Somatosensory & Motor Research
ISSN: 0899-0220 (Print) 1369-1651 (Online) Journal homepage: http://www.tandfonline.com/loi/ismr20
Vitamin B12 status does not influence central motor conduction time in asymptomatic elderly people: A transcranial magnetic stimulation study José Manuel Matamala, Carolina Nuñez, Renato J. Verdugo, Lydia Lera, Hugo Sánchez, Cecilia Albala & José Luis Castillo To cite this article: José Manuel Matamala, Carolina Nuñez, Renato J. Verdugo, Lydia Lera, Hugo Sánchez, Cecilia Albala & José Luis Castillo (2014) Vitamin B12 status does not influence central motor conduction time in asymptomatic elderly people: A transcranial magnetic stimulation study, Somatosensory & Motor Research, 31:3, 136-140, DOI: 10.3109/08990220.2014.897603 To link to this article: http://dx.doi.org/10.3109/08990220.2014.897603
Published online: 03 Apr 2014.
Submit your article to this journal
Article views: 66
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ismr20 Download by: [Cornell University Library]
Date: 27 September 2016, At: 12:52
http://informahealthcare.com/smr ISSN: 0899-0220 (print), 1369-1651 (electronic) Somatosens Mot Res, 2014; 31(3): 136–140 ! 2014 Informa UK Ltd. DOI: 10.3109/08990220.2014.897603
ORIGINAL ARTICLE
Vitamin B12 status does not influence central motor conduction time in asymptomatic elderly people: A transcranial magnetic stimulation study Jose´ Manuel Matamala1, Carolina Nun˜ez1, Renato J. Verdugo1, Lydia Lera2, Hugo Sa´nchez2, Cecilia Albala2, & Jose´ Luis Castillo1 1
Department of Neurological Science, Faculty of Medicine, University of Chile, Santiago, Chile and 2Public Health and Nutrition Unit, Nutrition and Food Technology Institute, University of Chile, Santiago, Chile Abstract
Keywords
Introduction: Vitamin B12 deficiency causes neurologic and psychiatric disease, especially in older adults. Subacute combined degeneration is characterized by damage to the posterior and lateral spinal cord affecting the corticospinal tract. Objective: To test corticospinal tract projections using motor evoked potentials (MEPs) by transcranial magnetic stimulation (TMS) in asymptomatic older adults with low vitamin B12 (B12) levels. Methods: Cross-sectional study of 53 healthy older adults (470 years). MEPs were recorded in the abductor pollicis brevis and tibialis anterior muscles, at rest and during slight tonic contraction. Central motor conduction time (CMCT) was derived from the latency of MEPs and peripheral motor conduction time (PMCT). Neurophysiological variables were analyzed statistically according to B12 status. Results: Median age was 74.3 ± 3.6 years (58.5% women). Twenty-six out of the 53 subjects had low vitamin B12 levels (B125221 pmol/l). MEPs were recorded for all subjects in upper and lower extremities. There were no significant differences in either latency or amplitude of MEPs and CMCT between low and normal B12 groups. There was a significant PMCT delay in the lower extremities in the low B12 group (p ¼ 0.014). Conclusions: No subclinical abnormality of the corticospinal tract is detected in asymptomatic B12-deficient older adults. The peripheral nervous system appears to be more vulnerable to damage attributable to this vitamin deficit. The neurophysiological evaluation of asymptomatic older adults with lower B12 levels should be focused mainly in peripheral nervous system evaluation.
Motor evoked potentials (MEPs), older adults, vitamin B12
Introduction Vitamin B12 or cyanocobalamin (B12) is a key hydrosoluble vitamin for central nervous system (CNS) function. B12 is involved in the methylation process necessary for the production of neurotransmitters, proteins, nucleotides, and phospholipids (Shane 2008). B12 deficiency may present as macrocytic anemia, subacute combined degeneration (SCD) of the spinal cord, and peripheral neuropathy. In older adults, it is often asymptomatic (Carmel 2006; Clarke 2006). SCD is characterized by damage to the posterior and lateral spinal cord affecting the corticospinal tract (Russell et al. 1900; Scalabrino 2005). Population-based surveys indicate that the prevalence of B12 deficiency in people 460 years is 6–20%, suggesting that Correspondence: J. M. Matamala and J. L. Castillo, Department of Neurological Science, Faculty of Medicine, University of Chile, Santiago, Chile. Tel: +56 2 9770517. Fax: +56 2 2360170. E-mail: [email protected] (J. M. Matamala); [email protected] (J. L. Castillo).
History Received 31 January 2014 Accepted 17 February 2014 Published online 3 April 2014
this age group is at higher risk than the younger population (Campbell et al. 2003). In the Chilean population, we found in older adults a prevalence of B12 deficiency of 12% (B125148 pmol/l) and 25.4% of marginal deficiency (B12 between 148 and 221 pmol/l) (Sa´nchez et al. 2010). This prevalence would be the result of age-related gastric atrophy, low acid, and intrinsic factor production (Carmel et al. 1988; Suter et al. 1991; Andres et al. 2004; Clarke et al. 2004). Many studies have supported the usefulness of neurophysiological evaluation of the corticospinal tract in patients with myelopathies of different cause (Abbruzzese et al. 1988; Maertens de Noordhout et al. 1991; Chistyakov et al. 1995). Nevertheless, information is scarce regarding the neurophysiological abnormalities in the corticospinal tract in patients with B12 deficiency. There have been reports of prolonged central motor conduction time (CMCT) in patients with SCD, with improvement of this parameter after B12 supplementation (Di Lazzaro et al. 1992; Hemmer et al. 1998; Misra et al. 2003; Atanassova et al. 2004). To date there are no studies assessing corticospinal tract function in
DOI: 10.3109/08990220.2014.897603
Central motor conduction time in vitamin B12 deficiency
asymptomatic older adults with low B12 levels. The aim of this study was to test corticospinal tract projections using motor evoked potentials (MEPs) by transcranial magnetic stimulation (TMS) in asymptomatic older adults with low B12 levels.
brevis (APB) and tibialis anterior (TA) on the right side, during rest and slight tonic contraction with a strength just enough to overcome gravity and maintained with the aid of auditory and visual electromyography feedback. The MEPs were amplified and band pass filtered between 2 Hz and 2 kHz using a Nicolet Viking Quest electromyographer. TMS was applied over Cz to record the MEP in the upper extremity and over Fz for the lower extremity, using the international 10–20 EEG system. To stimulate the left hemisphere, the current was applied clockwise. All motor responses analyzed were obtained at 80% of maximum output, which correspond to supramaximal stimulation intensity (Alexeeva et al. 1998). We confirmed that latency was not shortened by incrementing the intensity. The entire recording was done with subjects sitting comfortably. Motor latency was determined at the beginning of the negative deflection. Amplitude was measured between baseline and the peak of the negative deflection. MEPs with the shortest latency were selected from eight supramaximal stimulations (Groppa et al. 2012). The CMCT was calculated as the time between the latency of MEPs and peripheral motor conduction time (PMCT).
