A Retrospective Study on Clinical Assessment of Cognitive Impairment in a Swedish Cohort: Is There Inequality Between Natives and Foreign-Born?

BACKGROUND: People with a migration background are underrepresented in dementia research and disfavored in assessment and treatment, and many foreign-born individuals with dementia remain undiagnosed. OBJECTIVE: The aim of this study was to examine whether there is inequality in the clinical assessment of dementia between native and foreign-born individuals in Sweden. METHODS: Information was gathered retrospectively from a cohort of 91 native and 36 foreign-born patients attending four memory clinics in Skåne, Sweden. Data included information on cognitive test results, cerebrospinal fluid biomarkers, scores at structural imaging scales of global cortical atrophy (GCA), medial temporal lobe atrophy (MTA) and the Fazekas scale, laboratory measures of thyroid-stimulating hormone, calcium, albumin, homocysteine, hemoglobin, cobalamin (vitamin B12), and folate (vitamin B9), contact with health care, and treatment. RESULTS: Foreign-born patients had lower educational level and scored lower on Mini-Mental State Examination and Clock Drawing Test (p < 0.001-0.011). Relatives initiated contact with health care to a higher extent in the foreign-born group (p = 0.031). Foreign-born patients had less white matter lesions (p = 0.018). Additionally, Alzheimer's disease (AD) biomarkers were significantly less used in foreign-born patients to support an AD diagnosis (p = 0.001). No significant differences were found for scores on GCA and MTA, laboratory measures, or initiated treatment. CONCLUSION: Although native and foreign-born patients were predominantly homogenous regarding examined variables, differences in the diagnostic process and underlying biological correlates of dementia exist and need to be further investigated in a larger sample.

A New Approach for Dry Eye Management By Mucoadhesive In situ Gel of Vitamin B12: Formulation, In vitro and In vivo Assessment.

The commitment of the existent study was to develop a mucoadhesive in situ gel systems of vitamin B12 for the management of dry eye disease. The gels were prepared using pluronic F-127 and either of chitosan, carbapol 971P, sodium alginate, or hydroxy propyl methyl cellulose. Drug-excipients compatibility was investigated by means of differential scanning calorimetry and Fourier transform infrared spectroscopy. The gels were characterized for pH, clarity, gelling capacity, viscosity, and adhesion. In vitro release of vitamin B12 from the selected gels was investigated. In vivo effectiveness of the selected gel was determined in rabbit models using Schirmer's and fluorescein tests. The compatibility studies revealed the possibility of incidence of drug/polymer interaction in some formulations. F2-containing pluronic F127 and hydroxypropyl methyl cellulose showed the most appropriate physical characterization and in vitro release profile. The prepared gels showed prolonged drug release with drug release mechanism of combined diffusion and erosion. The in vivo study revealed good effectiveness of the prepared mucoadhesive in situ gel system of vitamin B12 in the treatment of dry eye disease that was comparable to that of the marketed drops.

Assessment of Reference Range of Serum Homocysteine from the Post-therapy Values of Cobalamin and Folate Deficiency Patients.

OBJECTIVES: Ideally, the upper reference limit of plasma or serum homocysteine (Hcy) is to be defined from the studies done on individuals with normal cobalamin and folate status. It is difficult to separate the truly healthy (Cobalamin/Folate Replete) individuals from the randomly selected, apparently healthy individuals who are sub-clinically deficient of cobalamin/folate. The present study was aimed at defining the reference values for the serum homocysteine from individuals with normalized cobalamin and folate status. METHODS: In our study, 215 patients with cobalamin, folic acid deficiency were treated accordingly till complete restoration of clinical and laboratory abnormalities. The post-therapy serum Hcy values were used as reference values. RESULTS: Post-therapy serum Hcy values 12.56 µmol/L (95th percentile), 11.4 µmol/L (85th percentile), 9.8 µmol/L (67th percentile) were seen. The hyperhomocysteinemia was more visible (17.3% gain in prevalence) in the same patient group if interpreted using the post-therapy Hcy value (11.4 µmol/L) as the cut-off. There was no difference between the genders and age groups in the pre or post-therapy Hcy values. CONCLUSIONS: The benefit of the gain in prevalence of disease or the increase in the sensitivity of the test, though small, gets magnified in common diseases and in populous countries. Selection of the individuals is as important as the method or the reagent used in the method when a particular parameter is studied. Repleting the vitamin stores in the confirmed vitamin-deficient patients is more appropriate and easily feasible, since anyway they require treatment, than doing the same on the apparently healthy people. The data thus obtained can be better used as the reference value, for a more meaningful interpretation. The reference range can in turn be used to identify the sub-clinically deficient but asymptomatic people and managed accordingly.

Characteristics of patients with vitamin B12-responsive neuropathy: a case series with systematic repeated electrophysiological assessment.

