Multiple Sclerosis Associated With Vitamin B12 Deficiency E. H.
Reynolds, FRCP;J. C. Linnell, PhD;J. E. Faludy cies.2 Following presentation of these
\s=b\ We describe 10 patients with a previously unreported, to our knowledge, association of multiple sclerosis and unusual vitamin B12 deficiency. The clinical features and the age at presentation were typical of multiple sclerosis, with eight cases occurring before age 40 years, which is a rare age for vitamin B12 deficiency. Nine patients had hematologic abnormalities, but only two were anemic. All six patients examined had low erythrocyte cobalamin levels. Only two patients had pernicious anemia; in the remaining patients the vitamin B12 deficiency was unexplained. A vitamin B12 binding and/or transport is suspected. The nature of the association of multiple sclerosis and vitamin B12 deficiency is unclear but is likely to be more than coincidental. Further studies of vitamin B12 metabolism, binding, and transport in multiple
The neurologic and hématologie findings in 10 patients are summarized in Tables 1 and 2. There were seven women and three men. The age at onset of the neurologic disorder ranged from 27 to 51 years (mean, 36 years). Eight patients presented before age 40 years. With the exception of patient 1, all the patients were found to have vitamin B12 defi¬ ciency at the time of presentation with the
neurology and hematology textbooks, multiple sclerosis is not listed among the several neurologic complica¬ tions of vitamin B12 deficiency. Vitamin B12 deficiency is not even recognized as being associated with multiple sclero¬ sis. There is no mention of vitamin B12 in
cious anemia." He continued to receive vita¬ min B12 therapy thereafter. His fluctuating neurologic illness began at age 39 years and included right-sided numbness and tremor, paraparesis and ataxia, and a brief rightsided homonymous hemianopia. Despite pre¬ vious vitamin B12 therapy, he was slightly macrocytic: Although his serum vitamin B12 level was high, his red blood cell cobalamin level was at the lower limit of the normal
sclerosis are indicated, as these cases may offer a clue to the understanding of a still mysterious neurologic disorder. (Arch Neuro/. 1991 ;48:808-811 )
the index of textbooks devoted to multi¬ ple sclerosis.1 Although the cause of multiple sclerosis remains elusive, it is widely suspected to be a viral and/or immunologie disorder. In a period of 5 years, we observed three cases of multiple sclerosis associ¬ ated with unusual vitamin B12 deficienAccepted for publication December 21,1990. From the Department of Neurology, King's College Hospital (Dr Reynolds), and the Department of Child Health, Westminster Children's Hospital (Dr Linnell and Ms Faludy), London, England. Reprint requests to the Department of Neurology, King's College Hospital, Denmark Hill, London SE5 9RS, England (Dr Reynolds).
to the
Association
of British Neurologists,3 seven additional cases have been referred by other neurolo¬ gists in a 1-year period.45 Herein, we report the neurologic and hématologie findings in these patients and discuss the possible implications for our under¬ standing of multiple sclerosis.
patients
PATIENTS AND METHODS
neurologic disorder. Patient 1 presented at age 27 years with megaloblastic anemia due to "juvenile perni¬
range.6
Patient 2 presented at age 47 years with a fluctuating asymmetrical paraparesis, atax¬
ia,
sensory symptoms in her limbs, and an internuclear ophthalmoplegia. Her mild ane¬ mia was initially thought to be due to iron deficiency, but when this deficiency was cor¬ rected, she was found to be macrocytic due to vitamin B12 deficiency. During 14 months of treatment with vitamin B12 (1000 µg intra¬ muscularly once monthly), her neurologic condition remained static, and she remained macrocytic (mean corpuscular volume, 100.7 to 106.1 fL). The latter was not due to alcohol abuse or folate deficiency. Patient 3 presented at age 35 years with an attack of diplopia that recovered within a few
Downloaded From: http://archneur.jamanetwork.com/ by a UQ Library User on 06/21/2015