Methods Cross-sectional study performed in 53 subjects (58.5% women) aged 70 years or older. The sample was randomly selected from the subjects recruited in two studies: (1) ‘‘Comparison of Two Modes of Vitamin B12 Supplementation on Neuroconduction and Cognitive Function among Older People Living in Santiago, Chile: A Cluster Randomized Controlled Trial’’ [ISRCTN 02694183] (Sa´nchez et al. 2011) and (2) ‘‘Obesity in the Elderly in Santiago, Chile and its Relationship with Mortality’’ (Albala et al. 2011). These studies collected data on creatinine, thyroid-stimulating hormone (TSH), fasting glycemia, B12, folic acid, and Mini Mental State Examination (MMSE). Blood count, folic acid, and B12 levels were measured at the time of the neurophysiological evaluation. Exclusion criteria were: (1) MMSE score 519; (2) creatinine clearance 530 ml/min calculated using the Cockcroft formula; (3) hypothyroidism (defined as TSH 46 mlU/l); (4) fasting blood glucose 4125 mg/dl and/or use of insulin or oral hypoglycemic agents; (5) history of stroke with or without residual deficits; (6) history of epilepsy; (7) metal implants or pacemaker; (8) any abnormality in sensory, motor, and reflex examination. When the results of the vitamin status were available, all the subjects were informed and individuals with B12 plasma levels 5221 pmol/l were referred to the health center for treatment with B12 supplements. The local ethics committee of the East Metropolitan Health Service of Santiago, Hospital del Salvador, approved the study. All subjects signed an informed consent form before participating in the study. Hematological and biochemical measures
137
Peripheral nerve conduction Nerve conduction studies of the right median and common peroneal nerves were performed using standard techniques with surface disc electrodes and controlled limb temperature (Kimura 2001). Motor nerve conduction was recorded from the APB and TA muscles using the same registration point for MEPs. Median and peroneal nerves were stimulated supramaximally at the wrist and the fibular head, respectively. Compound muscle action muscle potential (CMAP) amplitude, distal motor latency, and F-wave latency were measured. PMCT was derived from the recorded F-wave using the formula (F + M 1)/2 (Groppa et al. 2012). Statistical analysis
Each subject underwent a clinical neurological examination by two of the authors (JMM, CN) before the neurophysiological measurements, in order to detect abnormalities not spontaneously reported by the subject.
Mean and standard deviation were calculated for continuous variables and proportions expressed in percentage for categorical variables. Neurophysiological variables were analyzed statistically according to B12 status. To categorize B12 status, we considered normal values 221 pmol/l and low B12 values 5221 pmol/l (Allen 2004). Student’s independent t-tests were used to compare average latency of MEPs, amplitude, CMCT, and PMCT, according to B12 status. Pearson’s correlation coefficients were calculated for B12 levels and central and peripheral neurophysiological variables. Differences were considered significant at p50.05. All statistical analysis was performed using the software STATA 12.0 (2008; Stata Statistical Software: Version 12.0, StataCorp, College Station, TX, USA).
Motor evoked potentials (MEPs)
Results
MEPs were evoked using a MagstimÕ magnetic stimulator (Model 200, Magstim, Whitland, UK), capable of generating a maximal output of 2.0 T for each stimulator. Stimuli were applied with a circular handheld coil of 90 mm in external diameter. MEPs were recorded from the abductor pollicis
Mean age of the sample was 74.3 ± 3.6 years (range 71–86). Out of the 53 subjects, 27 (51%) were in the normal B12 group and 26 (49%) in the low B12 group. There were no significant differences for age, gender, height, hemoglobin, hematocrit, MCV, or folic acid between groups (Table I).
Hemoglobin (Hb), hematocrit (Ht), mean corpuscular volume (MCV), and red blood cell distribution were measured using a Cell-Dyn Model 1700 electronic particle counter (Abbott Diagnostics, Abbott Park, IL, USA). Plasma vitamin B12 and folate were measured using Abbott AxSYM radioassay. Hematological and biochemical measures were performed at the INTA Micronutrient Laboratory. Neurological examination
138
J. M. Matamala et al.
Somatosens Mot Res, 2014; 31(3): 136–140
Table I. Descriptive characteristics according to vitamin B12 status.
Characteristics
Normal (n ¼ 27; 51%)
Age Female, % Height, cm Hematocrit, % Hemoglobin, g/dl MCV, fl Folate, nmol/l
74.8 ± 4.2 66 156.2 ± 7.4 41.4 ± 3.6 14.5 ± 1.5 88.5 ± 3.4 10.5 ± 1.4
Low (n ¼ 26; 49%)
p Value
73.7 ± 2.6 50 159.1 ± 7.8 42.4 ± 2.9 14.8 ± 1.2 89.2 ± 3.9 10.4 ± 1.4
0.271 0.218 0.203 0.354 0.377 0.454 0.766
Normal: B12 221 pmol/l. Low: B125221 pmol/l. MCV: mean corpuscular volume. All variables were expressed as mean ± SD (standard deviation). Significance level for p value 50.05.
Table II. Motor evoked potentials according to vitamin B12 status in older adults.
Variables Abductor pollicis brevis Rest Distal latency, ms Amplitude, mV CMCT-f, ms Tonic contraction Distal latency, ms Amplitude, mV CMCT-f, ms Tibialis anterior Rest Distal latency, ms Amplitude, mV CMCT-f, ms Tonic contraction Distal latency, ms Amplitude, mV CMCT-f, ms
Table III. Peripheral motor conduction according to vitamin B12 status in older adults.