BACKGROUND: Vitamin B12 (B12) has a fundamental role in both central and peripheral nervous system function at all ages. Neurologic manifestations may be the earliest and often the only manifestation of B12 deficiency. Mostly because of the poor sensitivity of methods of determination for B12 levels, peripheral neuropathy remains a classical but underdiagnosed complication of B12 deficiency. So the clinical and electrophysiological characteristics of B12-responsive neuropathy are not well known. METHODS: A retrospective study of patients with B12-responsive neuropathy was conducted at our hospital on a 3-year period. The criteria for inclusion were: (a) neuropathy confirmed by the electrophysiological study (nerve conduction study); and (b) improvement of at least 1 point of the total Overall Neuropathy Limitations Scale score after vitamin B12 treatment. RESULTS: Nine patients were identified. Serum B12 level was low in only four. Four patients had sensorimotor (predominantly sensory) axonal polyneuropathy while five had only sensory neuronopathy. Six improved in less than 1 month after B12 supplementation. CONCLUSION: B12-responsive neuropathy is a more heterogeneous group of neuropathy than previously described. B12 deficiency is a cause of peripheral neuropathy and should systematically be ruled out in the clinical setting of idiopathic neuropathy or sensory neuronopathy because of potential reversibility. ABBREVIATIONS: B12: vitamin B12; CMAP: compound muscle action potentials; DRG: dorsal root ganglia; ENMG: electroneuromyography; MCCT: motor central conduction time; MEP: motor evoked potentials; MMA: methylmalonic acid; MMCoAM: L-methylmalonyl-CoenzymeA mutase; ONLS: overall neuropathy limitations scale; SCV: sensory conduction velocities; SNAP: sensory nerve action potentials; SNN: sensory neuronopathy; SSS: SNAP sum score.

Factors correlating to the propensity of general practitioners to substitute borderline vitamin B12 deficiency.

OBJECTIVE: This study aims to identify factors which correlate to the propensity of general practitioners (GPs) to prescribe supplementation for borderline vitamin B12 deficiency. DESIGN: Cross-sectional surveys were distributed in person. SETTING: Conferences held in Cairns, Palm Cove Beach, Mt Isa; educational meetings in Atherton; and meetings with individual general practices within the Cairns and Hinterland region. All located in Queensland, Australia. SUBJECTS: 128 practicing GP specialists and registrars (practitioners in training). MAIN OUTCOME MEASURES: Responses to the Likert scale statements with its five options scaling from 'strongly disagree' to 'strongly agree' were recoded to have binary outcomes for analysis. RESULTS: A survey response rate of 89% was achieved. Participants who felt patient demands influence the management of borderline vitamin B12 deficiency were more likely to prescribe supplementation (OR 2.4, p = 0.037). Participants who perceived an overuse of vitamin B12 were less likely to prescribe B12 (OR 0.39, p = 0.019). Participants who often saw patients with vitamin B12 deficiency were less likely to request for the complementary biomarkers plasma methylmalonic acid or total homocysteine (OR 0.41, p = 0.045). CONCLUSIONS: The identified disparity to prescribe vitamin B12 for borderline deficiency may be described as an attempt in the GP collective to seek a balance between being the patient's or the society's doctor. We propose that relevant authorities try to reduce this disparity by describing a management strategy for borderline vitamin B12 deficiency. Key points General practitioners hold different thresholds for commencing supplementation in cases of borderline vitamin B12 deficiency. Participants from Australia were asked to fill out a cross-sectional survey to explore factors which correlate with the propensity to prescribe in clinical practice. Our study identified that patient demands and a practitioner's perception of whether there is an overuse of vitamin B12 in the community influenced the propensity to treat for deficiency. The results give insight into reasons for initiating supplementation, and will help inform general practitioners on their current management.

The changing cost to prevent diabetes: A retrospective analysis of the Diabetes Prevention Program.

OBJECTIVES: Diabetes prevention interventions are poorly implemented. While health care costs generally increase, 2 factors affect the relative cost of diabetes prevention interventions: the declining cost of metformin (even without insurance) and the new recommendation for vitamin B12 monitoring during metformin treatment. The study's objective was to update the relative health system cost estimate of metformin for diabetes prevention by incorporating the current health system cost of metformin and the cost of addressing potential metformin-associated vitamin B12 deficiency. The study was designed to assess whether metformin with vitamin B12 supplementation is a cost-saving measure for diabetes prevention and for the updated cost estimate to be useful in assessing future implementation studies. METHODS: In 2012, the Diabetes Prevention Program Research Group published detailed per capita total direct health system costs for the Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS). The present analysis incorporated the declining cost of metformin and the increasing cost of metformin monitoring into the detailed per capita health system costs found in the DPP and DPPOS. The updated costs were used to assess the total cost of metformin use for diabetes prevention relative to placebo and lifestyle intervention. RESULTS: The current health system cost to acquire metformin ranges from $0 to $72 per year. The estimated health system cost to address potential metformin-associated vitamin B12 deficiency is $28 per metformin-treated patient per year. The 10-year total health system cost for metformin in diabetes prevention can decrease by $329 or increase by $21 depending on the cost to acquire metformin. Compared with placebo, the unadjusted cost savings of metformin is generally maintained, although it may double or quadruple depending on how metformin is acquired by patients. Metformin with vitamin B12 supplementation remained less costly and less effective than lifestyle intervention. CONCLUSION: Metformin is generally more cost-saving for diabetes prevention than previously reported because of decreasing costs for patients to acquire metformin. The cost savings was increased despite increased management cost associated with addressing metformin-associated vitamin B12 deficiency.

