Anemia and macrocytosis in the prediction of serum folate and vitamin B12 status, and treatment outcome in major depression

BACKGROUND: Folate and B12 deficiencies may result in macrocytic anemia, and are common in major depression; hypofolatemia may result in poorer antidepressant response. We wished to determine whether anemia or macrocytosis predict hypofolatemia, low B12, or refractoriness to antidepressants. METHODS: After obtaining serum folate, B12, and hematological indices, 213 depressed adults were treated with fluoxetine 20 mg/day. Amelioration of depressive symptoms was measured. RESULTS: Neither macrocytosis nor anemia predicted low serum folate/B12, or antidepressant refractoriness. Among 39 patients with hypofolatemia, none had macrocytosis; 28% had low HCT; 41% had low RBC. Among 25 patients with low B12, none had macrocytosis; 24% had low HCT; 28% had low RBC. Among non-responders, 3% had macrocytosis; 24% had low HCT; 25% had low RBC. CONCLUSION: Anemia and macrocytosis should not be used to predict folate or B12 deficiencies, or refractoriness to antidepressants. Measurement of folate and B12 should be considered when evaluating treatment refractoriness.     

Macrocytosis associated with divalproex treatment

Divalproex (DVP) is increasingly prescribed to children and adolescents in psychiatric practices. Among the hematologic adverse effects of DVP, decreased platelet count is well described in the medical literature. However, to date, few studies describe the occurrence of macrocytosis as an adverse effect of divalproex. We report two cases of pediatric patients who developed macrocytosis and decreasing platelet counts secondary to DVP treatment. Because macrocytosis remained an asymptomatic nonprogressive condition for our patients, we support the recommendation for closer surveillance of the patients' complete blood counts for development of anemia in addition to thrombocytopenia.     

Hematologic Manifestations of Long-Term Valproate Therapy

Sixty patients receiving long-term valproate (VPA) monotherapy were studied for hematologic side effects. All were patients in a long-term care facility and ranged in age from 2 to 29 years (mean 14.6 years). Twenty developed at least one prominent hematologic abnormality. Thrombocytopenia and macrocytosis were the most common findings. In patients with macrocytosis, platelet counts were inversely related to VPA levels. Serum B₁₂ levels were increased in 51 of the patients. In 12 patients with macrocytosis who were extensively studied, no etiology for the increased MCV could be identified. An increased number of Pelger-Huet-like cells was noted in these 12 patients. None of the patients demonstrated hepatic dysfunction. Hematologic toxicity was never severe enough to discontinue therapy and always responded to small decrements in VPA therapy. VPA was discontinued in only 1 patient, owing to poor seizure control.     

Azathioprine toxicity in neuromuscular disease

Azathioprine toxicity was examined in 64 consecutively treated patients with various neuromuscular diseases. Reversible leukopenia was seen in 14 patients (22%). Hepatotoxicity developed in six patients (9%), and a systemic reaction characterized by fever, abdominal pain, nausea, vomiting, and anorexia occurred in eight patients (12%). Toxic effects limited the dose of azathioprine in 27 patients (42%) and led to discontinuation of therapy in 13 (20%). Macrocytosis developed in 20% of patients, but did not require an adjustment in the dose. Two patients received allopurinol and azathioprine; both developed reversible leukopenia and macrocytosis. Patients with hematologic and hepatic toxicity, but not those with systemic toxicity, successfully tolerated retreatment with azathioprine. Toxicity was delayed as long as 56 weeks after starting azathioprine in some patients.     

Postoperative dementia: toxicity of nitrous oxide

INTRODUCTION: Post-operative neuropsychiatric manifestations represent a frequent situation and may be due to several aetiologies. The responsibility of vitamin B12 deficiency must be evoked, especially in case of anaesthesia with a currently used substance: nitrous oxide. CASE REPORT: A 65 year-old man with no medical history, presented problems walking and memory loss 16 days after surgery for femoral prosthesis. Neurological examination revealed paraplegia with syndrome of combined degeneration of the spinal cord. The exploration of cognitive functions showed disorientation in time with memory disorders and disturbance of executive functioning. There was no apraxia, aphasia or agnosia. There were neither psychotic symptoms nor mood changes. MMS was at 18/30. Red blood count revealed an anaemia with macrocytosis (MGV=120 3). Vitamin B12 rate was very low (less than 30 g/l). Folate blood level was normal. Brain MRI showed moderate cerebral atrophy. Other investigations led to the diagnosis of Biermer's disease (fundic atrophy at biopsy with presence in the serum of antibodies to intrinsic factor). The diagnosis of neurological attack related to a vitamin B12 deficiency secondary to Biermer's disease was established, but the appearance of disorders in the post-operative period suggested the existence of an added factor. The recovery of informations revealed that anaesthesia was maintained by nitrous oxide during two hours and the patient exhibited pre-operative anaemia with macrocytosis. The hypothesis of decompensation of latent vitamin B12 deficiency by nitrous oxide was evoked. Replacement therapy by vitamin B12 induced real improvement of the cognitive impairment. MMS increased to 25/30. DISCUSSION: Cognitive impairment due to vitamin B12 deficiency is rarely dominated by isolated memory disorders. An authentic dementia is exceptional. Our patient had a dementia diagnosed on the basis of DSM IV criteria including memory disorders, disturbance of executive functioning and significant impairment in social and occupational functioning, associated with a combined degeneration of the spinal cord, common in vitamin B12 deficiency. Furthermore, he had an unknown Biermer's disease responsible for pre-operative deficiency which was clinically latent (there was only macrocytosis anaemia). The appearance of problems in the post-operative period was due to an acute decompensation of the latent deficiency induced undoubtedly by nitrous oxide used in anaesthesia. According to Christensen, nitrous oxide causes irreversible oxidation of vitamin B12 cobalt's atom responsible for its inactivation and the appearance of clinical manifestations. Evolution under vitamin B12 replacement therapy depends on the rapidity of its founding. In our case, it led to an improvement, notably in cognitive functions. CONCLUSION: Through this observation, the authors underline the necessity to search for vitamin B12 deficiency in the case of cognitive features following general anaesthesia.     