Normal (n ¼ 27; 51%)
Low (n ¼ 26; 49%)
p Value
23.0 ± 1.7 2.6 ± 1.6 8.5 ± 1.5
23.3 ± 2.1 2.9 ± 2.0 8.1 ± 1.5
0.639 0.526 0.339
19.6 ± 1.9 4.4 ± 1.5 5.0 ± 1.4
19.8 ± 2.1 4.5 ± 2.3 4.6 ± 1.8
0.726 0.879 0.301
30.4 ± 2.2 0.8 ± 0.7 14.9 ± 2.3
31.3 ± 2.8 1.3 ± 1.3 14.8 ± 2.9
0.193 0.083 0.831
26.9 ± 2.2 2.2 ± 1.2 11.5 ± 2.7
27.5 ± 2.3 2.4 ± 1.4 11.0 ± 2.2
0.389 0.517 0.478
Normal: B12 221 pmol/l. Low: B125221 pmol/l. CMCT-f: central motor conduction time was calculated by subtracting peripheral conduction time, measured with the F-wave method, from the latency of the motor evoked potentials (F + M 1)/2. All variables were expressed as mean ± SD (standard deviation). Significance level for p value 50.05.
The level of B12 in the normal group was 316.3 ± 73.4 pmol/l vs. 154.8 ± 41.9 pmol/l in the low B12 group (p50.001). We recorded MEPs in the upper and lower extremities in all subjects (Table II). There were no significant differences in CMCT, latency of MEPs, and amplitude of MEPs between the normal and low B12 group (Table II) during rest and tonic contraction in upper and lower extremities. There was not correlation between B12 level and central motor conduction variables. In the low B12 group, M-wave latency was significantly prolonged in the common peroneal nerve (p ¼ 0.011), and F-wave latency was significantly prolonged in the median (p ¼ 0.38) and common peroneal nerves (p ¼ 0.043) (Table III). PMCT was significantly prolonged in the lower extremities in the low B12 group (p ¼ 0.014). There was a negative correlation between B12 levels and PMCT in the lower extremities (Pearson coefficient ¼ 0.27, p50.044).
Low (n ¼ 26; 49%)
p Value
Abductor pollicis brevis (median nerve) M-wave, ms 4.6 ± 1.1 F-wave, ms 25.5 ± 2.1 PMCT, ms 14.6 ± 1.4
4.6 ± 0.7 26.8 ± 2.2 15.2 ± 1.4
0.879 0.038 0.123
Tibialis anterior (peroneal nerve) M-wave, ms 2.4 ± 0.5 F-wave, ms 29.4 ± 2.7 PMCT, ms 15.5 ± 1.4
2.8 ± 0.6 31.2 ± 3.3 16.6 ± 1.7
0.011 0.043 0.014
Variables
Normal (n ¼ 27; 51%)
Normal: B12 221 pmol/l. Low: B125221 pmol/l. PMCT: peripheral motor conduction time was calculated using the F-wave method (F + M 1)/2. All variables were expressed as mean ± SD (standard deviation). Bold values indicate significance level for p value 50.05.
Discussion These results suggest that the corticospinal tract may be relatively resistant to damage by B12 deficiency, unlike the large caliber afferent peripheral fibers and posterior columns of the spinal cord (Krumholz et al. 1981; Soria and Fine 1992; Misra et al. 2003). Experimental models of B12 deficiency are controversial regarding involvement of the corticospinal tract. In gastrectomized rats and rats with dietary deficiency of B12, the corticospinal tract, including the bulbar pyramid, does not show pathological changes (Scalabrino et al. 1990; Tredici et al. 1998) even when there were demyelination and interstitial and intracellular edema in the posterior columns. These findings differ from those described for an experimental SCD monkey model where, as the cases of clinically evident SCD in humans (Pant et al. 1968), clinical and histopathological evidence of corticospinal tract damage has been found (Agamanolis et al. 1976). We used standard TMS methods recording MEPs and CMCT, to look for demyelination of the central motor pathway, loss of larger fibers, or slow summation of descending excitatory potentials in the corticospinal tract (Curra` et al. 2002). Several authors have investigated functional corticospinal tract impairment in symptomatic B12 deficient patients. These studies found prolonged CMCTs in 29–53% of patients (Hemmer et al. 1998; Misra and Kalita 2007). In a study by Misra and Kalita (2007), the corticospinal tract was found to be less affected than the posterior columns (56.6% vs. 87.3%). This finding is consistent with classic clinical descriptions of SCD, in which damage to the corticospinal tract (lateral columns) is characterized by a pyramidal syndrome and weakness in the lower extremities in the later stages of the disease (Di Lazzaro et al. 1992; Hemmer et al. 1998). A recent study in older adults reported that B12 deficiency was associated with hypoesthesia to light touch and impairment of sensory and motor peripheral nerve conduction velocity (Leishear et al. 2012). These findings are consistent with those described by Tredici et al. (1998), who reported damage to both thick and thin myelin peripheral fibers. We found a correlation between PMCT and B12 values,
DOI: 10.3109/08990220.2014.897603
Central motor conduction time in vitamin B12 deficiency
supporting the notion that the peripheral nervous system is more susceptible to damage from B12 deficiency. The need for a routine vitamin B12 supplementation in older adults in the absence of clinical deficit has not been established. The OPEN Study (Dangour et al. 2011) is currently evaluating the impact of B12 supplementation on neuroconduction and cognitive function in older people. Their primary outcome will be the amplitude of tibial motor evoked response, pointing to a major effect on the peripheral nervous system. This is in agreement with our findings of a peripheral motor involvement in older adults with low B12. While the primary objective of the study was to evaluate the corticospinal tract, it would have been interesting to evaluate other variables like motor threshold and silent period among others. In addition, it would have been attractive to evaluate the progression of our findings after vitamin supplementation, and see if vitamin statuses modify central or peripheral neurophysiological features. Our results found that the corticospinal tract does not show subclinical neurophysiological abnormalities in asymptomatic older adults with low B12 levels. Consistent with findings reported in other studies, we show that the peripheral nervous system is more vulnerable to damage from B12 deficiency, making the peripheral motor function a more sensitive indicator of neurological damage associated with B12 deficiency.
