Nutritional Neuroscience An International Journal on Nutrition, Diet and Nervous System
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Vitamin B12-responsive neuropathies: A case series Lawrence R. Solomon To cite this article: Lawrence R. Solomon (2015): Vitamin B12-responsive neuropathies: A case series, Nutritional Neuroscience To link to this article: http://dx.doi.org/10.1179/1476830515Y.0000000006
Published online: 28 Dec 2015.
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Vitamin B12-responsive neuropathies: A case series Lawrence R. Solomon
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Section of Palliative Care, Department of Medicine, Yale University School of Medicine and Smilow Cancer Hospital, New Haven, CT, USA Objectives: Neuropathies often accompany vitamin B12 deficiency. Since many neuropathies are linked to oxidative stress and since B12 has both antioxidant and neurotrophic properties, B12 may also be effective treatment in non-deficient subjects. Thus, the characteristics and predictors of B12-responsive neuropathies and their relationship to disorders associated with increased oxidative stress (oxidant risks) were examined. Methods: Retrospective review of 78 subjects with neurological abnormalities treated with B12 and evaluated by the measurement of B12 and the B12-dependent metabolites, methylmalonic acid (MMA), and homocysteine. Results: Sixty-five subjects had neurological improvement (83%), including 35 with other known causes of neuropathy. Only two responders had B12-responsive macrocytosis. Pretherapy B12, MMA, and homocysteine values were normal in 72, 33 and 54% of responders, with all three normal in 23%. Moreover, B12 therapy did not significantly decrease elevated MMA and homocysteine levels in 20 and 37%, respectively, of responders tested but did decrease both metabolites in 75% of evaluable nonresponders. At least one oxidant risk was present in 41 of the 46 responders with normal B12 levels (89%). Oral therapy was effective, but parenteral B12 improved responses in four subjects. Discussion: B12-responsive neuropathies are thus (1) common even when confounding disorders are present; (2) dissociated from the presence of hematological abnormalities; (3) dissociated from the presence of B12-responsive metabolical abnormalities; and (4) associated with the presence of oxidant risks when B12 levels are normal. Since no predictors of responses to B12 therapy were identified, empiric trials with parenteral B12 should be considered in appropriate subjects. Keywords: Neuropathy, Vitamin B12, Oxidative stress, Cobalamin, Methylmalonic acid, Homocysteine
Introduction Neurological disorders often accompany frank vitamin B12 deficiency which is defined by the presence of low-serum B12 levels along with increased values of the B12-dependent metabolites, methylmalonic acid (MMA) and/or homocysteine (HCys).1 Classically, B12 deficiency results from malabsorption or decreased dietary intake of the vitamin; develops over several years; and is associated with both macrocytic anemia and neurocognitive defects. However, it is now recognized that neurological impairment often occurs in the absence of overt hematological abnormalities.1,2 B12-responsive neuropathies also occur in the setting of ‘functional’ vitamin B12 deficiency, defined by the presence of elevated levels of MMA and/or HCys despite serum B12 levels well within the normal Correspondence to: Lawrence R. Solomon, Section of Palliative Care, Department of Medicine, Yale University School of Medicine, 403 www; 333 Cedar Street, P.O. Box 208021, New Haven, CT 06520–8021, USA. E-mail: [email protected]
© W. S. Maney & Son Ltd 2015 DOI 10.1179/1476830515Y.0000000006
reference range.1–10 Moreover, B12-responsive neuropathies have been described when measures of B12 nutriture were not determined and, in two instances, when both B12 and MMA values were normal.1,9,11–19 Finally, in vitro and animal studies suggest that B12 may also have analgesic and neurotrophic properties in non-deficient settings.1,20–26 In contrast, standard treatments for neuropathic pain with antidepressants and anticonvulsants are effective in a minority of subjects, do not improve nerve function, and are associated with significant side effects.27 In an earlier report, it was noted that tests for B12, MMA, and HCys were not predictive of the presence of B12-responsive clinical disorders in 37 subjects evaluated in an ambulatory care setting.9 This study was limited in that distinctions were not made between hematological and neurological patterns of response and the relationships between clinical responses and metabolic responses were not explored. Therefore, the current study focused on the relationship between B12 and neurological disorders in an expanded
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population of 74 clinical responders to B12 therapy, including 65 subjects with neurological responses, in order to (1) compare the patterns of neurological and hematological responses relative to the B12 status of these subjects; (2) understand the role of laboratory studies in predicting neurological responses to B12 treatment; and (3) define the relationship between neurological and metabolical responses to B12 therapy. Since increased oxidative stress is associated with both functional B12 deficiency and neuropathies seen in many settings, the association of B12-responsive neurological disorders with risk factors for oxidative stress was also evaluated.1,28–33
Materials and methods Laboratory methods Downloaded by [Deakin University Library] at 03:20 03 January 2016
Serum B12, serum MMA, and plasma HCys were measured as previously described.9 The normal range for cobalamin (Cbl)(B12) was 201–1100 pg/ml. However, since B12 deficiency is not infrequent in subjects with B12 levels of 200–300 pg/ml, B12 levels were considered normal if values were >300 pg/ml.9 The reference ranges for MMA and HCys were taken as 90–250 nmol/l and 5.4–12.1 μmol/l, respectively.9 When values were obtained on more than one occasion within a 4-week period, the lowest Cbl value and the highest metabolite values were used for analysis. Intrinsic factor antibodies (IF Abs) were also tested for in 50 of the 78 subjects with neurological signs and/or symptoms (64%).