Assessment of functional and structural damage in brain parenchyma in patients with vitamin B12 deficiency: A longitudinal perfusion and diffusion tensor imaging study.

INTRODUCTION: Vitamin B12 deficiency may cause neural tissue damage. Even in advanced stages, conventional imaging of brain usually appears normal in vitamin B12 deficient patients. The aim of this study was to assess the structural and functional changes in brain of patients with vitamin B12 deficiency before and after six weeks of vitamin B12 supplementation using diffusion tensor imaging and pseudo-continuous arterial spin labelling (PCASL). METHODS: MR imaging including DTI and PCASL and neuropsychological tests (NPT) were performed in 16 patients with vitamin B12 deficiency and 16 controls before and after 6weeks of therapy. Cerebral blood flow (CBF) derived from PCASL and DTI indices was calculated in brain of patients with vitamin B12 deficiency and controls. RESULTS: Patient with vitamin B12 deficiency showed altered neuropsychological scores and altered CBF as well as fractional anisotropy (FA) values in various brain regions as compared with controls. Both CBF values and neuropsychological scores showed complete reversibility at 6weeks post therapy. Though FA values showed significant recovery, it failed to show complete recovery. CONCLUSION: Our results suggest that micro-structural recovery lags behind functional recovery in patients with vitamin B12 deficiency following therapy and CBF change may be used as an early predictor of complete recovery in patients with B12 deficiency.

Revisión exploratoria de literatura: costo de la enfermedad, eficacia y costo-efectividad de intervenciones asociadas a demencia / Exploratory literature review: cost of disease, efficacy and cost-effectiveness of interventions associated with dementia

INTRODUCCIÓN: La demencia es un síndrome caracterizado por el deterioro de la función cognitiva que generalmente se acompaña o precede por el deterioro del control emocional, del comportamiento social o la motivación. La conciencia no se ve afectada y, en la mayoría de los casos, se trata de un trastorno crónico y progresivo. Cerca de un 70% de los casos de demencia corresponde a la enfermedad de Alzheimer, sin embargo, son también importantes la demencia vascular (cerca de un 25% de los casos), la demencia con cuerpos de Lewy, y diferentes enfermedades que conforman la demencia frontotemporal. En el año 2011, se calculó que a nivel mundial 35,6 millones de personas vivían con demencia y diversos estudios estiman que la cifra prácticamente se duplicará cada 20 años, 65,7 millones en 2030 y 115,4 millones en 2015. La prevalencia aumenta abruptamente con la edad, sólo entre un 2 a 10% de los casos comienzan antes de los 65 años, duplicándose cada 5 años después de esta edad. Con el creciente envejecimiento de la población se espera un aumento del número de personas afectadas. OBJETIVO: El propósito de este documento es entregar una visión general de los aspectos económicos asociados a la enfermedad de la demencia. Se revisan los costos asociados a la enfermedad y las intervenciones o métodos existentes para lidiar con los pacientes con demencia tanto desde la perspectiva de la efectividad como de su costo-efectividad. MÉTODO: Se trata de una revisión no sistemática tanto de abstracts de estudios de costo de enfermedad y revisiones sistemáticas de efectividad, como de resúmenes estructurados del Centre for Reviews and Dissemination (CRD) en el caso de costo-efectividad. La primera parte aborda la carga de enfermedad (CdE), donde se resume los abstracts de 18 estudios. La segunda parte reporta los resultados (en base a abstracts) de "revisiones sistemáticas" que abordan las diversas intervenciones que se utilizan en demencia, sus resultados y la manera de medirlos. Se seleccionaron 13 revisiones de literatura (RSL). Finalmente se revisan los estudios de costo-efectividad más recientes, identificados en la base de datos de CRD, en este caso la revisión se basa en los abstracts de los estudios y los comentarios de revisores de CRD. CONCLUSIONES: Esta revisión muestra que el CdE asociada a la demencia es alto y resulta específica al contexto. La forma en que el sistema de salud (y la sociedad) se organiza para brindar cuidados a los pacientes, la severidad de la enfermedad y tipo de residencia en que viven los pacientes impactan en los costos. En general, los costos relativos al cuidado son el mayor elemento de costo, sea este formal o informal. Se visualiza que existen variados enfoques para medir la CdE, optándose en general por una perspectiva social amplia. as intervenciones abordadas en las RSL consideran modificaciones del entorno (ambientales), entrenamiento cognitivo, terapias grupales y terapias farmacológicas. Además de intervenciones dirigidas al cuidador. Sin embargo, se plantea que la gran mayoría de los estudios primarios son de mala calidad metodológica, lo que limita la validez de sus resultados. Las intervenciones deberían ser personalizadas, dado que la evidencia sobre terapias grupales no es sólida. La implementación exitosa de estas estrategias requiere compromiso activo del personal a cargo. En términos de costo-efectividad los resultados son variados, con algunas intervenciones (4 de 10) con resultados favorables, mientras que en la mayoría de los estudios no se logra demostrar la mayor eficiencia de las intervenciones evaluadas, por sobre las forma de cuidado habitual. Un conocimiento más detallado de terminadas intervenciones, estrategias o modelos de atención de pacientes con demencia, requerirá de una revisión más focalizada, donde los documentos identificados se puedan revisar completamente. Las intervenciones abordadas en las RSL consideran modificaciones del entorno (ambientales), entrenamiento cognitivo, terapias grupales y terapias farmacológicas. Además de intervenciones dirigidas al cuidador. Sin embargo, se plantea que la gran mayoría de los estudios primarios son de mala calidad metodológica, lo que limita la validez de sus resultados. Las intervenciones deberían ser personalizadas, dado que la evidencia sobre terapias grupales no es sólida. La implementación exitosa de estas estrategias requiere compromiso activo del personal a cargo.