unexplained low serum cobalamin levels. Arch Intern Med 148: 1715–1719. Carmel R. 2006. Cobalamin. In: Shike M, editor. Modern nutrition in health and disease. 10th ed. Baltimore: Lippincott, Williams and Wilkins. Chistyakov AV, Soustiel JF, Hafner H, Feinsod M. 1995. Motor and somatosensory conduction in cervical myelopathy and radiculopathy. Spine 20:2135–2140. Clarke R, Grimley Evans J, Schneede J, Nexo E, Bates C, Fletcher A, Prentice A, Johnston C, Ueland PM, Refsum H, et al. 2004. Vitamin B12 and folate deficiency in later life. Age Ageing 33(Suppl 1):34–41. Clarke R. 2006. Vitamin B12, folic acid, and prevention of dementia. N Engl J Med 354:2817–2819. Curra` A, Modugno N, Inghilleri M, Manfredi M, Hallett M, Berardelli A. 2002. Transcranial magnetic stimulation techniques in clinical investigation. Neurology 59:1851–1859. Dangour AD, Allen E, Clarke R, Elbourne D, Fasey N, Fletcher AE, Letley L, Richards M, Whyte K, Mills K, et al. 2011. A randomised controlled trial investigating the effect of vitamin B12 supplementation on neurological function in healthy older people: The Older People and Enhanced Neurological function (OPEN) study protocol [ISRCTN54195799]. Nutr J 10:22. Di Lazzaro V, Restuccia D, Fogli D, Nardone R, Mazza S, Tonali P. 1992. Central sensory and motor conduction in vitamin B12 deficiency. Electroencephalogr Clin Neurophysiol 84:433–439. Groppa S, Oliviero A, Eisen A, Quartarone A, Cohen LG, Mall V, Kaelin-Lang A, Mima T, Rosi S, Thickbroom GW, et al. 2012. A practical guide to diagnostic transcranial magnetic stimulation: Report of an IFCN committee. Clin Neurophysiol 123:858–882. Hemmer B, Glocker FX, Schumacher M, Deuschl G, Lu¨cking CH. 1998. Subacute combined degeneration: Clinical, electrophysiological, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry 65:822–827. Kimura J. 2001. Electrodiagnosis in diseases of nerve and muscle. 3rd ed. Oxford: Oxford University Press. Krumholz A, Weiss HD, Goldstein PJ, Harris KC. 1981. Evoked responses in vitamin B12 deficiency. Ann Neurol 9:407–409. Leishear K, Boudreau RM, Studenski SA, Ferrucci L, Rosano C, de Rekeneire N, Houston DK, Kritchevsky SB, Schwartz AV, Vinik AI, et al. 2012. Relationship between vitamin B12 and sensory and motor peripheral nerve function in older adults. J Am Geriatr Soc 60: 1057–1063. Maertens de Noordhout A, Remacle JM, Pepin JL, Born JD, Delwaide PJ. 1991. Magnetic stimulation of the motor cortex in cervical spondylosis. Neurology 41:75–80. Misra UK, Kalita J, Das A. 2003. Vitamin B12 deficiency neurological syndromes: A clinical, MRI and electrodiagnostic study. Electromyogr Clin Neurophysiol 43:57–64. Misra UK, Kalita J. 2007. Comparison of clinical and electrodiagnostic features in B12 deficiency neurological syndromes with and without antiparietal cell antibodies. Postgrad Med J 83:124–127. Pant SS, Asbury AK, Richardson EP Jr. 1968. The myelopathy of pernicious anemia. A neuropathological reappraisal. Acta Neurol Scand 44(Suppl 5):1–36. Russell JSR, Batten FR, Collieri J. 1900. Subacute combined degeneration of the spinal cord. Brain 23:39–110. Sa´nchez H, Albala C, Herlramp FE, Verdugo R, Lavados M, Castillo JL, Lera L, Uauy R. 2010. Prevalence of vitamin B12 deficiency in older adults. Rev Med Chil 138:44–52. Sa´nchez H, Albala C, Lera L, Castillo JL, Verdugo R, Lavados M, Hertrampf E, Brito A, Allen L, Uauy R. 2011. Comparison of two modes of vitamin B12 supplementation on neuroconduction and cognitive function among older people living in Santiago, Chile: A cluster randomized controlled trial. A study protocol [ISRCTN 02694183]. Nutr J 10:100. Scalabrino G, Monzio-Compagnoni B, Ferioli ME, Lorenzini EC, Chiodini E, Candiani R. 1990. Subacute combined degeneration and induction of ornithine decarboxylase in spinal cords of totally gastrectomized rats. Lab Invest 62:297–304. Scalabrino G. 2005. Cobalamin (vitamin B12) in subacute combined degeneration and beyond: Traditional interpretations and novel theories. Exp Neurol 192:463–479.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. Funded: Fondecyt N 1070592 and 1080589; FIDECNO 2010.
References Abbruzzese G, Dall’Agata D, Morena M, Simonetti S, Spadavecchia L, Severi P, Andrioli GC, Favale E. 1988. Electrical stimulation of the motor tracts in cervical spondylosis. J Neurol Neurosurg Psychiatry 51:796–802. Agamanolis DP, Chester EM, Victor M, Kark JA, Hines JD, Harris JW. 1976. Neuropathology of experimental vitamin B12 deficiency in monkeys. Neurology 26:905–914. Albala C, Sa´nchez H, Lera L, Angel B, Cea X. 2011. Socioeconomic inequalities in active life expectancy and disability related to obesity among older people. Rev Med Chil 139:1276–1285. Alexeeva N, Broton JG, Calancie B. 1998. Latency of changes in spinal motoneuron excitability evoked by transcranial magnetic brain stimulation in spinal cord injured individuals. Electroencephalogr Clin Neurophysiol 109:297–303. Allen L. 2004. Folate and vitamin B-12 status in the Americas. Nutr Rev 62:S29–S33. Andres E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE, Noblet-Dick M, Maloisel F, Schlienger JL, Blickle JF. 2004. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 171: 251–259. Atanassova PA, Chalakova NT, Goranov SE, Ilieva EM, Sotirova KN, Massaldjieva RI. 2004. A case of encephalomyelopolyneuropathy in vitamin B12 deficiency. Folia Med 46:52–54. Campbell A, Millar J, Green R, Hann M, Allen L. 2003. Plasma vitamin B12 concentrations in an elderly Latino population are predicted by serum gastrin concentrations and crystalline vitamin B12 intake. J Nutr 133:2770–2776. Carmel R, Sinow RM, Siegel ME, Samloff IM. 1988. Food cobalamin malabsorption occurs frequently in patients with
139
140
J. M. Matamala et al.
Shane B. 2008. Folate and vitamin B12 metabolism: Overview and interaction with riboflavin, vitamin B6 and polymorphisms. Food Nutr Bull 29:5–16. Soria ED, Fine EJ. 1992. Somatosensory evoked potentials in the neurological sequelae of treated vitamin B12 deficiency. Electromyogr Clin Neurophysiol 32:63–71.
Somatosens Mot Res, 2014; 31(3): 136–140
Suter PM, Golner BB, Goldin BR, Morrow FD, Russell RM. 1991. Reversal of protein bound vitamin B12 malabsorption with antibiotics in atrophic gastritis. Gastroenterology 101:1039–1045. Tredici G, Buccellato FR, Braga M, Cavaletti G, Ciscato P, Moggio A, Scalabrino G. 1998. Polyneuropathy due to cobalamin deficiency in the rat. J Neurol Sci 156:18–29.