Participants A retrospective review of the medical records of all ambulatory, community-dwelling subjects followed regularly by the author and evaluated for possible B12 deficiency because of the presence of either hematological or neurological abnormalities between 1 August 1993 and 30 June 2005 was conducted as previously described.8,9 During the first 6 years of the study, only subjects with clinical abnormalities and metabolic evidence of B12 deficiency were treated with B12. Thereafter, all subjects with clinical abnormalities were offered B12 therapy even when B12, MMA, and HCys values were normal.9 Overall, 74 subjects with either hematological or neurological responses to B12 therapy were identified (responders) including 65 subjects with neurological (neuro) responses. An additional 13 subjects had neurological abnormalities that did not improve with B12 therapy (non-responders). At least 3 months of B12 therapy was required before a subject was classified as a non-responder. All active medical conditions present in each subject were identified and a Medline search was performed to determine which of these disorders were associated with increased systemic markers of oxidative stress (oxidant risks). At least one oxidant risk was present
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in 63 of the 78 subjects with neurological disorders (81%) including advanced age (≥70 years old) (n = 35); diabetes mellitus (n = 24); cigarette abuse (n = 14); alcohol abuse (n = 11); renal insufficiency (creatinine >1.3 mg/dl in women and >1.5 mg/dl in men) (n = 11); malignancy (n = 10); congestive heart failure (n = 7); neurodegenerative disorders (n = 5); chronic infections or inflammation (n = 4); rheumatological disorders (n = 3); medication-dependent asthma (n = 2); iron overload (n = 2); active renal transplant rejection (n = 1); and cirrhosis (n = 1). Disorders known to be associated with neurological abnormalities (confounders) were present in 51 of the 65 neuro responders (78%) and in 7 of the 13 neuro non-responders (54%) including diabetes (n = 25); alcohol abuse (n = 11); structural lesions of brain or vertebral column (n = 8); neurodegenerative disorders (n = 5); prior use of neurotoxic chemotherapeutic agents (n = 3); and advanced renal disease (n = 2; creatinine = 8.0 and 9.4 mg/dl). Subjects with neuro responses to B12 therapy were divided into four groups: (1) Group A (‘Definite’ B12 deficiency) defined by the presence of a low B12 value of ≤200 pg/ml; (2) Group B (‘Possible’ B12 deficiency) defined by the presence of a low-normal B12 value of 201–300 pg/ml with an increased level of MMA and/or HCys; (3) Group C (‘Functional’ B12 deficiency) defined by the presence of B12 values >300 pg/ml with an increased level of MMA and/or HCys; and (4) Group D (‘No’ metabolic B12 deficiency) defined by the presence of B12 values >300 pg/ml with normal values for both MMA and HCys (includes one subject with normal pretreatment MMA and HCys values on two occasions in whom a pretherapy B12 value was not available). This study conforms to the principles of the Declaration of Helsinki of 1975 as revised in 2008 and the institutional human investigation committee determined that further review was not required.
B12 (cyanocobalamin) treatment Patients were treated with cyanocobalamin 2 mg per day orally or 1 mg intramuscularly three times a week for 2 weeks, weekly for 8 weeks and monthly thereafter. All treated patients were reevaluated within 1–3 months after beginning B12 therapy. There were no other changes made in diet, the use of other medications, or the use of dietary supplements after the initiation of B12 therapy nor was physical or occupational therapy instituted in any subject. Hematological responses to B12 were considered to be significant if the mean corpuscular volume (MCV) decreased greater than 5 fl from a value of more than 98 fl or if the hematocrit increased by more than 0.05 from a value of less than 0.36 in
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Table 1 Characteristics of subjects with neurological responses to B12 therapy Group
n
Age (years)
Male gender (%)
A B C D
9 9 32 15
50.0 (28–69) 59.7 (28–83) 65.5 (39–86) 67.5 (40–82)
1 (11) 3 (33) 14 (44) 12 (75)
B12 (pg/ml)
Confounders present (%)
Positive IF Abs (%)
2 (22) 3 (33) 22 (69) 8 (53)
1/5 (20) 1/7 (14) 2/23 (9) 0/3 (0)
149 (58–186) 277 (263–297) 566 (319–2000) 505 (348–762)
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Values for age and B12 are given as the geometric means with ranges shown in brackets. IF Abs, intrinsic factor antibodies.
women or less than 0.39 in men. Neuro responses were considered to be present if either complete or partial improvement occurred in the signs or symptoms of peripheral or autonomic neuropathy identified at the time of initial evaluation. A metabolic response to B12 therapy was defined as a decrease in the metabolite from its highest pretreatment value by more than 1 SD greater than its mean intra-individual variability as previously defined in this population (i.e., >116 nmol/l for MMA and >3.6 μmol/l for HCys).9
Data analysis Population studies suggest skewed distributions for B12, MMA, and HCys.34 Thus, geometric means, two-tailed Student’s t tests using log-transformed data, Spearman correlation coefficients (r) and χ2 analyses were determined using StatPlus:mac (release 5.7, 2009, AnalystSoft, Vancouver, BC, Canada).
Results Neurological responses to B12 therapy Overall, 65 of the 78 subjects with neurological signs or symptoms had clinical responses to B12 therapy (83%). The response rates were the same in subjects with confounders (35 of 42 subjects) and in those with no confounders (30 of 36 subjects). Only 18 of the 65 neuro responders (28%) had either definite or possible B12 deficiency (Groups A and B) (Table 1). IF Abs were present in 4 of the 38 patients tested (11%), including 1 patient each in Group A and Group B and 2 of the 26 patients with normal B12 levels (8%). B12 levels were >500 pg/ml in 17 subjects in Group C (53%) and in 8 subjects in Group D (57%). Moreover, 7 Group C subjects had B12 levels >800 pg/ml (22%). Specific neurological responses are shown in Table 2. Two or more abnormalities improved in 37 of the neuro responders (57%) and 13 neuro responders had improvement in 3–5 abnormalities (20%). A complete response of at least one neurological abnormality was seen in 54 of the 65 neuro responders (83%).
Dissociation of neurological and hematological responses to B12 therapy Neurological responses alone were present in 62 subjects, hematological responses alone were present in
9 subjects, and 3 subjects (4%) had both neurological and hematological responses. Hematological responses occurred more frequently in subjects with ‘Definite’ or ‘Possible’ B12 deficiency (11 of 12; 92%) while neurological responses occurred more frequently in subjects with ‘Functional’ or ‘No’ metabolic B12 deficiency (47 of 65; 72%) (χ2 = 17.659; P < 0.001) (Fig. 1). The MCV was increased in 10 of 64 evaluable neurological responders (16%). Post-treatment MCV values were obtained in 8 of these 10 subjects, but decreased significantly in only 2 of them. Thus, only 2 of 62 evaluable neuro responders also had B12-responsive macrocytosis (3%).
Relationship of neurological response to pretherapy B12, MMA, and HCys values Prior to therapy, B12, MMA and HCys values were abnormal in 28, 67, and 46% of neuro responders, respectively (Table 3). In fact, all three parameters were normal in 23%. The pattern was the same whether or not confounders were present. Conversely, in neuro non-responders, pretherapy B12, MMA and HCys values were abnormal in 54, 100, and 75% of evaluable subjects with all three values abnormal in 54%.
Dissociation of neurological and metabolical responses to B12 therapy In neuro responders, 8 of 40 evaluable subjects with elevated MMA values (20%) and 10 of 27 evaluable subjects with elevated HCys values (37%) did not Table 2
Neurological responses to vitamin B12 therapy Response
Abnormality Paresthesias (48) Ataxic gait (34) Decreased vibration sense (29) Orthostatic hypotension (13) Restless legs (12) Decreased proprioception (5) Leg weakness (5) Decreased light touch (3) Abnormal Romberg test (2) Supranuclear palsy (2)
Complete (%)
Partial (%)
27 (56) 12 (35) 22 (76) 5 (38) 4 (33) 3 (60) 4 (80) 3 (100) 2 (100) 1 (50)
12 (25) 16 (47) 5 (17) 1 (8) 4 (33) – – – – –
Number of subjects with each abnormality is indicated in parentheses. Percentages given indicate the incidence of complete or partial responses for each sign or symptom.