Diffusion tensor tractography and neuropsychological assessment in patients with vitamin B12 deficiency.

INTRODUCTION: Structural imaging of the brain does not demonstrate any changes in a vast majority of patients with vitamin B12 deficiency, even in advanced stages. In this study, we aimed to assess and correlate the functional integrity of the brain fiber tracts using diffusion tensor tractography with neuropsychological examination in patients with vitamin B12 deficiency. METHODS: The study was conducted at two tertiary care centers. Thirty-two patients with vitamin B12 deficiency were enrolled and subjected to diffusion tensor tractography, as an extension of diffusion tensor imaging, and neuropsychological assessment. Tests of significance were done to detect changes, pre- and post-vitamin B12 supplementation in the diffusivity parameters (fractional anisotropy and mean diffusivity) and the neuropsychological test scores. RESULTS: Statistically significant changes were observed in the diffusivity parameters and the neuropsychological test scores between the controls and the patients with vitamin B12deficiency in the pre- and post-treatment phases. CONCLUSIONS: This is the first study to evaluate the diffusion tensor tractography (DTT) parameters in the light of clinical neuropsychological assessment in patients with vitamin B12 deficiency. Utilization of DTT parameters may antedate structural changes and may quantify the neurocognitive deficits.

Tratamento da dor neuropática: Eficácia, segurança e custo-efetividade de pregabalina ® e da associação vitamina B12, uridina e citidina (ETNA) / Treatment of diabetic neuropathic pain: Efficacy, safety and cost-effectiveness of pregabalin and the association of vitamin B12, uridine and cytidine / Tratamiento del dolor neuropático diabético: Eficacia, seguridad y coste-efectividad de pregabalina y de la asociación de la vitamina B12, uridina y citidina

TECNOLOGIAS: Medicamento Pregabalina e medicamento com Vitamina B12 associada à citidina e uridina (ETNA®). INDICAÇÃO: Tratamento da dor neuropática diabética. CARACTERIZAÇÃO DAS TECNOLOGIAS: A pregabalina é um anticonvulsivante indicado, entre outros, para o tratamento da dor neuropática em adultos. Seu mecanismo de ação é a redução do influxo de cálcio para regular a transmissão de mensagens excitatórias entre as células nervosas. O medicamento ETNA® é uma combinação de vitamina B12, e nucleotídeos uridina e citidina e é indicado para o tratamento de doenças dos nervos periféricos. PERGUNTA: As intervenções pregabalina e ETNA® são seguras, eficazes e custo-efetivas no tratamento da dor neuropática diabética, em relação às alternativas gabapentina e amitriptilina já disponíveis no SUS? BUSCA E ANÁLISE DE EVIDÊNCIAS CIENTÍFICAS: Foi realizada uma busca por revisões sistemáticas e estudos econômicos nas bases de dados The Cochrane Library (via Bireme), Medline (via Pubmed), LILACS e Centre for Reviews and Dissemination (CRD). Foi realizada também busca manual na internet e nas referências dos estudos encontrados. Foram selecionadas avaliações de tecnologias em saúde (ATS) em sites de agências internacionais e na Rede Brasileira de Avaliação de Tecnologias em Saúde (REBRATS). Foram selecionados estudos publicados em inglês, português ou espanhol. RESUMO DOS RESULTADOS DOS ESTUDOS SELECIONADOS: Foram incluídos nove estudos: quatro revisões sistemáticas, um ensaio clínico e quatro estudos econômicos. As revisões sistemáticas que consideraram a eficácia e segurança da pregabalina avaliaram como desfechos a redução na intensidade da dor, a taxa de resposta ao tratamento (≥50% na redução da dor), a impressão do paciente em relação à melhora e eventos adversos. Essas revisões apresentaram resultados a favor da pregabalina, porém em relação ao placebo. O ensaio clínico que avaliou a eficácia e segurança do medicamento ETNA® mostrou resultados a favor dessa intervenção, porém comparado somente à vitamina B12. Os resultados de custo-efetividade para a pregabalina consideraram como medida de efetividade o número de dias sem dor ou com dor leve, o número de dias com 30% e 50% de redução de dor e QALY (Anos de Visa Ajustados por Qualidade) ganhos. Apenas um estudo de custo-efetividade não favoreceu a pregabalina. RECOMENDAÇÕES: O tratamento da dor neuropática diabética é contemplado pelo Protocolo Clínico e Diretrizes Terapêuticas da Dor Crônica, o qual recomenda o medicamento amitriptilina em monoterapia (primeira escolha) ou a associação desta com gabapentina, em caso de falha terapêutica da monoterapia. As evidências avaliadas neste PTC permitem recomendar (fracamente) a pregabalina em substituição à gabapentina apenas em casos de falha terapêutica dos esquemas citados anteriormente, uma vez que nenhum estudo incluiu comparações diretas entre pregabalina e amitriptilina ou gabapentina, não comprovando haver superioridade terapêutica da tecnologia em relação aos medicamentos já disponíveis no SUS. Quanto ao ETNA®, a recomendação é contra o seu uso devido à escassez de estudos com evidências de qualidade suficiente para garantir a eficácia e segurança terapêutica dessa intervenção e justificar o gasto.(AU)

