Introduction:

Vitamin B12, also called cobalamin, is only obtained through dietary ingestion of animal products, and is an essential cofactor for the production of enzymes responsible for the synthesis of DNA, fatty acids and myelin.¹

Vitamin B12 deficiency is most commonly manifested by hematological changes, representing the main cause of megaloblastic anemia. However, its effects are not restricted to the hematological system.²

Its etiology can be associated to autoimmunity phenomena (eg Pernicious Anemia), malabsorption (metformin, history of gastric surgery, Inflammatory Bowel Disease and Celiac Disease), and dietary insufficiency.¹

Vitamin B12 deficiency accompanied by hematological and neurological changes is relatively uncommon.³ Data from the National Health and Nutrition Examination Survey estimate a prevalence of 2.9-25.4% in the US population, which increases with age³ and varies with underlying etiology.¹ It may be responsible for neurological manifestations through involvement of peripheral nerves (paresthesias), the spinal cord (balance and proprioception disorder) and in advanced cases brain function impairment or dementia. However, although uncommon, it can present as an epileptic seizure.

Clinical Case:

Male, caucasian, 76 years old, autonomous, with type 2 Diabetes Mellitus (under metformin 2 g daily), Hypertension, Dyslipidemia, history of Transient Ischemic Accident in 2015, smoker and mild alcohol comsumption. Admitted to the Emergency Department (ED) after generalized tonic-clonic epileptic seizure with reference to sphincter incontinence and few minutes duration. Prior to the crisis, he committed several infractions while driving, stopped answering questions and stopped the car. During transport to hospital, sedation with diazepam 5 mg and midazolam 4 mg was required. In addition, there was an history of diarrhea for the past 6 months. Fever, respiratory complaints or abdominal pain, previous changes in consciousness, epilepsy or similar previous episodes were absent.

In the ED, the patient presented as agitated and non-collaborating, with dysphasia and signs of a bitten tongue, unemarkable cardiac and pulmonary auscultation and cutaneous (pustular) lesions on the inframammary and lateral chest regions. Due to postictal psychomotor agitation, sedation and invasive ventilation were necessary.

The main laboratory findings (Table 1) were normocytic and normochromic anemia, leukocytosis, with 80.3% neutrophils, mild anisocytosis and anisochromic smears, and hypersegmented neutrophils, Lactic dehydrogenase (LDH) 337 UI/L, Creatinokinase (CK) 208 UI/L, Myoglobin 944 µg/dL. Urinary sediment was unremarkable. Urine test was negative for drugs of abuse. Chest X-ray: no relevant changes. ECG: sinus rhythm, 68 bpm, right branch occlusion. Cranioencephalic computed tomography (CT) showed brain volumetric reduction without lobar distribution. CT scan of the supra-aortic trunk: calcified millimeter atheromatous plaques in the internal carotid artery bulbs and carotid siphons not determining significant stenoses, anatomical variant characterized by hypoplasia of the left vertebral artery with right side dominance and no signs of vertebrobasilar system failure. Lumbar puncture: 3 cells - 3 leukocytes and 0 erythrocytes, glucose 117 mg/dL, proteins 44.8 mg/dL and LDH <30 UI/L.

Considering the clinical worsening, the need for sedoanalgesia and invasive ventilation, he was admitted to the Intensive Care Unit (IMU) and therapy with Aciclovir 10 mg/kg - 850 mg and Levetiracetam 1g 12/12h was started.

During hospitalization at the IMU, several unsuccessful attempts were carried out to suspend sedation and vasopressor support. The electroencephalogram (EEG) showed no evidence of epileptiform activity. Cerebral magnetic resonance imaging (CMRI) showed discrete hypersignal of the supratentorial periventricular white matter, as well as some hypersignal foci along the subcortical white matter than both cerebral hemispheres, the set translating incipient chronic leukoencephalopathy, at this age more likely due to small vessel disease. Lumbar puncture (48 hours later): 92 cells - 2 leukocytes, 90 erythrocytes, glucose 92, proteins 37.50, LDH <30 UI/L.

Regarding the etiological study (Table 2), vitamin B12 (<83 pg/mL) and iron (iron 21 ug/dL, CTFF 198 ug/dL, transferrin saturation 10%) deficits were identified and intramuscular cyanocobalamin (1 injection per week) and ferrous sulphate 329.7 mg (once a day) were started (Table 2).

On the 6th day of hospitalization, the patient achieved spontaneous ventilation. Bacteriological examination, capsular antigen screening, protein chain reaction (PCR) - varicella zoster virus, herpes simplex 2 virus, cytomegalovirus, epstein barr - virus and VDRL showed negative in the CSF. At this time, acyclovir suspended.

No new episodes of epileptic seizures. Repetition of EEG (without sedation), which remained without epileptiform activity. Due to clinical and hemodynamic stability, the patient was transferred to the Medical Ward.

On admission, he presented with mild psychomotor slowing and broad base gait, with the remaining neurological examination unchanged. During hospitalization, there was clinical improvement, with gradual recovery of amnesia from the event.

Considering the history of diarrhea, the patient underwent upper digestive endoscopy with duodenal biopsy: nodular mucosa, erythematous gastropathy, no evidence of Whipple disease, negative CSF T. whipple PCR, and negative anti-transglutaminase antibodies. Anti-negative parietal cell antibodies and anti-intrinsic factor were positive, allowing the diagnosis of with pernicious anemia. Repeated CMRI: overlapping.