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Figure 1 Relationship of neurological and hematological responses to B12 status. Numbers in parentheses indicate number of subjects in each response type and B12 group. *Group A had two patients with both neurological and hematological responses. § Group C had one patient with both neurological and hematological responses.
have a significant metabolic response to B12 therapy. Conversely, in neuro non-responders, significant responses in MMA and HCys were noted in 9 of 12 (75%) and 6 of 8 (75%) evaluable subjects, respectively. The patterns were similar in subjects with and without neurological confounders.
Relationship of neurological responses to oxidative stress risk factors In neuro responders, oxidant risks were present in 33% of Group A subjects, 68% of Group B subject and 89% of subjects in Groups C and D (P < 0.001 vs. Group A) (Fig. 2). MMA and HCys values were directly related to the number of oxidative risk factors in subjects in Groups C and D (r = +0.49, P < 0.001 for each metabolite) but not in subjects in Groups A and B (r = −0.03, P = 0.9 for MMA; r = +0.18, P = 0.51 for HCys). Group C subjects also had at least two oxidant risks (78%) significantly more frequently than subjects in Group D (20%) (P < 0.001). Table 3
Moreover, three or more oxidant risks were present in 47% of Group C subjects but in none of the Group D subjects (P = 0.001).
Effect of route of cyanocobalamin administration Of the neuro responders, 51 were treated parenterally, 6 received both oral and parenteral therapy, 7 were treated orally, and the route of therapy was not documented in 1 subject. Neuro non-responders received parenteral therapy on 10 occasions and oral therapy on 3 occasions. Response rates to parenteral and oral therapy were similar [51 of the 61 patients treated only parenterally (84%) vs. 7 of the 10 patients treated only orally (70%) (χ2 = 1.0634; P = 0.30)]. However, three Group C subjects who had only partial neurological responses after 3–6 months of oral therapy (two with paresthesias and 1 with ataxic gait) subsequently had complete resolution of neurological abnormalities after 2–3 months of weekly parenteral treatments. Similarly, one Group D subject
Pretherapy B12, MMA, and HCys values in subjects with neuropathy
Confounders Absent
Present
All
†
Parameter
Responders (%)
Non-responders (%)
B12 ≤300 pg/ml MMA >250 nmol/l HCys >12.1 μmol/l B12 ≤300 pg/ml MMA >250 nmol/l HCys >12.1 μmol/l B12 ≤300 pg/ml MMA >250 nmol/l HCys >12.1 μmol/l
13/30 (43) 17/28† (61) 13/28† (46) 5/34‡ (15) 25/35 (71) 16/35 (46) 18/64‡ (28) 42/63† (67) 29/63† (46)
4/6 (67) 6/6 (100) 5/6 (83) 2/7 (29) 7/7 (100) 4/6§ (67) 6/13 (46) 13/13 (100) 9/12§ (75)
Pretherapy MMA and HCys values were not obtained in two neuro-responders with confounders absent. Pretherapy B12 not obtained in one neuro-responder with confounders present. § Pretherapy HCys not obtained in one neuro non-responder with confounders present. ‡
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Figure 2 Presence of oxidative stress risk factors in neurological responders. Values plotted are the percent of subjects in each B12 group with (A) the presence of at least one known oxidant stress risk factor; and (B) the presence of at least two known oxidant stress risk factors.
with complete correction of ataxic gait after 2 months of parenteral therapy relapsed after 6 months of oral therapy. Reinstitution of weekly intramuscular therapy for 2 months again led to normalization of gait. Finally, one Group C subject with complete correction of ataxic gait after 4 months of parenteral therapy relapsed 9 months later despite regular monthly injections. However, 3 months after resuming weekly intramuscular therapy, ataxia again resolved.
Discussion In the present study, B12-responsive neuropathies were commonly encountered even when other known causes of neuropathy were apparent (Table 1). Significantly, B12-responsive hematological abnormalities were rarely present in these subjects and the presence of increased levels of the B12-dependent metabolites, MMA, and HCys, were neither necessary nor sufficient to predict a response to treatment (Fig. 1, Table 3). Moreover, most subjects (72%) had B12 values well within the normal reference range with values >500 pg/ml and >800 pg/ml present in 25 (38%) and 7 (11%) subjects, respectively. While ‘false normal’ B12 values have been reported in subjects with IF Abs, this was not a significant factor in the current population (Table 1).35 Finally, improvement in metabolite values after B12 therapy did not predict for neurological responses. While neurological improvement followed both the oral and parenteral routes of B12 administration, observations in four subjects suggest that intramuscular administration may be
more effective, at least when given weekly (see text), a finding consistent with other reports.13,36 Moreover, while therapy with monthly B12 injections maintained maximum neurological improvement in most subjects, one individual required weekly intramuscular treatment. The mechanism(s) of B12-responsive neuropathies when serum B12 levels are normal remain to be established. It is of note then that (1) neuropathies in many settings are associated with increased oxidative stress;28–33 (2) B12 can be readily inactivated by oxidation on the one hand and can act as an antioxidant on the other hand;1,37 (3) intracellular uptake of B12 may be impaired by oxidative inactivation of the megalin receptor;38 and (4) other medications with antioxidant properties have had therapeutic benefit in human neuropathies.31,32,39 Taken together, these observations suggest a relationship between oxidative stress and B12-responsive neuropathies. Indeed, almost all subjects with normal B12 values and B12-responsive neuropathies in the present study had at least one oxidant risk (89%) while two or more oxidant risks were present in 78% of the subjects with functional B12 deficiency (Group C) (Fig. 2). Since oxidative inactivation of B12 would not require prior depletion of vitamin stores, functional B12 deficiency may develop much more rapidly than classic B12 deficiency as has been shown to be the case after recreational exposure to nitrous oxide.40 Based on these considerations, a new classification of B12-responsive neurological disorders is proposed Nutritional Neuroscience
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Table 4
Proposed classification of B12-responsive neurological disorders
B12 status
B12 level
MMA and/or HCys
Oxidative stress
Neurological toxicity
Frank deficiency Functional deficiency – systemic Functional Deficiency – localized No deficiency
Low Normal Normal Normal
Increased Increased Normal Normal
Not necessary Moderate to severe Mild to moderate Mild to moderate
B12 related B12 related+oxidant related B12 related+oxidant related Possibly oxidant related