ISSN: 0899-0220 (Print) 1369-1651 (Online) Journal homepage: http://www.tandfonline.com/loi/ismr20
Vitamin B12 status does not influence central motor conduction time in asymptomatic elderly people: A transcranial magnetic stimulation study José Manuel Matamala, Carolina Nuñez, Renato J. Verdugo, Lydia Lera, Hugo Sánchez, Cecilia Albala & José Luis Castillo To cite this article: José Manuel Matamala, Carolina Nuñez, Renato J. Verdugo, Lydia Lera, Hugo Sánchez, Cecilia Albala & José Luis Castillo (2014) Vitamin B12 status does not influence central motor conduction time in asymptomatic elderly people: A transcranial magnetic stimulation study, Somatosensory & Motor Research, 31:3, 136-140, DOI: 10.3109/08990220.2014.897603 To link to this article: http://dx.doi.org/10.3109/08990220.2014.897603
Published online: 03 Apr 2014.
Submit your article to this journal
Article views: 66
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ismr20 Download by: [Cornell University Library]
Date: 27 September 2016, At: 12:52
http://informahealthcare.com/smr ISSN: 0899-0220 (print), 1369-1651 (electronic) Somatosens Mot Res, 2014; 31(3): 136–140 ! 2014 Informa UK Ltd. DOI: 10.3109/08990220.2014.897603
ORIGINAL ARTICLE
Vitamin B12 status does not influence central motor conduction time in asymptomatic elderly people: A transcranial magnetic stimulation study Jose´ Manuel Matamala1, Carolina Nun˜ez1, Renato J. Verdugo1, Lydia Lera2, Hugo Sa´nchez2, Cecilia Albala2, & Jose´ Luis Castillo1 1
Department of Neurological Science, Faculty of Medicine, University of Chile, Santiago, Chile and 2Public Health and Nutrition Unit, Nutrition and Food Technology Institute, University of Chile, Santiago, Chile Abstract
Keywords
Introduction: Vitamin B12 deficiency causes neurologic and psychiatric disease, especially in older adults. Subacute combined degeneration is characterized by damage to the posterior and lateral spinal cord affecting the corticospinal tract. Objective: To test corticospinal tract projections using motor evoked potentials (MEPs) by transcranial magnetic stimulation (TMS) in asymptomatic older adults with low vitamin B12 (B12) levels. Methods: Cross-sectional study of 53 healthy older adults (470 years). MEPs were recorded in the abductor pollicis brevis and tibialis anterior muscles, at rest and during slight tonic contraction. Central motor conduction time (CMCT) was derived from the latency of MEPs and peripheral motor conduction time (PMCT). Neurophysiological variables were analyzed statistically according to B12 status. Results: Median age was 74.3 ± 3.6 years (58.5% women). Twenty-six out of the 53 subjects had low vitamin B12 levels (B125221 pmol/l). MEPs were recorded for all subjects in upper and lower extremities. There were no significant differences in either latency or amplitude of MEPs and CMCT between low and normal B12 groups. There was a significant PMCT delay in the lower extremities in the low B12 group (p ¼ 0.014). Conclusions: No subclinical abnormality of the corticospinal tract is detected in asymptomatic B12-deficient older adults. The peripheral nervous system appears to be more vulnerable to damage attributable to this vitamin deficit. The neurophysiological evaluation of asymptomatic older adults with lower B12 levels should be focused mainly in peripheral nervous system evaluation.
Motor evoked potentials (MEPs), older adults, vitamin B12
Introduction Vitamin B12 or cyanocobalamin (B12) is a key hydrosoluble vitamin for central nervous system (CNS) function. B12 is involved in the methylation process necessary for the production of neurotransmitters, proteins, nucleotides, and phospholipids (Shane 2008). B12 deficiency may present as macrocytic anemia, subacute combined degeneration (SCD) of the spinal cord, and peripheral neuropathy. In older adults, it is often asymptomatic (Carmel 2006; Clarke 2006). SCD is characterized by damage to the posterior and lateral spinal cord affecting the corticospinal tract (Russell et al. 1900; Scalabrino 2005). Population-based surveys indicate that the prevalence of B12 deficiency in people 460 years is 6–20%, suggesting that Correspondence: J. M. Matamala and J. L. Castillo, Department of Neurological Science, Faculty of Medicine, University of Chile, Santiago, Chile. Tel: +56 2 9770517. Fax: +56 2 2360170. E-mail: [email protected] (J. M. Matamala); [email protected] (J. L. Castillo).
History Received 31 January 2014 Accepted 17 February 2014 Published online 3 April 2014
this age group is at higher risk than the younger population (Campbell et al. 2003). In the Chilean population, we found in older adults a prevalence of B12 deficiency of 12% (B125148 pmol/l) and 25.4% of marginal deficiency (B12 between 148 and 221 pmol/l) (Sa´nchez et al. 2010). This prevalence would be the result of age-related gastric atrophy, low acid, and intrinsic factor production (Carmel et al. 1988; Suter et al. 1991; Andres et al. 2004; Clarke et al. 2004). Many studies have supported the usefulness of neurophysiological evaluation of the corticospinal tract in patients with myelopathies of different cause (Abbruzzese et al. 1988; Maertens de Noordhout et al. 1991; Chistyakov et al. 1995). Nevertheless, information is scarce regarding the neurophysiological abnormalities in the corticospinal tract in patients with B12 deficiency. There have been reports of prolonged central motor conduction time (CMCT) in patients with SCD, with improvement of this parameter after B12 supplementation (Di Lazzaro et al. 1992; Hemmer et al. 1998; Misra et al. 2003; Atanassova et al. 2004). To date there are no studies assessing corticospinal tract function in
DOI: 10.3109/08990220.2014.897603
Central motor conduction time in vitamin B12 deficiency
asymptomatic older adults with low B12 levels. The aim of this study was to test corticospinal tract projections using motor evoked potentials (MEPs) by transcranial magnetic stimulation (TMS) in asymptomatic older adults with low B12 levels.
brevis (APB) and tibialis anterior (TA) on the right side, during rest and slight tonic contraction with a strength just enough to overcome gravity and maintained with the aid of auditory and visual electromyography feedback. The MEPs were amplified and band pass filtered between 2 Hz and 2 kHz using a Nicolet Viking Quest electromyographer. TMS was applied over Cz to record the MEP in the upper extremity and over Fz for the lower extremity, using the international 10–20 EEG system. To stimulate the left hemisphere, the current was applied clockwise. All motor responses analyzed were obtained at 80% of maximum output, which correspond to supramaximal stimulation intensity (Alexeeva et al. 1998). We confirmed that latency was not shortened by incrementing the intensity. The entire recording was done with subjects sitting comfortably. Motor latency was determined at the beginning of the negative deflection. Amplitude was measured between baseline and the peak of the negative deflection. MEPs with the shortest latency were selected from eight supramaximal stimulations (Groppa et al. 2012). The CMCT was calculated as the time between the latency of MEPs and peripheral motor conduction time (PMCT).
