Leukoencephalopathy associated with cobalamin deficiency Article abstract-Patients with cobalamin deficiency may experience cogn itive impairment or neuropsychiatric symptoms. Although abnormalit.ies of' central myelin a r e the presumed cause of these manifestations,, there is a paucity of reports of white matter lesions as shown on neuroimaging studies. and the effects of cobalamin replacement on these lesions a r e not known. WCL report a man with subacute cognitive impairment associated with cobalamin deficiency and remarkable confluent white matter abnormalities on MRl, confirmed by biopsy. With cobalamin replacement, both his cogn:itive deficits and imaging abnormalities partially resolved. This case indicates that leukoencephalopathy, in the absence of anemia or myelopathy, should be added to the spectrum of disorders associated with cobalamin deficiency. Early detection and treatment may be associated with a greater potential for recovery. NEUROLOGY 1996;46:832-834 Anjan Chatterjee, MD; Robert Yapurtdich, MD; Cheryl A. Palmer, MD; Daniel C. Marson, JD, F'hD; and Galen W. Mitchell, MD Cobalamin (vitamin B12)deficiency may produce cognitive and neuropsychiatric manifesl,ations.'.2The symptoms, which may be subtle and arise from atypical causes of cobalamin deficiency,.' are assumed to be reversible and produced by white matter abnormalities. Despite the presumed central myelin etiopathogenesis of cognitive impairment in this disorder;' white matter abnormalities on brain imaging are rarely reported,4 and the effects of cobalamin replacement therapy on such structural abnormalities are not known. We describe a patient with cobalamin deficiency who presented with subacute onset of cognitive impairment and marked white matter abnormalities on brain MRI and report the changes in both his cognitive abilities and MRI in response to therapy. C a s e report. A 76-year-old right-handed man with a history of hypertension, atrial fibrillation, h,ypothyroidism, and remote colon cancer was admitted because of a 6-month history of increasing forgetfulness, reading diffculty, and problems balancing his checkbook. He also complained of headaches, fatigue, weight loss, visual impairment, and gait abnormalities. His medications included enalapril, digoxin, warfarin, levothyroxine. and allopurinol. He had no history of tobacco or alcohol use. An initial mental status examination revealed a forward span of six digits and an inability to count backwards or state the days of the week backwards. He was unable to remember any of three words or any of 10 items in a short story after a delay. Spontaneous speech, naming, and repetition were normal. He could not count identical dots arrayed randomly in front of him or copy intersecting pentagons or a cube. Visually guided limb movements were slow but accurate, and his praxis performance of transitive limb gestures to command was normal. He had bilateral plantar extensor reflexes and a cautious gait that appeared to be due to his visual disturbance. He was spatially disoriented and unable to find the door of his room from his bed. Of note, his visual acuity was 20125 on t h e right and 20120 on the left, and his tongue, muscle tone and strength, reflex, sensory, and coordination examinations were normal. Ini832 (!iipyriglit, 0 I996 b y the Anierican Academy of Neurology tial neuropsychological testing5 was notable for mild gcnera1 cognitive impairment (Mattis dementia rating scalo. 124), severe nonlateralized deficits in visual attention (Mesulam cancellation tasks), attention a n d concentration (4%) and visual memory deficits (<1%,)on the W e c h s l ~ r memory scale-revised (WMS-R), and visual fbrm perception deficits on the Benton visual form discrimination (BVFD) test ( < l %He ~ ) had . moderate impairment of t h e abilities to acquire verbal material and to recall these after a delay (California verbal learning test). Naming (Boston naming test) was normal. He endorsed symptoms of mild depression on the Beck depression inventory. Laboratory evaluation revealed a low vitamin B , , ( 7 8 pg/ml; normal, 205-700 pglml) level. The following test,s were norma1:serum chemistries (SMA-18), complete blood count (hemoglobin, 15.9 g d d l ; hematocrit, 46%; mean corpuscular volume, 91 fl), thyroid function tests, sedimentiition rate, C-reactive protein, rapid plasma rea.gin, human immunodeficiency virus, antinuclear antibodies (homogenous, 120; speckled, 1:80), and Sjijgren antihodies. CSF analysis was only notable for a protein level of 111 mg/dl. CSF cytology, stains, and cultures (bacterial, fungal, acidfast bacilli) were negative. Brain MRI revealcd predomnantly bilateral temporo-occipital a n d parieto-occipital high-intensity changes on T,-weighted images that did not enhance with gadolinium contrast (figure 1).The Schilling test, EEG, and four-vessel cerebral angiograrn were normal. Stereotactic brain biopsy revealed gliosis and edema with vacuolization of axonal sheath myelin (figure 2). Immunocytochemistry did not reveal evidence of progressive multifocal leukoencephalopathy. Cyanocobalainin s u p p l ~ mentation (1000 kg IM every month) was the only treatment begun. On followup examinations a t 9 weeks and 10 months after discharge, he reported feeling better. His mood, appetite, and energy levels had improved. He no longer had headaches and was now able to read, although his wife noted persistent memory difficulties. He had ;t digit sp;-rn of six digits forward, was able to repeat and remember 9 of 10 items on a short story, and was able to draw intersecting pentagons and a cube. His spatial scanning had improved, as evidenced by normal dot counting. He was no