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to include frank (classic) B12 deficiency with decreased B12 levels and increased MMA and HCys values; systemic functional B12 deficiency with increased MMA and HCys values despite normal B12 levels; and no B12 deficiency with normal levels of B12, MMA and HCys (Table 4). Finally, the possibility of localized functional B12 deficiency due to increases in oxidative stress limited to the central nervous system has also been suggested.1,41 In this setting, B12, MMA, and HCys values in the peripheral blood would also be expected to be normal. In addition to restoration of functional B12 levels, the therapeutic benefit of pharmacological doses of B12 may result from reduction of the levels of neurotoxic reactive oxygen species;1,37 alteration of neurotoxic and neurotrophic growth factors and cytokine levels;1,22 and reduction of neurotoxic nitric oxide levels.1,40 Effects of B12 on interferon gamma, IL-6 and IGF-1 may also contribute to decreased neuropathic pain perception.42–44 At least some of these effects may be mediated by up-regulation of multiple neurotrophic factor genes.45 Interesting in this regard is the finding that B12 can decrease both DNA damage and oxidative stress associated with the use of the neurotoxic drug, paclitaxel.46 Finally, the possibility of another as yet undefined B12-dependent enzyme involved in neurological function has also been suggested.47 The strength of this study is that it is one of the largest series of subjects with B12-responsive neuropathies reported and the only one in which patients were treated even when all markers of B12 nutriture were known to be normal and when other known causes of neuropathy were readily apparent. Thus, responses were noted in 51 subjects (78%) with other neuropathic disorders who might not otherwise have been tested for B12 status; and in 15 subjects (23%) in whom B12, MMA, and HCys values were all normal who might not otherwise have been treated with B12. In fact, only two subjects have previously been reported with B12-responsive neuropathies in whom both vitamin B12 and MMA values were normal.11,19 The limitation of the present study is that it is an uncontrolled retrospective analysis and measurements of the biomarkers indicative of the severity of oxidative stress were not performed. It is concluded that B12-responsive neuropathies are: (1) common even in the presence of other confounding
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causes of neuropathy; (2) dissociated from the presence of hematological abnormalities; (3) dissociated from the presence of B12-responsive metabolic abnormalities; and (4) associated with the presence of oxidant risks when B12 levels are normal. Since no laboratory predictors of response to B12 therapy were identified, empiric trials with parenteral B12 should be considered in appropriate subjects. Prospective controlled studies with direct measures of oxidative stress are needed to confirm and extend these observations preferably using reduced forms of vitamin B12 for both the treatment and prevention of neuropathy.41
Acknowledgements The author thanks D. Bonke (Merck, Darmstadt, Germany) for his suggestion regarding the possible effect of oxidative stress on B12 metabolism and Dr R. Green (UC Davis, Sacremento, CA, USA) for his suggestion on the possible therapeutic use of reduced forms of vitamin B12.
Disclaimer statements Contributors None. Funding None. Conflicts of interest None. Ethics approval None.
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9 Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid and homocysteine testing. Blood 2005;105:978–85. 10 Johannsen P, Ostergaard K, Christensen JKJ, Worm M, Rasmussen K. Methylmalonic acid in serum from patients with neurological symptoms consistent with cobalamin deficiency. Europ J Neurol 1995;2:357–62. 11 Graber JJ, Sherman FT, Kaufman H, Kolodny EH, Sathe S. Vitamin B12-responsive severe leukoencephalopathy and autonomic dysfunction in a patient with ‘normal’ serum B12 levels. J Neurol Neurosurg Psychiatry 2010;81:1369–71. 12 Fonseca VA, Lavery LA, Thethi TK, Daoud Y, DeSouza C, Ovalle F et al. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. Am J Med 2013;126:141–9. 13 Xu G, Lv Z-W, Feng Y, Tang WZ, Xu GX. A single center randomized controlled trial of local methylcobalamin injection for subacute herpetic neuralgia. Pain Med 2013;14:884–94. 14 Talaei A, Mnsour S, Majidi H, Chehrei A. Vitamin B12 may be more effective than nortriptyline in improving painful diabetic neuropathy. Int J Food Sci Nutr 2009;60:71–6. 15 Kuwabara S, Nakazawa R, Azuma N, Suzuki M, Miyajima K, Fukutake T et al. Intravenous methylcobalamin treatment of uremic and diabetic neuropathy in chronic hemodialysis patients. Int Med 1999;38:472–5. 16 Mauro GL, Martorana U, Cataldo P, Brancato G, Letizia G. Vitamin B12 in low back pain: a randomized double-blind, placebo-controlled study. Eur Rev Med Pharmacol Sci 2000;4: 53–8. 17 Shibuya K, Misawa S, Nasu S, Sekiguchi Y, Beppu M, Iwai Y et al. Safety and efficacy of intravenous ultra-high dose methylcobalamin treatment for peripheral neuropathy: a phase I/II openlabel clinical trial. Intern Med 2014;53:1927–31. 18 Negrao L, Almeida P, Alcino S, Duro H, Liborio T, Silva UM et al. Effect of the combination of uridine nucleotides, folic acid and vitamin B12 on the clinical expression of peripheral neuropathies. Pain Manag 2014;4:191–6. 19 Olcay L, Irkkan C, Senbil N, Uzun H, Basmaci M, Gurere YKY. Progressive vacuolar myelopathy and leukoencephalopathy in childhood lymphoblastic leukemia and transient improvement with vitamin B12. Pediatr Blood Cancer 2007;49:754–8. 20 Caram-Salas NL, Reyes-Garcia G, Medina-Santillan R, Granados-Soto V. Thiamine and cyanocobalamin relieve neuropathic pain in rats: synergy with dexamethasone. Pharmacol 2006;77:53–62. 21 Jian-bo L, Cheng-ya W, Jai-wei C, Xiao-lu L, Zhen-qing F, Hogtai M. The preventive efficacy of methylcobalamin on rat peripheral neuropathy influenced by diabetes via neural IGF-1 levels. Nutr Neurosci 2010;13:79–86. 22 Hosseinzadeh H, Moallem SA, Moshiri M, Sarnavazi MS, Etermad L. Anti-nocioceptive and anti-inflammatory effects of cyanocobalamin (vitamin B12) against acute and chronic pain and inflammation in mice. Arzneimittel-Forschung 2012;62: 324–9. 23 Sun H, Yang T, Li Q, Zhu Z, Wang L, Bai G et al. Dexamethasone and vitamin B12 synergistically promote peripheral nerve regeneration in rats by upregulation the expression of brain-derived neurotrophic factor. Arch Med Sci 2012;8:924–30. 24 Okada K, Tanaka H, Temporin K, Kuroda Y, Moritomo H, Murase T et al. Akt/mamallian target of rapamycin signaling pathway regulates neurite outgrowth in cerebellar granular neurons stimulated by methylcobalamin. Neurosci Lett 2011; 495:201–4. 25 Morani AS, Bodhankar SL. Early coadministration of vitamin E acetate and methylcobalamin improves thermal hyperalgesia and motor nerve conduction velocity following sciatic nerve crural injury in rats. Pharmacol Reports 2010;62:405–9. 26 Granados-Soto V, Sanchez-Ramirez G, Rosas-de la Torre M, Caram-Salas NL, Medina-Santillan R, Reyes-Garcia G. Effect of diclofenac on the anti allodynic activity of vitamin B12 in a neuropathic pain model in the rat. Proc West Pharmacol Soc 2004;47:92–4.