weeks. Two further attacks, one associated with sensory symptoms in his legs, occurred during a period of 2 years. Although not ane¬ mic, he was macrocytic with a megaloblastic bone marrow due to vitamin B12 deficiency. His magnetic resonance imaging scan re¬ vealed an unsuspected pinealoma in addition to the multiple white-matter lesions, consis¬ tent with a diagnosis of multiple sclerosis. Patient 4 had an unexplained paraparesis at age 31 years, which resolved within 1 year. At age 51 years, she presented with a fluctu¬ ating paraparesis and later with a left arm weakness, associated with a megaloblastic anemia due to vitamin B12 deficiency. Patient 5 presented at age 31 years with a short history of fluctuating ataxia and leftsided weakness, and later with left-sided fa¬ cial and right-sided numbness, associated with macrocytosis due to vitamin B12 defi¬ ciency. A myelogram was normal. Patient 6 presented at age 47 years with a 3-month history of frequent transient at¬ tacks of left-sided facial numbness and right upper limb weakness. He also had a slight left optic disc pallor. Although he was not macrocytic, he had a borderline low serum vitamin B12 level. Patient 7 presented at age 27 years with a 6-month history of numerous remitting sen¬ sory symptoms involving the trunk, the left side ofthe face and tongue, the left arm, the hands and legs, and including Lhermitte's symptom. For 1 week, she had had weakness of her legs, ataxia, and slight loss of bladder control. She had mild asymmetrical pyrami¬ dal signs in her legs, incoordination associ¬ ated with impairment of all sensory modal¬ ities in her legs, and a sensory level at T-8. She was macrocytic with a low serum vitamin B12 level. Patient 8 presented at age 53 years with a
3-year progressive asymmetrical parapare¬ sis, incoordination in her left limbs, ataxic gait, left-sided sensory level at T-10, and impairment of vibration and joint position sense in her legs. A myelogram was normal. She was macrocytic with a borderline low vitamin B12 level and a low red blood cell folate level. Patient 9, who was of Indian origin, came serum
to England at age 10 years. She presented at age 35 years with a 6-month history of fluctu¬
ating paresthesia and heaviness in her legs and later developed intermittent paresthesia
in her hands and blurred vision. She also had a 2-year history of personality change, be¬ coming more apathetic and irritable, with
slight cognitive impairment. She was macro¬ cytic and megaloblastic due to vitamin B12 deficiency and had evidence of pernicious
anemia. Patient 10 came to England from Mauriti¬ us at age 24 years. At age 34 years, she had attacks of left- and right-sided retrobulbar neuritis within 3 months of each other. She later developed paresthesia in her hands and Lhermitte's symptom. She was macrocytic and megaloblastic due to vitamin B12
deficiency. In six patients (patients 2,3, and 6 through 9), we had the opportunity to examine red
blood cell cobalamin levels before any vita¬ min B12 administration, either for the Schil¬ ling test or for treatment. The red blood cell cobalamin level was assayed by the method of Linnell et al,7 as modified by Faludy and Linnell.8 In all six cases, the red blood cell
Table
Patient/Age at Onset, y/Sex
Multiple Lesions
cobalamin level was well below a control range of 62 to 190 pg/mL (mean, 110 pg/mL) in 17 normal subjects aged 18 to 54 years
(Table 2).
COMMENT
The evidence for a diagnosis of multi¬ ple sclerosis seemed convincing in nine of our 10 patients, and multiple sclerosis was the probable diagnosis in the other patient (No. 8). The age at onset of neu¬ rologic disease was typical of multiple sclerosis but unusually young for vita¬ min B12 deficiency. All the patients had clinical and/or neurophysiologic and magnetic resonance imaging evidence of multiple lesions in the nervous sys¬ tem. Nine patients had a fluctuating course. All seven patients who under¬ went magnetic resonance imaging ofthe brain showed multiple lesions in the white matter consistent with multiple sclerosis. One patient had fluctuating white-matter lesions on serial computed
1.—Neurologic Findings in 10 Patients* Fluctuating Course
Abnormal VERs
Oligoclonal Banding in CSF
MRI
Peripheral
Nerve Function
1/39/M 2/37/F 3/35/M 4/31/F 5/31/F
6/47/M 7/27/F 8/50/F 9/33/F + + + + + 10/34/F * VERs indicates visual evoked responses; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging scan showing multiple lesions consistent with multiple sclerosis; plus sign, present; minus sign, absent; and N, nor¬ mal. tFluctuating white-matter lesions on serial computed tomographic scans.
