of vitamin B12 therapy show remarkable interval resolution of abnormal T2 signal in the brain stem and cerebellar peduncles (B), and in the left cerebral peduncle and supratentoriaI periventricular white matter tracts, with residual encephalomalacia in the left occipital lobe (D).
138 spheres with a periventricular predominance and some cerebral atrophy on T2-weighted images have been reported. 1,2 In our patient, the increased signal on the fluid attenuated inversion recovery (FLAIR) sequence within more extensive areas, (i.e., the cerebellum, pons, and midbrain, as well as the periventricular and deep white matter tracts in the cerebral hemispheres) was seen. The improvement of the white matter changes in the posterior fossa with vitamin B12 supplementation for 6 months was remarkable. Because reversible myelopathy associated with vitamin B12 deficiency has been reported, 3 it is reasonable that presumed demyelination of the same cause, followed by remyelination, might be observed in infratentorial areas including the cerebellum and the brain stem. These observations suggest that a phase of injury without destruction may occur and may account for the reversibility seen in our patient. In addition to presumed demyelination, our patient also had cerebral atrophy and left anterior and posterior cerebral artery territorial infarctions. Dementia can be associated with a vitamin B12 deficiency,4 but also with cerebrovascular disease, s This might explain w h y our patient had little clinical improvement in cognitive function. Furthermore, recent studies have not shown a reversal of cognitive impairment after replacement of vitamin B12.6 The elevated level of homocysteine might have contributed to our patient's cerebral infarction through a mechanism of accelerated atherosclerosis. 7 Although carotid and transcranial Doppler ultrasound scans were unremarkable, intracranial branch occlusive disease was not eliminated by these studies. Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) may also produce dementia and diffuse white matter changes that can be seen on MRI scans, and family history alone may not be definitive because asymptomatic individuals with imaging findings of leukoencephalopathy have been reported, s Although we did not perform genetic testing or test skin biopsy specimens for CADASIL in our patient, it is unlikely that the arteriopathy (and, therefore, the imaging changes) associated with CADASIL would respond to vitamin B12 replenishment. Our patient had low serum levels of vitamin B12, high serum levels of homocysteine and methylmalonic acid,
S. SU ET AL.
borderline anemia, and normal mean corpuscular volume. Vitamin B12 supplementation corrected serum levels of vitamin B12, homocysteine and methylmalonic acid, and to a significant degree, leukoencephalopathy. It is recognized that neurological symptoms caused by vitamin B12 deficiency may be correlated with serum levels of homocysteine and methylmalonic acid, without anemia or macrocytosis. 9 It remains unclear if the levels of these 2 metabolic products correlate with the extent of leukoencephalopathy. Additional research with the use of animal models may elucidate the toxic effects of this metabolic disorder. In patients with dementia and leukoencephalopathy, a high index of suspicion for a vitamin B12 deficiency is important, because vitamin B12 supplementation may produce at least some degree of improvement.
References 1. Chatterjee A, Yapundich R, Palmer CA, et al. Leukoencephalopathy associated with cobalamin deficiency. Neurology 1996;46:832-834. 2. Stojsavljevic N, Levic Z, Drulovic J, et al. A 44-month clinical-brain MRI follow-up in a patient with B12 deficiency. Neurology 1997;49:878-881. 3. Berger JR, Quencer RM. Reversal myelopathy with pernicious anemia: Clinical and MR correlation. Neurology 1991;41:947-948. 4. Saracaceanu E, Tramoni AV, Henry JM. An association between subcortical dementia and pernicious anemia--a psychiatric mask. Compr Psychiatry 1997;38:349-351. 5. Konno S, Meyer JS, Terayama Y, et al. Classification, diagnosis and treatment of vascular dementia. Drugs Aging 1997;11:361-373. 6. Hutto BR. Folate and Cobalamin in psychiatric illness. Compr Psychiatry 1997;38:305-314. 7. van den Berg M, van der Knaap MS, Boers GHJ, et al. Hyperhomocysteinaemia; with reference to its neuroradiological aspects. Neuroradiology 1995;37:403-411. 8. Ragno M, Tournier-Lasserve E, Fiori MG, et al. An Italian kindred with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Ann Neurol 1995;38:231-236. 9. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1998;26:1720-1728.