TECHNOLOGIES: Pregabalin and vitamin B12 associated with uridine and cytidine (ETNA®) . INDICATION: Treatment of diabetic neuropathic pain. TECHNOLOGIES CHARACTERIZATION: Pregabalin is an anticonvulsant indicated for the treatment of neuropathic pain in adults. Its mechanism of action is the reduction of calcium influx to regulate transmission of excitatory messages between nerve cells. ETNA ® is a combination of vitamin B12, uridine and cytidine nucleotides and it is indicated for the treatment of peripheral nerves diseases. QUESTION: Are ETNA ® and pregabalin safe, effective and cost-effective options in the treatment of diabetic neuropathic pain, regarding the alternatives amitriptyline and gabapentin available at SUS? SEARCH AND ANALYSIS OF SCIENTIFIC EVIDENCE: a search for systematic reviews and economic studies was performed in the databases The Cochrane Library (via Bireme), Medline (via Pubmed), LILACS and Centre for Reviews and Dissemination (CRD). Manual search was also conducted on the internet and in the references of the studies found. Health Technology Assessments (HTA) have been selected in international agencies and in Brazilian Network for Health Technology Assessment (REBRATS). Studies published in English, Portuguese or Spanish were selected. SUMMARY OF RESULTS OF THE SELECTED STUDIES: Nine studies were included, four systematic reviews, one clinical trial and four economic studies. Systematic reviews considering efficacy and safety of pregabalin evaluated the following outcomes: reduction in pain intensity, treatment response rate (≥50% on pain reduction), the Patient Global Impression of Change and adverse events. These reviews showed results in favor of pregabalin compared to placebo. The ETNA® Clinical trial showed results in favor of the intervention but compared to vitamin B12 alone. The results of cost-effectiveness for pregabalin considered as a measure of effectiveness the number of days with no pain or mild pain, the number of days with 30% and 50% reduction in pain and QALY gains. Only one cost-effectiveness study has not favored pregabalin. RECOMMENDATIONS: The treatment for neuropathic pain is contemplated in the therapeutic guideline for chronic disease, which recommends the use of amitriptyline in monotherapy as first choice or its association with gabapentin in cases of therapeutic failure with the monotherapy. The evidences appraised here allow recommending (weakly) the use of pregabalin in replacement of gabapentin only in cases of therapeutic failure of the schemes mentioned above, since no study included direct comparisons between pregabalin and amitriptyline or gabapentin, making it impossible to support the therapeutic superiority of pregabalin compared to other drugs already used in Brazil. The recommendation is against ETNA® use due to lack of studies with sufficient evidence of quality to ensure the efficacy and safety of this intervention and justify the expense.(AU)