Methods Cross-sectional study performed in 53 subjects (58.5% women) aged 70 years or older. The sample was randomly selected from the subjects recruited in two studies: (1) ‘‘Comparison of Two Modes of Vitamin B12 Supplementation on Neuroconduction and Cognitive Function among Older People Living in Santiago, Chile: A Cluster Randomized Controlled Trial’’ [ISRCTN 02694183] (Sa´nchez et al. 2011) and (2) ‘‘Obesity in the Elderly in Santiago, Chile and its Relationship with Mortality’’ (Albala et al. 2011). These studies collected data on creatinine, thyroid-stimulating hormone (TSH), fasting glycemia, B12, folic acid, and Mini Mental State Examination (MMSE). Blood count, folic acid, and B12 levels were measured at the time of the neurophysiological evaluation. Exclusion criteria were: (1) MMSE score 519; (2) creatinine clearance 530 ml/min calculated using the Cockcroft formula; (3) hypothyroidism (defined as TSH 46 mlU/l); (4) fasting blood glucose 4125 mg/dl and/or use of insulin or oral hypoglycemic agents; (5) history of stroke with or without residual deficits; (6) history of epilepsy; (7) metal implants or pacemaker; (8) any abnormality in sensory, motor, and reflex examination. When the results of the vitamin status were available, all the subjects were informed and individuals with B12 plasma levels 5221 pmol/l were referred to the health center for treatment with B12 supplements. The local ethics committee of the East Metropolitan Health Service of Santiago, Hospital del Salvador, approved the study. All subjects signed an informed consent form before participating in the study. Hematological and biochemical measures
137
Peripheral nerve conduction Nerve conduction studies of the right median and common peroneal nerves were performed using standard techniques with surface disc electrodes and controlled limb temperature (Kimura 2001). Motor nerve conduction was recorded from the APB and TA muscles using the same registration point for MEPs. Median and peroneal nerves were stimulated supramaximally at the wrist and the fibular head, respectively. Compound muscle action muscle potential (CMAP) amplitude, distal motor latency, and F-wave latency were measured. PMCT was derived from the recorded F-wave using the formula (F + M 1)/2 (Groppa et al. 2012). Statistical analysis
Each subject underwent a clinical neurological examination by two of the authors (JMM, CN) before the neurophysiological measurements, in order to detect abnormalities not spontaneously reported by the subject.
Mean and standard deviation were calculated for continuous variables and proportions expressed in percentage for categorical variables. Neurophysiological variables were analyzed statistically according to B12 status. To categorize B12 status, we considered normal values 221 pmol/l and low B12 values 5221 pmol/l (Allen 2004). Student’s independent t-tests were used to compare average latency of MEPs, amplitude, CMCT, and PMCT, according to B12 status. Pearson’s correlation coefficients were calculated for B12 levels and central and peripheral neurophysiological variables. Differences were considered significant at p50.05. All statistical analysis was performed using the software STATA 12.0 (2008; Stata Statistical Software: Version 12.0, StataCorp, College Station, TX, USA).
Motor evoked potentials (MEPs)
Results
MEPs were evoked using a MagstimÕ magnetic stimulator (Model 200, Magstim, Whitland, UK), capable of generating a maximal output of 2.0 T for each stimulator. Stimuli were applied with a circular handheld coil of 90 mm in external diameter. MEPs were recorded from the abductor pollicis
Mean age of the sample was 74.3 ± 3.6 years (range 71–86). Out of the 53 subjects, 27 (51%) were in the normal B12 group and 26 (49%) in the low B12 group. There were no significant differences for age, gender, height, hemoglobin, hematocrit, MCV, or folic acid between groups (Table I).
Hemoglobin (Hb), hematocrit (Ht), mean corpuscular volume (MCV), and red blood cell distribution were measured using a Cell-Dyn Model 1700 electronic particle counter (Abbott Diagnostics, Abbott Park, IL, USA). Plasma vitamin B12 and folate were measured using Abbott AxSYM radioassay. Hematological and biochemical measures were performed at the INTA Micronutrient Laboratory. Neurological examination
138
J. M. Matamala et al.
Somatosens Mot Res, 2014; 31(3): 136–140
Table I. Descriptive characteristics according to vitamin B12 status.
Characteristics
Normal (n ¼ 27; 51%)
Age Female, % Height, cm Hematocrit, % Hemoglobin, g/dl MCV, fl Folate, nmol/l
74.8 ± 4.2 66 156.2 ± 7.4 41.4 ± 3.6 14.5 ± 1.5 88.5 ± 3.4 10.5 ± 1.4
Low (n ¼ 26; 49%)
p Value
73.7 ± 2.6 50 159.1 ± 7.8 42.4 ± 2.9 14.8 ± 1.2 89.2 ± 3.9 10.4 ± 1.4
0.271 0.218 0.203 0.354 0.377 0.454 0.766
Normal: B12 221 pmol/l. Low: B125221 pmol/l. MCV: mean corpuscular volume. All variables were expressed as mean ± SD (standard deviation). Significance level for p value 50.05.
Table II. Motor evoked potentials according to vitamin B12 status in older adults.
Variables Abductor pollicis brevis Rest Distal latency, ms Amplitude, mV CMCT-f, ms Tonic contraction Distal latency, ms Amplitude, mV CMCT-f, ms Tibialis anterior Rest Distal latency, ms Amplitude, mV CMCT-f, ms Tonic contraction Distal latency, ms Amplitude, mV CMCT-f, ms
Table III. Peripheral motor conduction according to vitamin B12 status in older adults.
Normal (n ¼ 27; 51%)
Low (n ¼ 26; 49%)
p Value
23.0 ± 1.7 2.6 ± 1.6 8.5 ± 1.5
23.3 ± 2.1 2.9 ± 2.0 8.1 ± 1.5
0.639 0.526 0.339
19.6 ± 1.9 4.4 ± 1.5 5.0 ± 1.4
19.8 ± 2.1 4.5 ± 2.3 4.6 ± 1.8
0.726 0.879 0.301
30.4 ± 2.2 0.8 ± 0.7 14.9 ± 2.3
31.3 ± 2.8 1.3 ± 1.3 14.8 ± 2.9
0.193 0.083 0.831
26.9 ± 2.2 2.2 ± 1.2 11.5 ± 2.7
27.5 ± 2.3 2.4 ± 1.4 11.0 ± 2.2
0.389 0.517 0.478
Normal: B12 221 pmol/l. Low: B125221 pmol/l. CMCT-f: central motor conduction time was calculated by subtracting peripheral conduction time, measured with the F-wave method, from the latency of the motor evoked potentials (F + M 1)/2. All variables were expressed as mean ± SD (standard deviation). Significance level for p value 50.05.