Multiple sclerosis and vitamin B12 metabolism

Multiple sclerosis (MS) is occasionally associated with vitamin B12 deficiency. Recent studies have shown and increase risk of macrocytosis, low serum and/or CSF vitamin B12 levels, raised plasma homocysteine and raised unsaturated R-binder capacity in MS. The aetiology of the vitamin B12 deficiency in MS is often uncertain and a disorder of vitamin B12 binding or transport is suspected. The nature of the association of vitamin B12 deficiency and MS is unclear but is likely to be more than coincidental. There is a remarkable similarity in the epidemiology of MS and pernicious anaemia. Vitamin B12 deficiency should always be looked for in MS. The deficiency may aggravate MS or impair recovery. There is evidence that vitamin B12 is important for myelin synthesis and integrity but further basic studies are required.     

Cobalamin deficiency presenting as obsessive compulsive disorder: case report

Cobalamin deficiency commonly presents with a wide range of neuropsychiatric manifestations ranging from myelopathy, neuropathy, optic neuritis and dementia to mood disorders, chronic fatigue and psychosis even without classical hematological abnormalities like anemia and macrocytosis. However, obsessive compulsive disorder (OCD) in relation to vitamin B12 deficiency has not been described so far. We report a case of middle-aged man presenting with OCD, low serum cobalamin and a positive family history of vitamin B12 deficiency who responded well to methylcobalamin replacement.     

Azathioprine in myasthenia gravis: Observations in 41 patients and a review of literature

We report azathioprine treatment of 41 patients with myasthenia gravis, with a follow-up of more than 3 yr. The data show that azathioprine is effective in controlling the disease, both as a single drug as well as in combination with prednisone. In addition it may be steroid sparing. Older patients derived more benefit from the medicament. Side-effects could be managed fairly well, except for one patient who developed a non-Hodgkin lymphoma. Data from this study do not support the supposition that the therapeutic effect of azathioprine is dependent on macrocytosis. Fluctuations of serum levels of antibodies to the acetylcholine receptor were simultaneous with clinical changes and thus were not of predictive volume for the clinical course.     

Masked deficit of vitamin B12 in the patient with heterozygous beta-thalassemia and spastic paraparesis

The spinal cord, brain, optic nerves and peripheral nerves may be affected by vitamin B12 (cobalamin) deficiency. Deficiency of vitamin B12 also causes megaloblastic anaemia, meaning that the red blood cells are usually larger than normal. In this paper we report a 16-year old girl who was referred to us for the evaluation of mild paraparesis and paresthesias marked by tingling "pins and needles" feelings and general weakness. The patient, her parents and sisters were on a strict vegan diet, which made us believe that vitamin B12 deficiency may be the possible cause of the neurologic clinical manifestations. The serum level of vitamin B12 was low, but there was no macrocytosis in the routine blood examination. The electrophoresis of haemoglobin was pathologic, there was 3.7% of HbA2 and 11.6% of HbF (heterozygous form of beta-thalassaemia). When megaloblastic anaemia occurs in combination with a condition that gives rise to microcytic anaemia, many megaloblastic features may be masked. Instead of being macrocytic, the anaemia could be normocytic or even microcytic. Vitamin B12 deficiency is a diagnosis that must not be overlooked. This case report turns the light on the fact that increased MCV is a hallmark in vitamin B12 deficiency, but it is not an obligatory sign.     

Nitrous oxide anesthesia-associated myelopathy

BACKGROUND: The role of nitrous oxide exposure in neurologic complications of subclinical cobalamin deficiency has been reported, but few cases are well documented. OBSERVATION: Two weeks after surgery for prosthetic adenoma, a 69-year-old man developed ascending paresthesia of the limbs, severe ataxia of gait, tactile sensory loss on the 4 limbs and trunk, and absent tendon reflexes. After a second surgical intervention, the patient became confused. Four months after onset, the patient had paraplegia, severe weakness of the upper limbs, cutaneous anesthesia sparing the head, and confusion. Moderate macrocytosis, low serum B12 levels, and a positive Schilling test result led to the diagnosis of pernicious anemia. Results of electrophysiologic examinations showed a diffuse demyelinating neuropathy. Magnetic resonance imaging of the spinal cord disclosed hyperintensities of the dorsal columns on T2-weighted images. CONCLUSIONS: Pernicious anemia can result in severe neurologic symptoms with only mild hematologic changes. The role of nitrous oxide anesthesia in revealing subclinical B12 deficiency must be emphazised. Magnetic resonance imaging of the spinal cord might be helpful in making the diagnosis.