History
An 8-year-old 3.5-kg (7.7-lb) spayed female domestic shorthair cat was examined for long-term, progressive behavioral changes. The cat had been adopted 1 year earlier and ever since then had had soft feces, inappropriate urination, and signs of partial visual deficits and disorientation. Physical examination revealed a body condition score (BCS) of 3 on a scale from 1 (emaciated) to 9 (extremely obese). On neurologic examination, the cat appeared disoriented (displayed minimal spontaneous activity and was inattentive and less responsive to environmental stimuli) but had a clinically normal gait. Marked proprioceptive deficits were detected in the left thoracic and pelvic limbs. Cranial nerve examination revealed absent menace response and absent nasal sensation on the left side. Thus, neuroanatomic localization of an underlying lesion was the right prosencephalon, and the main differential diagnosis list included neoplasia, inflammation, infection, and, less likely, metabolic diseases.
Results of a CBC, serum biochemical analyses, abdominal ultrasonography, and thoracic radiography were un-remarkable, except for high serum total thyroxine concentration (9.83 µg/dL; reference range, 1.3 to 3.7 µg/dL). The cat underwent general anesthesia for MRI of the brain (Figure 1).
Transverse plane T1-weighted (A), T2-weighted (B), and FLAIR (C) and dorsal plane T2-weighted (D) MRI images of the brain of an 8-year-old 3.5-kg (7.7-lb) spayed female domestic shorthair cat examined because of long-term, progressive behavioral changes. A through C—The images are at the level of the temporal lobes, the cat's right is toward the left, and the lines represent the plane of the dorsal image. D— Rostral for the cat is toward the top of the image, and the line represents the plane of the transverse images.
Citation: Journal of the American Veterinary Medical Association 259, 3; 10.2460/javma.259.3.245
Diagnostic Imaging Findings and Interpretation
Low-field MRI of the cat's brain revealed well-defined large lesions in the temporal and frontal lobes of both cerebral hemispheres (Figure 2). The lesions were homogeneously hyperintense on T2-weighted (T2W) images and slightly heterogeneously hypointense on T1-weighted (T1W) and FLAIR images. No contrast enhancement or mass effect was observed, and MRI findings were consistent with fluid-filled lesions in the temporal and frontal lobes of both cerebral hemispheres, with the lesions slightly larger on the right side. Additionally, there was a widening of the subarachnoid space surrounding the cerebral sulci, consistent with diffuse cerebral cortical atrophy. The lateral cerebral ventricles, including the olfactory recesses of the lateral ventricles, were enlarged. These findings suggested loss of brain parenchyma in the cortical and subcortical areas of the frontal and temporal lobes of both cerebral hemispheres. In addition, a focal cavitated lesion that was hyperintense on T2W images and hypointense on T1W and FLAIR images, consistent with a focus of fluid accumulation, was seen in the area of the left caudate nucleus.
Same images as in Figure 1. There are large, bilateral, fluid-filled lesions (arrows) that are almost symmetric (slightly larger on the right side) in the temporal and frontal lobes of both cerebral hemispheres. Also evident are a focal fluid-filled lesion in the area of the left caudate nuclei (arrowheads), widened sulci (brackets), and enlarged lateral ventricles (asterisks), including dilatation of the olfactory recesses of the lateral ventricles (black outlined square).
Citation: Journal of the American Veterinary Medical Association 259, 3; 10.2460/javma.259.3.245
Findings on MRI were consistent with bilateral frontotemporal encephalomalacia combined with either diffuse cortical atrophy or congenital dysplasia. The main differential diagnosis for symmetric malacia was metabolic disease or toxicosis; however, previous episodes of multifocal brain hypoxia or ischemia were also considered. Although no clinical history was available from before the cat's adoption, we considered a congenital anomaly unlikely because the cat's condition was progressive. For the unilateral left caudate nucleus lesion, a chronic ischemic cerebrovascular accident was also considered.
Treatment and Outcome
Results of cerebellomedullary CSF analysis included a total nucleated cell count of 0 cells/µL (reference range, < 5 cells/µL) and total protein concentration of 16.3 mg/dL (reference range, < 25 mg/dL). Thus, an underlying infectious or inflammatory cause was unlikely. Considering the cat's concurrent hyperthyroidism and chronic diarrhea, a metabolic disorder interfering with brain energy metabolism was strongly suspected; therefore, serum analyses for cobalamin, folate, thiamine, and methylmalonic acid concentrations and feline trypsin-like immunoreactivity were performed. Results indicated severe cobalamin deficiency (concentration undetectable [< 150 ng/L]; reference range, 200 to 1,000 ng/L). Serum methylmalonic acid concentration was 500 nmol/L, and because to our knowledge there was no published reference range for methylmalonic acid concentration in cats, the result was compared with the serum methylmalonic acid concentration of a matched healthy control cat (100 nmol/L). The remaining results were within reference limits. With all findings considered, encephalomalacia and diffuse cerebral cortical atrophy secondary to hypocobalaminemia and methylmalonic acidemia were diagnosed.