TECNOLOGÍAS: Pregabalina y vitamina B12 asociado a uridina y citidina (ETNA®). INDICACIÓN: Tratamiento de la neuropatía diabética. CARACTERIZACIÓN DE LAS TECNOLOGÍAS: La pregabalina es un anticonvulsivo indicado, entre otras cosas, para el tratamiento de la neuropatía diabética en adultos. Su mecanismo de acción es la reducción de la afluencia de calcio para regular la transmisión de mensajes excitatorios entre las células nerviosas. ETNA ® es una combinación de vitamina B12 y de nucleótidos de uridina y citidina y está indicado para el tratamiento de enfermedades de los nervios periféricos. PREGUNTA: ¿Las intervenciones pregabalina y ETNA ® son seguros, eficaces y coste-efectiva en el tratamiento de la neuropatía diabética, en comparación con las alternativas gabapentina y amitriptylina ya disponible en el SUS? BÚSQUEDA Y ANÁLISIS DE LA EVIDENCIA CIENTÍFICA: una búsqueda de revisiones sistemáticas y estudios económicos se realizó en las bases de datos de la Cochrane Library (vía Bireme), MEDLINE (vía PubMed), LILACS y Centre for Reviews and Dissemination (CRD). Búsqueda manual también se llevó a cabo. Comentarios de las tecnologías de la salud han sido seleccionadas en las agencias internacionales y en la Red Brasileña de Evaluación de Tecnologías Sanitarias (REBRATS). Se seleccionaron los estudios publicados en inglés, portugués o español. RESUMEN DE LOS RESULTADOS DE LOS ESTUDIOS SELECCIONADOS: Se incluyeron nueve estudios, cuatro revisiones sistemáticas, un ensayo clínico y cuatro estudios económicos. Revisiones sistemáticas de eficacia e seguridad de pregabalina encontraron como resultados la reducción de la intensidad del dolor, la tasa de respuesta al tratamiento, la impresión del paciente con respecto a la mejora y los eventos adversos. Estos exámenes mostraron resultados a favor de la pregabalina, pero en relación con el placebo. El ensayo clínico que evaluó la eficacia de la droga ETNA ® mostró resultados a favor de la intervención, pero en comparación con la vitamina B12 en monoterapia. Los resultados de coste-efectividad de pregabalina han considerado como una medida de efectividad el número de días sin dolor o dolor leve , el número de días con 30 % y 50% de reducción en el dolor y AVAC (años de vida ajustado por calidad) . Sólo un estudio de costo-efectividad no ha favorecido la pregabalina. RECOMENDACIONES: El tratamiento de la neuropatía diabética se contempla en las guías clínicas y terapéuticas del dolor crónico, que recomienda el uso de amitriptylina en monoterapia (primera elección) o asociado con la gabapentina, en caso de fracaso terapéutico con la monoterapia. Las evidencias evaluadas aquí permiten recomendar (débilmente) el uso de pregabalina en el reemplazo de la gabapentina sólo en casos de fracaso terapéutico de los sistemas antes mencionados, ya que ningún estudio incluyó comparaciones directas entre pregabalina y amitriptilina o gabapentina, no probando superioridad terapéutica de la pregabalina en comparación con otros fármacos ya utilizados en Brasil. En cuanto a ETNA, la recomendación es contra su uso debido a la falta de estudios con pruebas de calidad suficiente para garantizar la eficacia y seguridad de esta intervención y justificar el gasto.(AU)

Effectiveness of the National Program of Complementary Feeding for older adults in Chile on vitamin B12 status in older adults; secondary outcome analysis from the CENEX Study (ISRCTN48153354).

BACKGROUND: Older people are at increased risk of vitamin B12 deficiency and the provision of fortified foods may be an effective way to ensure good vitamin B12 status in later life. AIM: To evaluate the effectiveness of a vitamin B12 fortified food provided by a national program of complementary food for older people on plasma vitamin B12 levels. SUBJECTS AND METHODS: A random sub-sample of 351 subjects aged 65-67 y from a large cluster randomised controlled trial provided blood samples at baseline and after 24 months of intervention. The intervention arm (10 clusters 186 participants) received a vitamin B12 fortified food designed to deliver 1.4 µg/day, while the control arm did not receive complementary food (10 clusters, 165 participants). Serum vitamin B12 and folate levels determined by radioimmunoassay were used to estimate the effect of intervention on vitamin B12 levels, adjusting for baseline levels and sex. RESULTS: Attrition at 24 months was 16.7% and 23.6% in the intervention and control arms respectively (p = 0.07). Over 24 months of intervention, mean (95% CI) serum vitamin B12 decreased from 392 (359-425) pmol/dL to 357 (300-414) pmol/dL (p < 0.07) in the intervention arm and from 395 (350-440) pmol/dL to 351 (308-395) pmol/dL in the control arm. There was no significant effect of the intervention on folate status. DISCUSSION: Our findings suggest that foods fortified with 1.4 µg/daily vitamin B12 as provided by Chile's national programme for older people are insufficient to ensure adequate vitamin B12 levels in this population. Chile has a long and successful experience with nutrition intervention programs; however, the country's changing demographic and nutritional profiles require a constant adjustment of the programs.

Vitamin B12 and cognitive function: an evidence-based analysis.