Table 2.—Hématologie Findings in 10 Patients
Patient
Hemoglobin, g/L
MCV,
138
103§
108
79 103
fL
Bone
Serum Vitamin
Marrow
B,2, pmol/L 530§
89
100
140
98
Normal
156
>98 fL), five of whom had mean corpus¬ cular volumes greater than 100 fL.
Neurologie Presentation*
Red Blood Cell Cobalamin,
pmol/Lt
Red Blood Cell Folate, nmol/L 350
80
Mégalo Mégalo
148 143
on
tomographic scans. Although peripher¬ al neuropathy is probably the most common neurologic manifestation of vi¬ tamin B12 deficiency,9 no electrical evi¬ dence of peripheral neuropathy was found in any of the patients examined, again in keeping with a diagnosis ofmul¬ tiple sclerosis. Further support for the diagnosis included abnormal visual evoked responses in nine of 10 patients examined and the detection of oligo¬ clonal bands in cerebrospinal fluid in eight of nine patients examined. In sev¬ en patients referred by other neurolo¬ gists, a diagnosis of multiple sclerosis had already been made. All the patients had evidence of vita¬ min BI2 deficiency at the time of presen¬ tation with neurologic symptoms, ex¬ cept patient 1, who had been taking vitamin B12 intermittently for 12 years because he had presented previously with megaloblastic anemia due to juve¬ nile pernicious anemia. Perusal of his old hospital records revealed that he had complained of sensory symptoms in his legs at the time ofthe anemia, but no signs were recorded. Despite his subse¬ quent vitamin B12 treatment and his high serum vitamin B12 level, he too was macrocytic with evidence of a surpris¬ ingly low red blood cell cobalamin level at the time of presentation with neuro¬ logic symptoms.6 The other nine pa¬ tients all had serum vitamin B12 levels below 150 pmol/L (six had levels below 110 pmol/L), three of which were less than 70 pmol/L. Lindenbaum et al10 have shown that neurologic disease can occur at serum vitamin B12 levels of 150 pmol/L and below. Eight patients were macrocytic (mean corpuscular volume,
60
860
150 98 99
Test
Antibodies^ Gastric, IF Gastric
31
100
Schilling
Reynolds, FRCP;J. C. Linnell, PhD;J. E. Faludy cies.2 Following presentation of these
\s=b\ We describe 10 patients with a previously unreported, to our knowledge, association of multiple sclerosis and unusual vitamin B12 deficiency. The clinical features and the age at presentation were typical of multiple sclerosis, with eight cases occurring before age 40 years, which is a rare age for vitamin B12 deficiency. Nine patients had hematologic abnormalities, but only two were anemic. All six patients examined had low erythrocyte cobalamin levels. Only two patients had pernicious anemia; in the remaining patients the vitamin B12 deficiency was unexplained. A vitamin B12 binding and/or transport is suspected. The nature of the association of multiple sclerosis and vitamin B12 deficiency is unclear but is likely to be more than coincidental. Further studies of vitamin B12 metabolism, binding, and transport in multiple
The neurologic and hématologie findings in 10 patients are summarized in Tables 1 and 2. There were seven women and three men. The age at onset of the neurologic disorder ranged from 27 to 51 years (mean, 36 years). Eight patients presented before age 40 years. With the exception of patient 1, all the patients were found to have vitamin B12 defi¬ ciency at the time of presentation with the
neurology and hematology textbooks, multiple sclerosis is not listed among the several neurologic complica¬ tions of vitamin B12 deficiency. Vitamin B12 deficiency is not even recognized as being associated with multiple sclero¬ sis. There is no mention of vitamin B12 in
cious anemia." He continued to receive vita¬ min B12 therapy thereafter. His fluctuating neurologic illness began at age 39 years and included right-sided numbness and tremor, paraparesis and ataxia, and a brief rightsided homonymous hemianopia. Despite pre¬ vious vitamin B12 therapy, he was slightly macrocytic: Although his serum vitamin B12 level was high, his red blood cell cobalamin level was at the lower limit of the normal
sclerosis are indicated, as these cases may offer a clue to the understanding of a still mysterious neurologic disorder. (Arch Neuro/. 1991 ;48:808-811 )
the index of textbooks devoted to multi¬ ple sclerosis.1 Although the cause of multiple sclerosis remains elusive, it is widely suspected to be a viral and/or immunologie disorder. In a period of 5 years, we observed three cases of multiple sclerosis associ¬ ated with unusual vitamin B12 deficienAccepted for publication December 21,1990. From the Department of Neurology, King's College Hospital (Dr Reynolds), and the Department of Child Health, Westminster Children's Hospital (Dr Linnell and Ms Faludy), London, England. Reprint requests to the Department of Neurology, King's College Hospital, Denmark Hill, London SE5 9RS, England (Dr Reynolds).