longer spatially disoriented. With the exception of a mildly Figure 1. T,-weighted MRI showing significant leukoencephalopathy involving right more than left posterior white matter regions. cautious gait and a left plantar extensor response, his neurologic examination, including optokinetic nystagmus response, was normal. Neuropsychological testing5 10 months after discharge revealed a Mattis dementia rating scale of 127. His WAIS-R verbal IQ was estimated at 106. He showed improvement in measures of attention and concentration (61%),verbal acquisition, visual memory (138) on WMS-R, and visual form perception (12%))on the BVFD test. Verbal memory continued to be significantly impaired. His vitamin B,, level 9 weeks after discharge was 1167 pgiml. A followup brain MRI scan revealed considerable resolution of white matter changes in the inferoposterior aspect of both hemispheres (figure 3). Discussion. Cognitive impairment associated with cobalamin deficiency, in the absence of the more typical myelopathy or macrocytic anemia, is becoming increasingly recognized.' The normal Schilling test Figure 2. Diffuse white matter uacuolizatiori with gliosis and rnyelin sheath swelling (hematox-ylin and eosin, X4600, before 51% reduction). in our patient suggests a food cobalamine absorption defect, and places him in the unusual category of patients with a subtle expression and a n atypical etiology of cobalamine deficiency.,3 He had partial resolution of cognitive impairment and MRI abnormalities after cobalamine replacement. His cognitive impairments were most notable for problems with attention and working memory, verbal memory, and visuospatial processing. With cobalamin replacement, his attention and working memory improved, as did some aspects of visuospatial processing. His verbal memory remained significantly impaired. The pathogenesis of the neurologic abnormalities associated with cobalamin deficiency is not well understood. However, abnormalities of myelin are thought to be causative. Because myelin replacement is heavily dependent on fatty acid synthesis, the integrity of two cobalamin-dependent enzymes involved in fatty acid metabolism is implicated.' Impairment of methylmalonyl- coenzyme A (CoA) mutase results in accumulation of propionyl CoA, which is thought to replace succinyl CoA and acetyl CoA as substrates in the synthesis of fatty acids leading to the formation of anomalous fatty acids. Impairment of methionine synthase activity affects essential methylation reactions and may cause cerebral myelination defects in patients with inherited disorders selectively affecting activity of this enzyme. % These effects on methylation reactions may reduce the supply of adenosylmethionine and interfere with protein and neurotransmitter synthesis, although the specific clinical consequences of such defects are unclear:' Older reports describe scattered areas of vacuolization within the central myelin of patients with cobalamin defi~iency."~ Similar pathologic changes are present in primate models" and were seen in the brain biopsy of our patient. The March 1996 NEUROLOGY 46 833 F i g i i r ~9. T,-iueighted MRI showing partial resolution of leukoencephalopathy after cobalamin replacenwrit thvrcipy. single other MR.1 report of‘ cobalamin deficiency demonstrated only nonspecific periventricular hyperintensities.‘ We are unaware of any cases reported with confluent white matter changes that were followed by partial resolution of cognitive impairment and imaging abnormalities after treatment. Our observations extend the spectrum of cobalamin deficiency-associated neurologic abnormalities (in the absence of macrocytic anemia or clinical myelopathy I ) t o include significant leukoencephalopathy. The partial resolution of symptoms in our case, similar to other reports,2 suggests that early detection and treatment of such patients with white matter abnormalities may critically affect their response to treatment. Clinicians should consider subtle and atypical cobalamin deficiency states in evaluating a wide range of cognitive and neuropsychiatric symptoms. Frnm the Departmitnt of Neurology (Drs. Chatterjee, Yapundich, I’almcr. Marson, and Mitchell) a n d Pathology ( L k . Palmer), and the Alzheimer’s Disease Center (Drs. Chatterjee and Marson), The LJnivrrsit.y of Alabama a t Birmingham, Birmingham, AL. Received April 6, 1995. Accepted in final form J u n e 12, 1995. 834 NEIIROLOGY 46 March 1996 Address correspondence to Dr Anjan Chatterlee, UAB Ncur ologv 1720 7th Ave South, 454 Sparks Center, Birmingham, AL X 2 9 t 0017 References 1. Lindenbaum J, Healton EB, Savage DG, e t al. Nourop ric disorders caused by cobalamin deficiency in the ahsence (if anemia or macrocytosis. N Engl J Mcd 1988; 318:3720-3728. 2. Healton EB, Savage DG, Brust JCM, Garrett T,J, 1,indenh;iurn J. Neurologic aspects of cobalamin deficiency. Modicinc! 1119 I : 70:229-245. 3. Carmel R. Subtle and atypical cobalamin deficiency statcts. AIII J Hematol 1990; 34:108-114. 4. Haan J , Haupts M, Uhlenbrock D. 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Neurology 1996;46;832-834 DOI 10.1212/WNL.46.3.832 This information is current as of March 1, 1996 Updated Information & Services including high resolution figures, can be found at: http://www.neurology.org/content/46/3/832.full.html Citations This article has been cited by 6 HighWire-hosted articles: http://www.neurology.org/content/46/3/832.full.html##otherarticle s Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions Reprints Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright Copyright 1996 by the Advanstar Communication Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.