Throughout hospitalization, the patient showed signs of clinical improvement; he was conscious, oriented, without evident language deficits, with some faults in evocative memory and ideomotor praxis, without changes in cranial nerves or motor function. At the time of discharge, he was medicated with cyanocobalamin (1 for 3 weeks and then 1 / month), levetiracetam (500 + 1000 mg - for 1 week - and then 500 + 500 mg 12/12 h) and oral ferrous sulfate 12/12 h. Upon reevaluation as an outpatient, there was progressive clinical improvement without further periods of confusion or epileptic seizures.

Discussion:

Although rare, considering the recovery of neurological deficits after cyanocobalamin supplementation, vitamin B12 deficiency, in a patient with pernicious anemia and under therapeutic with metformin, was taken as the etiological factor of delirium and epileptic seizure with prolonged postictal agitation requiring admission to IMU.

According to results from the meta-analysis of Biancheri, R., et al., it was found that partial seizures happened more frequently in patients with this deficiency, and in the EEG some abnormalities can be identified (diffuse, focal or multifocal delta rhythms, changes during sleep).⁴ However, some authors suggest that both EEG and MRI may be normal.⁵

The pathophysiological mechanisms responsible for these changes are only partially known⁴:

- Myelin synthesis of cortical neurons is dependent on normal levels of methylcobalamin and, in case of deficiency, central demyelination occurs, leading to epileptogenesis by increased susceptibility to cytotoxic effects of glutamate⁶ - involved in the initiation and spread of epileptic seizures.⁴

- Homocysteine and folate accumulation may also play a role in inducing epileptic seizures in adults.^4,7

Pernicious Anemia is an autoimmune disease that affects the body and fundus of the stomach, regions where the production of intrinsic factor (IF) and hydrochloric acid by the parietal gastric cells occur. It is characterized by the production of anti-IF antibodies that impair the absorption of Vitamin B12 in the terminal ileum. On the other hand, gastric atrophy resulting from hydrochloric acid deficit (HCL) also hinders iron absorption,⁸ also found in the presented case.

Metformin has also potencial to lower vitamin B12 levels, by interfeering with it´s absortion and bioavailability.⁹

The associated symptomatology is reversible with appropriate therapy and not entirely dependent on antiepileptics. It is also important to note that some anti-epileptics may paradoxically exacerbate the problem, leading to poor seizure control in these patients.⁷

Neurological involvement may occur concurrently with the development of anemia. However, it is important to note that this can occur in the absence of any hematological changes.⁵

After researching the various clinical cases reporting epileptic seizures in patients with vitamin B12 deficiency, it is possible to extrapolate that the occurrence of this association, although rarely described, is not as uncommon as previously thought, and vitamin B12 dosing is recommended in individuals with epileptic seizures without a clear cause.⁵

Quadro I

Analysis at Urgency Service Admission

ALT - Alanina aminotransferase, AST - Aspartato aminotransferase, APTT - Activated Partial Tromboplastin Time, CK – Creatinocinase, LHD - Lactate Dehydrogenase, GGT – Gamaglutamiltranspeptidase, INR - International normalized ratio, PT - Prothrombin Time.

Quadro II

Etiological Study

ANA -Antinuclear Antibodies , ANCA -Antineutrophil cytoplasmic antibodies , HBsAg –, Hepatitis B surface antigen, Anti-HBc – Hepatitis B core antibody, Anti-HBs – Hepatitis B surface antibody, TIBC – Total iron-binding capacity , Ig - Immunoglobulin, TSH - Thyroid Stimulating Hormone, VDRL - Venereal Disease Research Laboratory, HCV - Hepatitis C Virus , HIV - Human Immunodeficiency Virus

  BIBLIOGRAFIA  

References:

1. Ankar, A. and S.S. Bhimji, Vitamin, B12 (Cobalamin), Deficiency, in StatPearls. 2018, StatPearls PublishingStatPearls Publishing LLC.: Treasure Island (FL).

2. Green, R., Vitamin B12 deficiency from the perspective of a practicing hematologist. Blood, 2017. 129(19): p. 2603-11.

3. Green, R., et al., Vitamin B12 deficiency. Nat Rev Dis Primers, 2017. 3: p. 17040.

4. Biancheri, R., et al., Early-onset cobalamin C/D deficiency: epilepsy and electroencephalographic features. Epilepsia, 2002. 43(6): p. 616-22.

5. Dogan, M., et al., Psychotic disorder, hypertension and seizures associated with vitamin B12 deficiency: a case report. Hum Exp Toxicol, 2012. 31(4): p. 410-3.

6. Anastogiannis, H., et al., Cobalamin deficiency triggering de novo status epilepticus. Epileptic Disord, 2014. 16(1): p. 138-9.

7. Naha, K., et al., Vitamin B(1)(2) deficiency: an unusual cause for recurrent generalised seizures with pancytopaenia. BMJ Case Rep, 2012. 2012.

8. Toh, B.H., Pathophysiology and laboratory diagnosis of pernicious anemia. Immunol Res, 2017. 65(1): p. 326-30.

9. Ahmed MA, Metformin and Vitamin B12 Deficiency: Where do we stand? J Pharm Pharm Si, 2016, Jul-Sep; 19(3): 382-98