The level of B12 in the normal group was 316.3 ± 73.4 pmol/l vs. 154.8 ± 41.9 pmol/l in the low B12 group (p50.001). We recorded MEPs in the upper and lower extremities in all subjects (Table II). There were no significant differences in CMCT, latency of MEPs, and amplitude of MEPs between the normal and low B12 group (Table II) during rest and tonic contraction in upper and lower extremities. There was not correlation between B12 level and central motor conduction variables. In the low B12 group, M-wave latency was significantly prolonged in the common peroneal nerve (p ¼ 0.011), and F-wave latency was significantly prolonged in the median (p ¼ 0.38) and common peroneal nerves (p ¼ 0.043) (Table III). PMCT was significantly prolonged in the lower extremities in the low B12 group (p ¼ 0.014). There was a negative correlation between B12 levels and PMCT in the lower extremities (Pearson coefficient ¼ 0.27, p50.044).
Low (n ¼ 26; 49%)
p Value
Abductor pollicis brevis (median nerve) M-wave, ms 4.6 ± 1.1 F-wave, ms 25.5 ± 2.1 PMCT, ms 14.6 ± 1.4
4.6 ± 0.7 26.8 ± 2.2 15.2 ± 1.4
0.879 0.038 0.123
Tibialis anterior (peroneal nerve) M-wave, ms 2.4 ± 0.5 F-wave, ms 29.4 ± 2.7 PMCT, ms 15.5 ± 1.4
2.8 ± 0.6 31.2 ± 3.3 16.6 ± 1.7
0.011 0.043 0.014
Variables
Normal (n ¼ 27; 51%)
Normal: B12 221 pmol/l. Low: B125221 pmol/l. PMCT: peripheral motor conduction time was calculated using the F-wave method (F + M 1)/2. All variables were expressed as mean ± SD (standard deviation). Bold values indicate significance level for p value 50.05.
Discussion These results suggest that the corticospinal tract may be relatively resistant to damage by B12 deficiency, unlike the large caliber afferent peripheral fibers and posterior columns of the spinal cord (Krumholz et al. 1981; Soria and Fine 1992; Misra et al. 2003). Experimental models of B12 deficiency are controversial regarding involvement of the corticospinal tract. In gastrectomized rats and rats with dietary deficiency of B12, the corticospinal tract, including the bulbar pyramid, does not show pathological changes (Scalabrino et al. 1990; Tredici et al. 1998) even when there were demyelination and interstitial and intracellular edema in the posterior columns. These findings differ from those described for an experimental SCD monkey model where, as the cases of clinically evident SCD in humans (Pant et al. 1968), clinical and histopathological evidence of corticospinal tract damage has been found (Agamanolis et al. 1976). We used standard TMS methods recording MEPs and CMCT, to look for demyelination of the central motor pathway, loss of larger fibers, or slow summation of descending excitatory potentials in the corticospinal tract (Curra` et al. 2002). Several authors have investigated functional corticospinal tract impairment in symptomatic B12 deficient patients. These studies found prolonged CMCTs in 29–53% of patients (Hemmer et al. 1998; Misra and Kalita 2007). In a study by Misra and Kalita (2007), the corticospinal tract was found to be less affected than the posterior columns (56.6% vs. 87.3%). This finding is consistent with classic clinical descriptions of SCD, in which damage to the corticospinal tract (lateral columns) is characterized by a pyramidal syndrome and weakness in the lower extremities in the later stages of the disease (Di Lazzaro et al. 1992; Hemmer et al. 1998). A recent study in older adults reported that B12 deficiency was associated with hypoesthesia to light touch and impairment of sensory and motor peripheral nerve conduction velocity (Leishear et al. 2012). These findings are consistent with those described by Tredici et al. (1998), who reported damage to both thick and thin myelin peripheral fibers. We found a correlation between PMCT and B12 values,
DOI: 10.3109/08990220.2014.897603
Central motor conduction time in vitamin B12 deficiency
supporting the notion that the peripheral nervous system is more susceptible to damage from B12 deficiency. The need for a routine vitamin B12 supplementation in older adults in the absence of clinical deficit has not been established. The OPEN Study (Dangour et al. 2011) is currently evaluating the impact of B12 supplementation on neuroconduction and cognitive function in older people. Their primary outcome will be the amplitude of tibial motor evoked response, pointing to a major effect on the peripheral nervous system. This is in agreement with our findings of a peripheral motor involvement in older adults with low B12. While the primary objective of the study was to evaluate the corticospinal tract, it would have been interesting to evaluate other variables like motor threshold and silent period among others. In addition, it would have been attractive to evaluate the progression of our findings after vitamin supplementation, and see if vitamin statuses modify central or peripheral neurophysiological features. Our results found that the corticospinal tract does not show subclinical neurophysiological abnormalities in asymptomatic older adults with low B12 levels. Consistent with findings reported in other studies, we show that the peripheral nervous system is more vulnerable to damage from B12 deficiency, making the peripheral motor function a more sensitive indicator of neurological damage associated with B12 deficiency.