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27 Finnerup NB, Sindrup SH, Iensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain 2010;150: 573–81. 28 Obeid R, Shannon B, Herrmann W. Advanced glycation end products overload might explain cobalamin deficiency in renal dysfunction, diabetes and aging. Medical Hypotheses 2011;77: 884–8. 29 Ziegler D, Sohr CGH, Nourooz-Zadeh J. Oxidative stress and antioxidant defense in relation to the severity of diabetic polyneuropathy and cardiovascular autonomic neuropathy. Diabetes Care 2004;27:2178–83. 30 Sims-Robinson C, Hur J, Hayes JM, Dauch JR, Keller PJ, Brooks SV et al. The role of oxidative stress in nervous system aging. PLOS One 2013;8:e68011. 31 Kandhare AD, Raygude KS, Ghosh P, Ghule AE, Bodhankar SL. Therapeutic role of curcumin in prevention of biochemical and behavioral aberration induced by alcoholic neuropathy in laboratory animals. Neurosci Lett 2012;511:18–22. 32 DiCesare Manelli L, Zanardelli M, Failli P, Ghelardini C. Oxaliplatin-induced neuropathy: oxidative stress as a pathological mechanism; protective effect of silibin. J Pain 2012;13: 276–84. 33 Meshkini A, Yazdanparast R. Involvement of oxidatives stress in taxol-induced apoptosis in chronic myelogenous leukemia K562 cells. Exper Toxicol Pathol 2012;64:357–65. 34 Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2003. Am J Clin Nutr 2005; 82:442–50. 35 Carmel R, Agrawal YP. Failure of cobalamin assays in pernicious anemia. New Engl J Med 2012;367:385–86. 36 Solomon LR. Oral pharmacologic doses of cobalamin may not be as effective as parenteral cobalamin therapy in reversing hyperhomocysteinemia and methylmalonic acidemia in apparently normal subjects. Clin Lab Haematol 2006;28:275–8. 37 Birch CS, Brasch NE, McCaddon A, Williams JH. A novel role for vitamin B12: cobalamins are intracellular antioxidants in vitro. Free Radic Biol Med 2009;47:184–8. 38 Obeid R, Kuhlman MK, Kirsch C-M, Herrmann W. Cellular uptake of vitamin B12 in patients with chronic renal failure. Nephron Clin Pract 2005;99:c42–8. 39 Ziegler D, Nowak H, Klempert P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant ∝-lipoic acid. Diabetic Med 2004;21:114–21. 40 Alt RS, Morrissey RP, Gang MA, Hoffman RS, Schaumburg HH. Severe myeloneuropathy from acute high-dose nitrous oxide (N2O) abuse. J Emerg Med 2011;41:378–80. 41 McCaddon A, Regland B, Hudson P, Davies G. Functional vitamin B12 deficiency and Alzheimer disease. Neurology 2002; 58:1395–99. 42 Yamashiki M, Nishimura A, Yosaka Y. Effects of methylcobalamin (vitamin B12) on in vitro cytokine production of peripheral blood mononuclear cells. J Clin Lab Immunol 1992;37: 173–82. 43 Racz I, Nadal X, Alferink J, Banos JE, Rehnelt J, Martin M et al. Interferon gamma is a critical modulator of CB2 cannabinoid receptor signaling during neuropathic pain. J Neurosci 2008;28:12136–45. 44 Flatters SJL, Fox AJ, Dickerson AH. Spinal interleukin-6 (IL-6) inhibits nocioceptive transmission following neuropathy. Brain Res 2003;984:54–62. 45 Gan L, Qian M, Shi K, Chen G, Gu Y, Du W et al. Restorative effect and mechanism of mecocobalamin on sciatic nerve crush injury in mice. Nerual Regen Res 2014;9:1979–84. 46 Alzoubi K Khabour O, Khader M, Mhaidat N, Al-Azzam S. Evaluation of vitamin B12 effects on DNA damage induced by paclitaxel. Drug Chem Toxicol 2014;37:276–80. 47 Allen RH, Stabler SP, Savage DG, Lindenbaum J. Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. FASEB J 1993;7:1344–53.
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ISSN: 1028-415X (Print) 1476-8305 (Online) Journal homepage: http://www.tandfonline.com/loi/ynns20
Vitamin B12-responsive neuropathies: A case series Lawrence R. Solomon To cite this article: Lawrence R. Solomon (2015): Vitamin B12-responsive neuropathies: A case series, Nutritional Neuroscience To link to this article: http://dx.doi.org/10.1179/1476830515Y.0000000006
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Vitamin B12-responsive neuropathies: A case series Lawrence R. Solomon
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Section of Palliative Care, Department of Medicine, Yale University School of Medicine and Smilow Cancer Hospital, New Haven, CT, USA Objectives: Neuropathies often accompany vitamin B12 deficiency. Since many neuropathies are linked to oxidative stress and since B12 has both antioxidant and neurotrophic properties, B12 may also be effective treatment in non-deficient subjects. Thus, the characteristics and predictors of B12-responsive neuropathies and their relationship to disorders associated with increased oxidative stress (oxidant risks) were examined. Methods: Retrospective review of 78 subjects with neurological abnormalities treated with B12 and evaluated by the measurement of B12 and the B12-dependent metabolites, methylmalonic acid (MMA), and homocysteine. Results: Sixty-five subjects had neurological improvement (83%), including 35 with other known causes of neuropathy. Only two responders had B12-responsive macrocytosis. Pretherapy B12, MMA, and homocysteine values were normal in 72, 33 and 54% of responders, with all three normal in 23%. Moreover, B12 therapy did not significantly decrease elevated MMA and homocysteine levels in 20 and 37%, respectively, of responders tested but did decrease both metabolites in 75% of evaluable nonresponders. At least one oxidant risk was present in 41 of the 46 responders with normal B12 levels (89%). Oral therapy was effective, but parenteral B12 improved responses in four subjects. Discussion: B12-responsive neuropathies are thus (1) common even when confounding disorders are present; (2) dissociated from the presence of hematological abnormalities; (3) dissociated from the presence of B12-responsive metabolical abnormalities; and (4) associated with the presence of oxidant risks when B12 levels are normal. Since no predictors of responses to B12 therapy were identified, empiric trials with parenteral B12 should be considered in appropriate subjects. Keywords: Neuropathy, Vitamin B12, Oxidative stress, Cobalamin, Methylmalonic acid, Homocysteine