to the
Association
of British Neurologists,3 seven additional cases have been referred by other neurolo¬ gists in a 1-year period.45 Herein, we report the neurologic and hématologie findings in these patients and discuss the possible implications for our under¬ standing of multiple sclerosis.
patients
PATIENTS AND METHODS
neurologic disorder. Patient 1 presented at age 27 years with megaloblastic anemia due to "juvenile perni¬
range.6
Patient 2 presented at age 47 years with a fluctuating asymmetrical paraparesis, atax¬
ia,
sensory symptoms in her limbs, and an internuclear ophthalmoplegia. Her mild ane¬ mia was initially thought to be due to iron deficiency, but when this deficiency was cor¬ rected, she was found to be macrocytic due to vitamin B12 deficiency. During 14 months of treatment with vitamin B12 (1000 µg intra¬ muscularly once monthly), her neurologic condition remained static, and she remained macrocytic (mean corpuscular volume, 100.7 to 106.1 fL). The latter was not due to alcohol abuse or folate deficiency. Patient 3 presented at age 35 years with an attack of diplopia that recovered within a few
Downloaded From: http://archneur.jamanetwork.com/ by a UQ Library User on 06/21/2015
weeks. Two further attacks, one associated with sensory symptoms in his legs, occurred during a period of 2 years. Although not ane¬ mic, he was macrocytic with a megaloblastic bone marrow due to vitamin B12 deficiency. His magnetic resonance imaging scan re¬ vealed an unsuspected pinealoma in addition to the multiple white-matter lesions, consis¬ tent with a diagnosis of multiple sclerosis. Patient 4 had an unexplained paraparesis at age 31 years, which resolved within 1 year. At age 51 years, she presented with a fluctu¬ ating paraparesis and later with a left arm weakness, associated with a megaloblastic anemia due to vitamin B12 deficiency. Patient 5 presented at age 31 years with a short history of fluctuating ataxia and leftsided weakness, and later with left-sided fa¬ cial and right-sided numbness, associated with macrocytosis due to vitamin B12 defi¬ ciency. A myelogram was normal. Patient 6 presented at age 47 years with a 3-month history of frequent transient at¬ tacks of left-sided facial numbness and right upper limb weakness. He also had a slight left optic disc pallor. Although he was not macrocytic, he had a borderline low serum vitamin B12 level. Patient 7 presented at age 27 years with a 6-month history of numerous remitting sen¬ sory symptoms involving the trunk, the left side ofthe face and tongue, the left arm, the hands and legs, and including Lhermitte's symptom. For 1 week, she had had weakness of her legs, ataxia, and slight loss of bladder control. She had mild asymmetrical pyrami¬ dal signs in her legs, incoordination associ¬ ated with impairment of all sensory modal¬ ities in her legs, and a sensory level at T-8. She was macrocytic with a low serum vitamin B12 level. Patient 8 presented at age 53 years with a
3-year progressive asymmetrical parapare¬ sis, incoordination in her left limbs, ataxic gait, left-sided sensory level at T-10, and impairment of vibration and joint position sense in her legs. A myelogram was normal. She was macrocytic with a borderline low vitamin B12 level and a low red blood cell folate level. Patient 9, who was of Indian origin, came serum
to England at age 10 years. She presented at age 35 years with a 6-month history of fluctu¬
ating paresthesia and heaviness in her legs and later developed intermittent paresthesia
in her hands and blurred vision. She also had a 2-year history of personality change, be¬ coming more apathetic and irritable, with
slight cognitive impairment. She was macro¬ cytic and megaloblastic due to vitamin B12 deficiency and had evidence of pernicious
anemia. Patient 10 came to England from Mauriti¬ us at age 24 years. At age 34 years, she had attacks of left- and right-sided retrobulbar neuritis within 3 months of each other. She later developed paresthesia in her hands and Lhermitte's symptom. She was macrocytic and megaloblastic due to vitamin B12
deficiency. In six patients (patients 2,3, and 6 through 9), we had the opportunity to examine red
blood cell cobalamin levels before any vita¬ min B12 administration, either for the Schil¬ ling test or for treatment. The red blood cell cobalamin level was assayed by the method of Linnell et al,7 as modified by Faludy and Linnell.8 In all six cases, the red blood cell
Table
Patient/Age at Onset, y/Sex
Multiple Lesions
cobalamin level was well below a control range of 62 to 190 pg/mL (mean, 110 pg/mL) in 17 normal subjects aged 18 to 54 years
(Table 2).