BACKGROUND: More than 2.9 million serum vitamin B12 tests were performed in 2010 in Ontario at a cost of $40 million. Vitamin B12 deficiency has been associated with a few neurocognitive disorders. OBJECTIVE: To determine the clinical utility of B12 testing in patients with suspected dementia or cognitive decline. METHODS: Three questions were addressed: Is there an association between vitamin B12 deficiency and the onset of dementia or cognitive decline? Does treatment with vitamin B12 supplementation improve cognitive function in patients with dementia or cognitive decline and vitamin B12 deficiency? What is the effectiveness of oral versus parenteral vitamin B12 supplementation in those with confirmed vitamin B12 deficiency? A literature search was performed using MEDLINE, Embase, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the Centre for Reviews and Dissemination database, from January 2002 until August 2012. RESULTS: Eighteen studies (7 systematic reviews and 11 observational studies) were identified to address the question of the association between B12 and the onset of dementia. Four systematic reviews were identified to address the question of the treatment of B12 on cognitive function. Finally, 3 randomized controlled trials were identified that compared oral B12 to intramuscular B12. CONCLUSIONS: Based on very low quality evidence, there does appear to be an association between elevated plasma homocysteine levels (a by-product of B vitamins) and the onset of dementia. Based on moderate quality evidence, but with less than optimal duration of follow-up, treatment with B12 supplementation does not appreciably change cognitive function. Based on low to moderate quality of evidence, treatment with vitamin B12 and folate in patients with mild cognitive impairment seems to slow the rate of brain atrophy. Based on moderate quality evidence, oral vitamin B12 is as effective as parenteral vitamin B12 in patients with confirmed B12 deficiency. PLAIN LANGUAGE SUMMARY: Low levels of vitamin B12 have been associated with neurocognitive disorders. This evidence-based analysis assessed the usefulness of serum vitamin B12 testing as it relates to brain function. This review found very low quality evidence that suggests a connection between high plasma homocysteine levels (a by-product of B vitamin metabolism in the body) and the onset of dementia. Moderate quality of evidence indicates treatment with vitamin B12 does not improve brain function. Moderate quality of evidence also indicates treatment using oral vitamin B12 supplements is as effective as injections of vitamin B12.

Oral versus intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency: a pragmatic, randomised, multicentre, non-inferiority clinical trial undertaken in the primary healthcare setting (Project OB12).

BACKGROUND: The oral administration of vitamin B12 offers a potentially simpler and cheaper alternative to parenteral administration, but its effectiveness has not been definitively demonstrated. The following protocol was designed to compare the effectiveness of orally and intramuscularly administered vitamin B12 in the treatment of patients ≥65 years of age with vitamin B12 deficiency. METHODS/DESIGN: The proposed study involves a controlled, randomised, multicentre, parallel, non-inferiority clinical trial lasting one year, involving 23 primary healthcare centres in the Madrid region (Spain), and patients ≥65 years of age. The minimum number of patients required for the study was calculated as 320 (160 in each arm). Bearing in mind an estimated 8-10% prevalence of vitamin B12 deficiency among the population of this age group, an initial sample of 3556 patients will need to be recruited. Eligible patients will be randomly assigned to one of the two treatment arms. In the intramuscular treatment arm, vitamin B12 will be administered as follows: 1 mg on alternate days in weeks 1 and 2, 1 mg/week in weeks 3-8,and 1 mg/month in weeks 9-52. In the oral arm, the vitamin will be administered as: 1 mg/day in weeks 1-8 and 1 mg/week in weeks 9-52. The main outcome variable to be monitored in both treatment arms is the normalisation of the serum vitamin B12 concentration at weeks 8, 26 and 52; the secondary outcome variables include the serum concentration of vitamin B12 (in pg/ml), adherence to treatment, quality of life (EuroQoL-5D questionnaire), patient 3satisfaction and patient preferences. All statistical tests will be performed with intention to treat and per protocol. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors or factors that might alter the effect recorded will be taken into account in analyses. DISCUSSION: The results of this study should help establish, taking quality of life into account, whether the oral administration of vitamin B12 is an effective alternative to its intramuscular administration. If this administration route is effective, it should provide a cheaper means of treating vitamin B12 deficiency while inducing fewer adverse effects. Having such an alternative would also allow patient preferences to be taken into consideration at the time of prescribing treatment. TRIAL REGISTRATION: This trial has been registered with ClinicalTrials.gov, number NCT 01476007, and under EUDRACT number 2010-024129-20.

Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing.

Early recognition of cobalamin (Cbl)-responsive disorders in the ambulatory care setting is essential to prevent irreversible neurologic deficits. However, diagnostic algorithms using Cbl, methylmalonic acid (MMA), and homocysteine (HCys) measurements reflect studies in academic centers, and their negative predictive values have not been established. Thus, records of 456 ambulatory patients evaluated for Cbl deficiency at a staff model HMO were reviewed. Pretherapy Cbl, MMA, and HCys values in individual patients varied by 23%, 23%, and 17%, respectively, over 2 to 6 weeks. Hematologic or neurologic responses to pharmacologic doses of Cbl occurred in 37 of the 95 evaluable patients. In these patients, pretherapy Cbl, MMA, and HCys values were normal in 54%, 23%, and 50%, respectively. If therapy had been restricted to symptomatic patients with both low or intermediate Cbl levels and increased metabolite values, 63% of responders would not have been treated. Twenty-five patients did not respond to treatment, including 5 of 11 patients (45%) with low Cbl, 22 of 49 patients (45%) with high MMA, and 13 of 30 patients (43%) with high HCys values. It is concluded that Cbl, MMA, and HCys levels fluctuate with time and neither predict nor preclude the presence of Cbl-responsive hematologic or neurologic disorders.