Introduction Neurological disorders often accompany frank vitamin B12 deficiency which is defined by the presence of low-serum B12 levels along with increased values of the B12-dependent metabolites, methylmalonic acid (MMA) and/or homocysteine (HCys).1 Classically, B12 deficiency results from malabsorption or decreased dietary intake of the vitamin; develops over several years; and is associated with both macrocytic anemia and neurocognitive defects. However, it is now recognized that neurological impairment often occurs in the absence of overt hematological abnormalities.1,2 B12-responsive neuropathies also occur in the setting of ‘functional’ vitamin B12 deficiency, defined by the presence of elevated levels of MMA and/or HCys despite serum B12 levels well within the normal Correspondence to: Lawrence R. Solomon, Section of Palliative Care, Department of Medicine, Yale University School of Medicine, 403 www; 333 Cedar Street, P.O. Box 208021, New Haven, CT 06520–8021, USA. E-mail: [email protected]
© W. S. Maney & Son Ltd 2015 DOI 10.1179/1476830515Y.0000000006
reference range.1–10 Moreover, B12-responsive neuropathies have been described when measures of B12 nutriture were not determined and, in two instances, when both B12 and MMA values were normal.1,9,11–19 Finally, in vitro and animal studies suggest that B12 may also have analgesic and neurotrophic properties in non-deficient settings.1,20–26 In contrast, standard treatments for neuropathic pain with antidepressants and anticonvulsants are effective in a minority of subjects, do not improve nerve function, and are associated with significant side effects.27 In an earlier report, it was noted that tests for B12, MMA, and HCys were not predictive of the presence of B12-responsive clinical disorders in 37 subjects evaluated in an ambulatory care setting.9 This study was limited in that distinctions were not made between hematological and neurological patterns of response and the relationships between clinical responses and metabolic responses were not explored. Therefore, the current study focused on the relationship between B12 and neurological disorders in an expanded
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population of 74 clinical responders to B12 therapy, including 65 subjects with neurological responses, in order to (1) compare the patterns of neurological and hematological responses relative to the B12 status of these subjects; (2) understand the role of laboratory studies in predicting neurological responses to B12 treatment; and (3) define the relationship between neurological and metabolical responses to B12 therapy. Since increased oxidative stress is associated with both functional B12 deficiency and neuropathies seen in many settings, the association of B12-responsive neurological disorders with risk factors for oxidative stress was also evaluated.1,28–33
Materials and methods Laboratory methods Downloaded by [Deakin University Library] at 03:20 03 January 2016
Serum B12, serum MMA, and plasma HCys were measured as previously described.9 The normal range for cobalamin (Cbl)(B12) was 201–1100 pg/ml. However, since B12 deficiency is not infrequent in subjects with B12 levels of 200–300 pg/ml, B12 levels were considered normal if values were >300 pg/ml.9 The reference ranges for MMA and HCys were taken as 90–250 nmol/l and 5.4–12.1 μmol/l, respectively.9 When values were obtained on more than one occasion within a 4-week period, the lowest Cbl value and the highest metabolite values were used for analysis. Intrinsic factor antibodies (IF Abs) were also tested for in 50 of the 78 subjects with neurological signs and/or symptoms (64%).
Participants A retrospective review of the medical records of all ambulatory, community-dwelling subjects followed regularly by the author and evaluated for possible B12 deficiency because of the presence of either hematological or neurological abnormalities between 1 August 1993 and 30 June 2005 was conducted as previously described.8,9 During the first 6 years of the study, only subjects with clinical abnormalities and metabolic evidence of B12 deficiency were treated with B12. Thereafter, all subjects with clinical abnormalities were offered B12 therapy even when B12, MMA, and HCys values were normal.9 Overall, 74 subjects with either hematological or neurological responses to B12 therapy were identified (responders) including 65 subjects with neurological (neuro) responses. An additional 13 subjects had neurological abnormalities that did not improve with B12 therapy (non-responders). At least 3 months of B12 therapy was required before a subject was classified as a non-responder. All active medical conditions present in each subject were identified and a Medline search was performed to determine which of these disorders were associated with increased systemic markers of oxidative stress (oxidant risks). At least one oxidant risk was present
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in 63 of the 78 subjects with neurological disorders (81%) including advanced age (≥70 years old) (n = 35); diabetes mellitus (n = 24); cigarette abuse (n = 14); alcohol abuse (n = 11); renal insufficiency (creatinine >1.3 mg/dl in women and >1.5 mg/dl in men) (n = 11); malignancy (n = 10); congestive heart failure (n = 7); neurodegenerative disorders (n = 5); chronic infections or inflammation (n = 4); rheumatological disorders (n = 3); medication-dependent asthma (n = 2); iron overload (n = 2); active renal transplant rejection (n = 1); and cirrhosis (n = 1). Disorders known to be associated with neurological abnormalities (confounders) were present in 51 of the 65 neuro responders (78%) and in 7 of the 13 neuro non-responders (54%) including diabetes (n = 25); alcohol abuse (n = 11); structural lesions of brain or vertebral column (n = 8); neurodegenerative disorders (n = 5); prior use of neurotoxic chemotherapeutic agents (n = 3); and advanced renal disease (n = 2; creatinine = 8.0 and 9.4 mg/dl). Subjects with neuro responses to B12 therapy were divided into four groups: (1) Group A (‘Definite’ B12 deficiency) defined by the presence of a low B12 value of ≤200 pg/ml; (2) Group B (‘Possible’ B12 deficiency) defined by the presence of a low-normal B12 value of 201–300 pg/ml with an increased level of MMA and/or HCys; (3) Group C (‘Functional’ B12 deficiency) defined by the presence of B12 values >300 pg/ml with an increased level of MMA and/or HCys; and (4) Group D (‘No’ metabolic B12 deficiency) defined by the presence of B12 values >300 pg/ml with normal values for both MMA and HCys (includes one subject with normal pretreatment MMA and HCys values on two occasions in whom a pretherapy B12 value was not available). This study conforms to the principles of the Declaration of Helsinki of 1975 as revised in 2008 and the institutional human investigation committee determined that further review was not required.