unexplained low serum cobalamin levels. Arch Intern Med 148: 1715–1719. Carmel R. 2006. Cobalamin. In: Shike M, editor. Modern nutrition in health and disease. 10th ed. Baltimore: Lippincott, Williams and Wilkins. Chistyakov AV, Soustiel JF, Hafner H, Feinsod M. 1995. Motor and somatosensory conduction in cervical myelopathy and radiculopathy. Spine 20:2135–2140. Clarke R, Grimley Evans J, Schneede J, Nexo E, Bates C, Fletcher A, Prentice A, Johnston C, Ueland PM, Refsum H, et al. 2004. Vitamin B12 and folate deficiency in later life. Age Ageing 33(Suppl 1):34–41. Clarke R. 2006. Vitamin B12, folic acid, and prevention of dementia. N Engl J Med 354:2817–2819. Curra` A, Modugno N, Inghilleri M, Manfredi M, Hallett M, Berardelli A. 2002. Transcranial magnetic stimulation techniques in clinical investigation. Neurology 59:1851–1859. Dangour AD, Allen E, Clarke R, Elbourne D, Fasey N, Fletcher AE, Letley L, Richards M, Whyte K, Mills K, et al. 2011. A randomised controlled trial investigating the effect of vitamin B12 supplementation on neurological function in healthy older people: The Older People and Enhanced Neurological function (OPEN) study protocol [ISRCTN54195799]. Nutr J 10:22. Di Lazzaro V, Restuccia D, Fogli D, Nardone R, Mazza S, Tonali P. 1992. Central sensory and motor conduction in vitamin B12 deficiency. Electroencephalogr Clin Neurophysiol 84:433–439. Groppa S, Oliviero A, Eisen A, Quartarone A, Cohen LG, Mall V, Kaelin-Lang A, Mima T, Rosi S, Thickbroom GW, et al. 2012. A practical guide to diagnostic transcranial magnetic stimulation: Report of an IFCN committee. Clin Neurophysiol 123:858–882. Hemmer B, Glocker FX, Schumacher M, Deuschl G, Lu¨cking CH. 1998. Subacute combined degeneration: Clinical, electrophysiological, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry 65:822–827. Kimura J. 2001. Electrodiagnosis in diseases of nerve and muscle. 3rd ed. Oxford: Oxford University Press. Krumholz A, Weiss HD, Goldstein PJ, Harris KC. 1981. Evoked responses in vitamin B12 deficiency. Ann Neurol 9:407–409. Leishear K, Boudreau RM, Studenski SA, Ferrucci L, Rosano C, de Rekeneire N, Houston DK, Kritchevsky SB, Schwartz AV, Vinik AI, et al. 2012. Relationship between vitamin B12 and sensory and motor peripheral nerve function in older adults. J Am Geriatr Soc 60: 1057–1063. Maertens de Noordhout A, Remacle JM, Pepin JL, Born JD, Delwaide PJ. 1991. Magnetic stimulation of the motor cortex in cervical spondylosis. Neurology 41:75–80. Misra UK, Kalita J, Das A. 2003. Vitamin B12 deficiency neurological syndromes: A clinical, MRI and electrodiagnostic study. Electromyogr Clin Neurophysiol 43:57–64. Misra UK, Kalita J. 2007. Comparison of clinical and electrodiagnostic features in B12 deficiency neurological syndromes with and without antiparietal cell antibodies. Postgrad Med J 83:124–127. Pant SS, Asbury AK, Richardson EP Jr. 1968. The myelopathy of pernicious anemia. A neuropathological reappraisal. Acta Neurol Scand 44(Suppl 5):1–36. Russell JSR, Batten FR, Collieri J. 1900. Subacute combined degeneration of the spinal cord. Brain 23:39–110. Sa´nchez H, Albala C, Herlramp FE, Verdugo R, Lavados M, Castillo JL, Lera L, Uauy R. 2010. Prevalence of vitamin B12 deficiency in older adults. Rev Med Chil 138:44–52. Sa´nchez H, Albala C, Lera L, Castillo JL, Verdugo R, Lavados M, Hertrampf E, Brito A, Allen L, Uauy R. 2011. Comparison of two modes of vitamin B12 supplementation on neuroconduction and cognitive function among older people living in Santiago, Chile: A cluster randomized controlled trial. A study protocol [ISRCTN 02694183]. Nutr J 10:100. Scalabrino G, Monzio-Compagnoni B, Ferioli ME, Lorenzini EC, Chiodini E, Candiani R. 1990. Subacute combined degeneration and induction of ornithine decarboxylase in spinal cords of totally gastrectomized rats. Lab Invest 62:297–304. Scalabrino G. 2005. Cobalamin (vitamin B12) in subacute combined degeneration and beyond: Traditional interpretations and novel theories. Exp Neurol 192:463–479.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. Funded: Fondecyt N 1070592 and 1080589; FIDECNO 2010.
References Abbruzzese G, Dall’Agata D, Morena M, Simonetti S, Spadavecchia L, Severi P, Andrioli GC, Favale E. 1988. Electrical stimulation of the motor tracts in cervical spondylosis. J Neurol Neurosurg Psychiatry 51:796–802. Agamanolis DP, Chester EM, Victor M, Kark JA, Hines JD, Harris JW. 1976. Neuropathology of experimental vitamin B12 deficiency in monkeys. Neurology 26:905–914. Albala C, Sa´nchez H, Lera L, Angel B, Cea X. 2011. Socioeconomic inequalities in active life expectancy and disability related to obesity among older people. Rev Med Chil 139:1276–1285. Alexeeva N, Broton JG, Calancie B. 1998. Latency of changes in spinal motoneuron excitability evoked by transcranial magnetic brain stimulation in spinal cord injured individuals. Electroencephalogr Clin Neurophysiol 109:297–303. Allen L. 2004. Folate and vitamin B-12 status in the Americas. Nutr Rev 62:S29–S33. Andres E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE, Noblet-Dick M, Maloisel F, Schlienger JL, Blickle JF. 2004. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 171: 251–259. Atanassova PA, Chalakova NT, Goranov SE, Ilieva EM, Sotirova KN, Massaldjieva RI. 2004. A case of encephalomyelopolyneuropathy in vitamin B12 deficiency. Folia Med 46:52–54. Campbell A, Millar J, Green R, Hann M, Allen L. 2003. Plasma vitamin B12 concentrations in an elderly Latino population are predicted by serum gastrin concentrations and crystalline vitamin B12 intake. J Nutr 133:2770–2776. Carmel R, Sinow RM, Siegel ME, Samloff IM. 1988. Food cobalamin malabsorption occurs frequently in patients with
139
140
J. M. Matamala et al.
Shane B. 2008. Folate and vitamin B12 metabolism: Overview and interaction with riboflavin, vitamin B6 and polymorphisms. Food Nutr Bull 29:5–16. Soria ED, Fine EJ. 1992. Somatosensory evoked potentials in the neurological sequelae of treated vitamin B12 deficiency. Electromyogr Clin Neurophysiol 32:63–71.
Somatosens Mot Res, 2014; 31(3): 136–140
Suter PM, Golner BB, Goldin BR, Morrow FD, Russell RM. 1991. Reversal of protein bound vitamin B12 malabsorption with antibiotics in atrophic gastritis. Gastroenterology 101:1039–1045. Tredici G, Buccellato FR, Braga M, Cavaletti G, Ciscato P, Moggio A, Scalabrino G. 1998. Polyneuropathy due to cobalamin deficiency in the rat. J Neurol Sci 156:18–29.