COMMENT
The evidence for a diagnosis of multi¬ ple sclerosis seemed convincing in nine of our 10 patients, and multiple sclerosis was the probable diagnosis in the other patient (No. 8). The age at onset of neu¬ rologic disease was typical of multiple sclerosis but unusually young for vita¬ min B12 deficiency. All the patients had clinical and/or neurophysiologic and magnetic resonance imaging evidence of multiple lesions in the nervous sys¬ tem. Nine patients had a fluctuating course. All seven patients who under¬ went magnetic resonance imaging ofthe brain showed multiple lesions in the white matter consistent with multiple sclerosis. One patient had fluctuating white-matter lesions on serial computed
1.—Neurologic Findings in 10 Patients* Fluctuating Course
Abnormal VERs
Oligoclonal Banding in CSF
MRI
Peripheral
Nerve Function
1/39/M 2/37/F 3/35/M 4/31/F 5/31/F
6/47/M 7/27/F 8/50/F 9/33/F + + + + + 10/34/F * VERs indicates visual evoked responses; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging scan showing multiple lesions consistent with multiple sclerosis; plus sign, present; minus sign, absent; and N, nor¬ mal. tFluctuating white-matter lesions on serial computed tomographic scans.
Table 2.—Hématologie Findings in 10 Patients
Patient
Hemoglobin, g/L
MCV,
138
103§
108
79 103
fL
Bone
Serum Vitamin
Marrow
B,2, pmol/L 530§
89
100
140
98
Normal
156
>98 fL), five of whom had mean corpus¬ cular volumes greater than 100 fL.
Neurologie Presentation*
Red Blood Cell Cobalamin,
pmol/Lt
Red Blood Cell Folate, nmol/L 350
80
Mégalo Mégalo
148 143
on
tomographic scans. Although peripher¬ al neuropathy is probably the most common neurologic manifestation of vi¬ tamin B12 deficiency,9 no electrical evi¬ dence of peripheral neuropathy was found in any of the patients examined, again in keeping with a diagnosis ofmul¬ tiple sclerosis. Further support for the diagnosis included abnormal visual evoked responses in nine of 10 patients examined and the detection of oligo¬ clonal bands in cerebrospinal fluid in eight of nine patients examined. In sev¬ en patients referred by other neurolo¬ gists, a diagnosis of multiple sclerosis had already been made. All the patients had evidence of vita¬ min BI2 deficiency at the time of presen¬ tation with neurologic symptoms, ex¬ cept patient 1, who had been taking vitamin B12 intermittently for 12 years because he had presented previously with megaloblastic anemia due to juve¬ nile pernicious anemia. Perusal of his old hospital records revealed that he had complained of sensory symptoms in his legs at the time ofthe anemia, but no signs were recorded. Despite his subse¬ quent vitamin B12 treatment and his high serum vitamin B12 level, he too was macrocytic with evidence of a surpris¬ ingly low red blood cell cobalamin level at the time of presentation with neuro¬ logic symptoms.6 The other nine pa¬ tients all had serum vitamin B12 levels below 150 pmol/L (six had levels below 110 pmol/L), three of which were less than 70 pmol/L. Lindenbaum et al10 have shown that neurologic disease can occur at serum vitamin B12 levels of 150 pmol/L and below. Eight patients were macrocytic (mean corpuscular volume,
60
860
150 98 99
Test
Antibodies^ Gastric, IF Gastric
31
100
Schilling