Treatment of vitamin b(12)-deficiency anemia: oral versus parenteral therapy.

OBJECTIVE: To evaluate the use of oral cyanocobalamin therapy in the treatment of cobalamin (vitamin B(12))-deficient anemia. DATA SOURCES: Primary and review articles were identified by MEDLINE search (1966-May 2000) and through secondary sources. DATA SYNTHESIS: Cobalamin-deficient anemia is among the most common diagnoses in older populations. Cobalamin-deficient anemia may be diagnosed as pernicious anemia, resulting from the lack of intrinsic factor required for cobalamin absorption or as protein malabsorption from the inability to displace cobalamin from protein food sources. Several studies provide evidence that daily oral cyanocobalamin as opposed to monthly parenteral formulations may adequately treat both types of cobalamin-deficient anemias. CONCLUSIONS: Daily oral cyanocobalamin at doses of 1000-2000 microg can be used for treatment in most cobalamin-deficient patients who can tolerate oral supplementation. There are inadequate data at the present time to support the use of oral cyanocobalamin replacement in patients with severe neurologic involvement.

Vitamin B12 injections versus oral supplements. How much money could be saved by switching from injections to pills?

OBJECTIVE: To estimate savings, using a third-party payer perspective, if all elderly patients currently receiving vitamin B12 (cobalamin) injections were switched to high-dose oral therapy. DESIGN: We modeled high-dose oral B12 supplement costs to include drugs, pharmacists' fees, and one-time conversion costs consisting of two physician visits and laboratory monitoring. The number of vitamin-injection visits avoided by switching to oral therapy was predicted using a multivariate model that considered covariates for overall patient illness. SETTING: Ontario family physicians' and internists' practices. PARTICIPANTS: Population-based administrative databases for Ontario were used to identify all people between 65 and 100 years who received parenteral vitamin B12 during 1995 and 1996. MAIN OUTCOME MEASURES: The cost of parenteral vitamin B12 for each patient, including drugs, injections, pharmacists' fees, and injection-associated physician visits, was measured directly from the databases. RESULTS: The annual cost of parenteral vitamin B12 therapy averaged $145.88 per person and totaled a maximum $25 million over 5 years. Converting all patients to high-dose oral B12 and treating them for 5 years would cost $7.4 million. Depending on how many vitamin-injection visits are avoided by switching to oral therapy, between $2.9 million and $17.6 million would be saved. Switching to oral B12 administration saved costs as long as 16.3% of injection-associated visits were avoided. CONCLUSION: Switching all patients from B12 injections to oral cobalamin therapy could result in substantial savings.

Potential clinical and economic effects of homocyst(e)ine lowering.

BACKGROUND: Elevated total homocyst(e)ine levels (>/=11 micromol/L) have been identified as a potential risk factor for coronary heart disease. However, the benefits expected from lowering homocyst(e)ine levels with folic acid and vitamin B(12) supplementation have yet to be demonstrated in clinical trials. SUBJECTS AND METHODS: We constructed a decision analytic model to estimate the clinical benefits and economic costs of 2 homocyst(e)ine-lowering strategies: (1) "treat all"-no screening, daily supplementation with folic acid (400 microg) and vitamin B(12) (cyanocobalamin; 500 microg) for all; (2) "screen and treat"-screening, followed by daily supplementation with folic acid and vitamin B(12) for individuals with elevated homocyst(e)ine levels. Simulated cohorts of 40-year-old men and 50-year-old women in the general population were evaluated. In the base-case analysis, we assumed that lowering elevated levels would reduce excess coronary heart disease risk by 40%; however, this assumption and others were evaluated across a broad range of potential values using sensitivity analysis. Primary outcomes were discounted costs per life-year saved. RESULTS: Although the treat-all strategy was slightly more effective overall, the screen and treat strategy resulted in a much lower cost per life-year saved ($13,600 in men and $27,500 in women) when compared with no intervention. Incremental cost-effectiveness ratios for the treat-all strategy compared with the screen and treat strategy were more than $500,000 per life-year saved in both cohorts. Sensitivity analysis showed that cost-effectiveness ratios for the screen and treat strategy remained less than $50,000 per life-year saved under several unfavorable scenarios, such as when effective homocyst(e)ine lowering was assumed to reduce the relative risk of coronary heart disease-related death by only 11% in men or 23% in women. CONCLUSIONS: Homocyst(e)ine lowering with folic acid and vitamin B(12) supplementation could result in substantial clinical benefits at reasonable costs. If homocyst-(e)ine lowering is considered, a screen and treat strategy is likely to be more cost-effective than universal supplementation. Arch Intern Med. 2000;160:3406-3412.