B12 (cyanocobalamin) treatment Patients were treated with cyanocobalamin 2 mg per day orally or 1 mg intramuscularly three times a week for 2 weeks, weekly for 8 weeks and monthly thereafter. All treated patients were reevaluated within 1–3 months after beginning B12 therapy. There were no other changes made in diet, the use of other medications, or the use of dietary supplements after the initiation of B12 therapy nor was physical or occupational therapy instituted in any subject. Hematological responses to B12 were considered to be significant if the mean corpuscular volume (MCV) decreased greater than 5 fl from a value of more than 98 fl or if the hematocrit increased by more than 0.05 from a value of less than 0.36 in
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Table 1 Characteristics of subjects with neurological responses to B12 therapy Group
n
Age (years)
Male gender (%)
A B C D
9 9 32 15
50.0 (28–69) 59.7 (28–83) 65.5 (39–86) 67.5 (40–82)
1 (11) 3 (33) 14 (44) 12 (75)
B12 (pg/ml)
Confounders present (%)
Positive IF Abs (%)
2 (22) 3 (33) 22 (69) 8 (53)
1/5 (20) 1/7 (14) 2/23 (9) 0/3 (0)
149 (58–186) 277 (263–297) 566 (319–2000) 505 (348–762)
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Values for age and B12 are given as the geometric means with ranges shown in brackets. IF Abs, intrinsic factor antibodies.
women or less than 0.39 in men. Neuro responses were considered to be present if either complete or partial improvement occurred in the signs or symptoms of peripheral or autonomic neuropathy identified at the time of initial evaluation. A metabolic response to B12 therapy was defined as a decrease in the metabolite from its highest pretreatment value by more than 1 SD greater than its mean intra-individual variability as previously defined in this population (i.e., >116 nmol/l for MMA and >3.6 μmol/l for HCys).9
Data analysis Population studies suggest skewed distributions for B12, MMA, and HCys.34 Thus, geometric means, two-tailed Student’s t tests using log-transformed data, Spearman correlation coefficients (r) and χ2 analyses were determined using StatPlus:mac (release 5.7, 2009, AnalystSoft, Vancouver, BC, Canada).
Results Neurological responses to B12 therapy Overall, 65 of the 78 subjects with neurological signs or symptoms had clinical responses to B12 therapy (83%). The response rates were the same in subjects with confounders (35 of 42 subjects) and in those with no confounders (30 of 36 subjects). Only 18 of the 65 neuro responders (28%) had either definite or possible B12 deficiency (Groups A and B) (Table 1). IF Abs were present in 4 of the 38 patients tested (11%), including 1 patient each in Group A and Group B and 2 of the 26 patients with normal B12 levels (8%). B12 levels were >500 pg/ml in 17 subjects in Group C (53%) and in 8 subjects in Group D (57%). Moreover, 7 Group C subjects had B12 levels >800 pg/ml (22%). Specific neurological responses are shown in Table 2. Two or more abnormalities improved in 37 of the neuro responders (57%) and 13 neuro responders had improvement in 3–5 abnormalities (20%). A complete response of at least one neurological abnormality was seen in 54 of the 65 neuro responders (83%).
Dissociation of neurological and hematological responses to B12 therapy Neurological responses alone were present in 62 subjects, hematological responses alone were present in
9 subjects, and 3 subjects (4%) had both neurological and hematological responses. Hematological responses occurred more frequently in subjects with ‘Definite’ or ‘Possible’ B12 deficiency (11 of 12; 92%) while neurological responses occurred more frequently in subjects with ‘Functional’ or ‘No’ metabolic B12 deficiency (47 of 65; 72%) (χ2 = 17.659; P < 0.001) (Fig. 1). The MCV was increased in 10 of 64 evaluable neurological responders (16%). Post-treatment MCV values were obtained in 8 of these 10 subjects, but decreased significantly in only 2 of them. Thus, only 2 of 62 evaluable neuro responders also had B12-responsive macrocytosis (3%).
Relationship of neurological response to pretherapy B12, MMA, and HCys values Prior to therapy, B12, MMA and HCys values were abnormal in 28, 67, and 46% of neuro responders, respectively (Table 3). In fact, all three parameters were normal in 23%. The pattern was the same whether or not confounders were present. Conversely, in neuro non-responders, pretherapy B12, MMA and HCys values were abnormal in 54, 100, and 75% of evaluable subjects with all three values abnormal in 54%.
Dissociation of neurological and metabolical responses to B12 therapy In neuro responders, 8 of 40 evaluable subjects with elevated MMA values (20%) and 10 of 27 evaluable subjects with elevated HCys values (37%) did not Table 2
Neurological responses to vitamin B12 therapy Response
Abnormality Paresthesias (48) Ataxic gait (34) Decreased vibration sense (29) Orthostatic hypotension (13) Restless legs (12) Decreased proprioception (5) Leg weakness (5) Decreased light touch (3) Abnormal Romberg test (2) Supranuclear palsy (2)
Complete (%)
Partial (%)
27 (56) 12 (35) 22 (76) 5 (38) 4 (33) 3 (60) 4 (80) 3 (100) 2 (100) 1 (50)
12 (25) 16 (47) 5 (17) 1 (8) 4 (33) – – – – –
Number of subjects with each abnormality is indicated in parentheses. Percentages given indicate the incidence of complete or partial responses for each sign or symptom.
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Figure 1 Relationship of neurological and hematological responses to B12 status. Numbers in parentheses indicate number of subjects in each response type and B12 group. *Group A had two patients with both neurological and hematological responses. § Group C had one patient with both neurological and hematological responses.
have a significant metabolic response to B12 therapy. Conversely, in neuro non-responders, significant responses in MMA and HCys were noted in 9 of 12 (75%) and 6 of 8 (75%) evaluable subjects, respectively. The patterns were similar in subjects with and without neurological confounders.
Relationship of neurological responses to oxidative stress risk factors In neuro responders, oxidant risks were present in 33% of Group A subjects, 68% of Group B subject and 89% of subjects in Groups C and D (P < 0.001 vs. Group A) (Fig. 2). MMA and HCys values were directly related to the number of oxidative risk factors in subjects in Groups C and D (r = +0.49, P < 0.001 for each metabolite) but not in subjects in Groups A and B (r = −0.03, P = 0.9 for MMA; r = +0.18, P = 0.51 for HCys). Group C subjects also had at least two oxidant risks (78%) significantly more frequently than subjects in Group D (20%) (P < 0.001). Table 3
Moreover, three or more oxidant risks were present in 47% of Group C subjects but in none of the Group D subjects (P = 0.001).
Effect of route of cyanocobalamin administration Of the neuro responders, 51 were treated parenterally, 6 received both oral and parenteral therapy, 7 were treated orally, and the route of therapy was not documented in 1 subject. Neuro non-responders received parenteral therapy on 10 occasions and oral therapy on 3 occasions. Response rates to parenteral and oral therapy were similar [51 of the 61 patients treated only parenterally (84%) vs. 7 of the 10 patients treated only orally (70%) (χ2 = 1.0634; P = 0.30)]. However, three Group C subjects who had only partial neurological responses after 3–6 months of oral therapy (two with paresthesias and 1 with ataxic gait) subsequently had complete resolution of neurological abnormalities after 2–3 months of weekly parenteral treatments. Similarly, one Group D subject
Pretherapy B12, MMA, and HCys values in subjects with neuropathy
Confounders Absent
Present
All
†
Parameter
Responders (%)
Non-responders (%)
B12 ≤300 pg/ml MMA >250 nmol/l HCys >12.1 μmol/l B12 ≤300 pg/ml MMA >250 nmol/l HCys >12.1 μmol/l B12 ≤300 pg/ml MMA >250 nmol/l HCys >12.1 μmol/l
13/30 (43) 17/28† (61) 13/28† (46) 5/34‡ (15) 25/35 (71) 16/35 (46) 18/64‡ (28) 42/63† (67) 29/63† (46)
4/6 (67) 6/6 (100) 5/6 (83) 2/7 (29) 7/7 (100) 4/6§ (67) 6/13 (46) 13/13 (100) 9/12§ (75)
Pretherapy MMA and HCys values were not obtained in two neuro-responders with confounders absent. Pretherapy B12 not obtained in one neuro-responder with confounders present. § Pretherapy HCys not obtained in one neuro non-responder with confounders present. ‡
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Figure 2 Presence of oxidative stress risk factors in neurological responders. Values plotted are the percent of subjects in each B12 group with (A) the presence of at least one known oxidant stress risk factor; and (B) the presence of at least two known oxidant stress risk factors.
with complete correction of ataxic gait after 2 months of parenteral therapy relapsed after 6 months of oral therapy. Reinstitution of weekly intramuscular therapy for 2 months again led to normalization of gait. Finally, one Group C subject with complete correction of ataxic gait after 4 months of parenteral therapy relapsed 9 months later despite regular monthly injections. However, 3 months after resuming weekly intramuscular therapy, ataxia again resolved.
Discussion In the present study, B12-responsive neuropathies were commonly encountered even when other known causes of neuropathy were apparent (Table 1). Significantly, B12-responsive hematological abnormalities were rarely present in these subjects and the presence of increased levels of the B12-dependent metabolites, MMA, and HCys, were neither necessary nor sufficient to predict a response to treatment (Fig. 1, Table 3). Moreover, most subjects (72%) had B12 values well within the normal reference range with values >500 pg/ml and >800 pg/ml present in 25 (38%) and 7 (11%) subjects, respectively. While ‘false normal’ B12 values have been reported in subjects with IF Abs, this was not a significant factor in the current population (Table 1).35 Finally, improvement in metabolite values after B12 therapy did not predict for neurological responses. While neurological improvement followed both the oral and parenteral routes of B12 administration, observations in four subjects suggest that intramuscular administration may be
more effective, at least when given weekly (see text), a finding consistent with other reports.13,36 Moreover, while therapy with monthly B12 injections maintained maximum neurological improvement in most subjects, one individual required weekly intramuscular treatment. The mechanism(s) of B12-responsive neuropathies when serum B12 levels are normal remain to be established. It is of note then that (1) neuropathies in many settings are associated with increased oxidative stress;28–33 (2) B12 can be readily inactivated by oxidation on the one hand and can act as an antioxidant on the other hand;1,37 (3) intracellular uptake of B12 may be impaired by oxidative inactivation of the megalin receptor;38 and (4) other medications with antioxidant properties have had therapeutic benefit in human neuropathies.31,32,39 Taken together, these observations suggest a relationship between oxidative stress and B12-responsive neuropathies. Indeed, almost all subjects with normal B12 values and B12-responsive neuropathies in the present study had at least one oxidant risk (89%) while two or more oxidant risks were present in 78% of the subjects with functional B12 deficiency (Group C) (Fig. 2). Since oxidative inactivation of B12 would not require prior depletion of vitamin stores, functional B12 deficiency may develop much more rapidly than classic B12 deficiency as has been shown to be the case after recreational exposure to nitrous oxide.40 Based on these considerations, a new classification of B12-responsive neurological disorders is proposed Nutritional Neuroscience
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Table 4
Proposed classification of B12-responsive neurological disorders
B12 status
B12 level
MMA and/or HCys
Oxidative stress
Neurological toxicity
Frank deficiency Functional deficiency – systemic Functional Deficiency – localized No deficiency
Low Normal Normal Normal
Increased Increased Normal Normal
Not necessary Moderate to severe Mild to moderate Mild to moderate
B12 related B12 related+oxidant related B12 related+oxidant related Possibly oxidant related
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to include frank (classic) B12 deficiency with decreased B12 levels and increased MMA and HCys values; systemic functional B12 deficiency with increased MMA and HCys values despite normal B12 levels; and no B12 deficiency with normal levels of B12, MMA and HCys (Table 4). Finally, the possibility of localized functional B12 deficiency due to increases in oxidative stress limited to the central nervous system has also been suggested.1,41 In this setting, B12, MMA, and HCys values in the peripheral blood would also be expected to be normal. In addition to restoration of functional B12 levels, the therapeutic benefit of pharmacological doses of B12 may result from reduction of the levels of neurotoxic reactive oxygen species;1,37 alteration of neurotoxic and neurotrophic growth factors and cytokine levels;1,22 and reduction of neurotoxic nitric oxide levels.1,40 Effects of B12 on interferon gamma, IL-6 and IGF-1 may also contribute to decreased neuropathic pain perception.42–44 At least some of these effects may be mediated by up-regulation of multiple neurotrophic factor genes.45 Interesting in this regard is the finding that B12 can decrease both DNA damage and oxidative stress associated with the use of the neurotoxic drug, paclitaxel.46 Finally, the possibility of another as yet undefined B12-dependent enzyme involved in neurological function has also been suggested.47 The strength of this study is that it is one of the largest series of subjects with B12-responsive neuropathies reported and the only one in which patients were treated even when all markers of B12 nutriture were known to be normal and when other known causes of neuropathy were readily apparent. Thus, responses were noted in 51 subjects (78%) with other neuropathic disorders who might not otherwise have been tested for B12 status; and in 15 subjects (23%) in whom B12, MMA, and HCys values were all normal who might not otherwise have been treated with B12. In fact, only two subjects have previously been reported with B12-responsive neuropathies in whom both vitamin B12 and MMA values were normal.11,19 The limitation of the present study is that it is an uncontrolled retrospective analysis and measurements of the biomarkers indicative of the severity of oxidative stress were not performed. It is concluded that B12-responsive neuropathies are: (1) common even in the presence of other confounding
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causes of neuropathy; (2) dissociated from the presence of hematological abnormalities; (3) dissociated from the presence of B12-responsive metabolic abnormalities; and (4) associated with the presence of oxidant risks when B12 levels are normal. Since no laboratory predictors of response to B12 therapy were identified, empiric trials with parenteral B12 should be considered in appropriate subjects. Prospective controlled studies with direct measures of oxidative stress are needed to confirm and extend these observations preferably using reduced forms of vitamin B12 for both the treatment and prevention of neuropathy.41
Acknowledgements The author thanks D. Bonke (Merck, Darmstadt, Germany) for his suggestion regarding the possible effect of oxidative stress on B12 metabolism and Dr R. Green (UC Davis, Sacremento, CA, USA) for his suggestion on the possible therapeutic use of reduced forms of vitamin B12.
Disclaimer statements Contributors None. Funding None. Conflicts of interest None. Ethics approval None.
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