The cat was treated with cobalamin (250 µg, SC, q 7 days for 6 weeks, then q 30 days) and methimazole (2.5 mg, PO, q 12 h) and was transitioned to a hypoallergenic diet. Ten months later, the cat had no progression of behavioral or neurologic changes but had improved gastrointestinal signs and BCS (5/9) and results within reference limits for serum concentrations of cobalamin (737 ng/L) and total thyroxine (2.03 µg/dL).
Comments
The cat of the present report had presumed bilateral frontotemporal encephalomalacic lesions secondary to hypocobalaminemia and methylmalonic acidemia, with MRI findings that reflected brain parenchymal loss owing to energy deprivation caused by chronic hypocobalaminemia. In contrast to our findings for this cat, a previous report1 describes a cat with cobalamin deficiency but with a shorter duration of clinical signs and different encephalic lesions on MRI: symmetric, bilateral hyperintense lesions in the gray matter of the mesencephalon and pons evident on T2W images but not evident on T1W images. The differences in MRI findings between the 2 cats could have been explained, in part, by the long-term, progressive nature of the condition in the cat of the present report.
In humans, the most frequent neurologic manifestation of cobalamin deficiency is a subacute presentation with clinical signs localizing the lesion to the spinal cord, basal ganglia, or both.2 However, humans with chronic cobalamin deficiency and those with confirmed methylmalonic acidemia develop lesions mainly in the frontal and temporal lobes, as did the cat of the present report. Also, in humans with chronic hypocobalaminemia, MRI findings include cerebral cortical atrophy that is more severe in the frontotemporal area, enlargement of the ventricular system, thinning of the corpus callosum, and subcortical loss of white matter with progression to gray matter.3–7 Similarly, the MRI findings for the cat of the present report suggested loss of brain parenchyma in the cortical and subcortical areas of the frontal and temporal lobes. Additionally, this cat's left caudate nucleus lesion could have been secondary to cobalamin deficiency combined with methylmalonic acidemia; however, we could not rule out a potential underlying cause secondary to hyperthyroidism or a chronic ischemic infarct unrelated to cobalamin deficiency. Lesions involving the basal ganglia, including necrotic lesions, T2W hyperintense lesions, and calcified lesions, are commonly described but are typically bilateral in humans with cobalamin deficiency or methylmalonic acidemia.2–5 Interestingly, cobalamin also acts as a cofactor for the enzyme methionine synthase, and cobalamin deficiency leads to an increase in total homocysteine in the blood. High serum homocysteine concentration increases the risk of cerebrovascular disease in humans.8 In veterinary medicine, results of a study evaluating cobalamin deficiency and serum homocysteine concentration in cats with cardiomyopathy and arterial thromboembolism suggest that cobalamin deficiency may contribute to arterial thromboembolism.9
Cobalamin is an essential cofactor for many enzymatic reactions, including the conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA and the conversion of homocysteine to methionine. Thus, in addition to neuronal function, cobalamin contributes to DNA and amino acid synthesis because of the role of succinyl-CoA in the Krebs cycle.1 Chronic cobalamin deficiency and subsequent methylmalonic acid accumulation lead to neuronal death, and MRI evidence of which, including nervous tissue loss (cerebral cortical atrophy) and ventricular enlargement (secondary to nervous tissue loss), was observed for the cat of the present report. Serum concentration of methylmalonic acid is considered a more reliable marker of cobalamin deficiency than is low serum cobalamin concentration10; however, to our knowledge, the reference range for serum methylmalonic acid concentration in cats has not been reported.
Diagnosis of hypocobalaminemia in the cat of the present report was supported with the fact that its serum concentration of cobalamin was initially undetectable, its serum concentration of methylmalonic acid was 5-fold the concentration of that in a healthy cat used as a matched control, and its clinical signs stopped progressing and in some aspects improved after treatment. After early cobalamin supplementation, resolution or improvement of clinical signs, MRI lesions, or both has been reported in humans6,7 and a cat1 with hypocobalaminemia. In the cat of the present report, neurologic signs remained stable, and no further progression of clinical signs was noticed during the 10-month follow-up period. We did not expect neurologic improvement in this patient because of the chronicity of the neurologic signs and the presence of lesions consistent with malacia, given the fact that similarly affected human patients have irreversible neurologic impairment despite treatment.4,5 Further, the cessation of progressive decline in our patient supported our conclusion that its clinical signs and MRI lesions were results of chronic cobalamin deficiency and methylmalonic acidemia. Follow-up measurement of serum methylmalonic acid concentration and recheck MRI were declined by the owner; thus, it was not possible for us to assess for any changes in either.
The underlying cause of cobalamin deficiency in the cat of the present report was suspected to have been secondary to chronic diarrhea caused by hyper-thyroidism, gastrointestinal disease, or both.11,12 Because the cat's diarrhea resolved after starting treatment with thyroxine and cobalamin supplementation and changing the cat's diet, gastrointestinal biopsy was not performed. Results for the cat of the present report highlighted that, although hypocobalaminemia is rarely reported with neurologic signs in cats, methylmalonic acidemia and hypocobalaminemia should be included among differential diagnoses for cats with MRI findings consistent with encephalomalacia and with bilateral frontal and temporal lobe lesions that are hyperintense on T2W images and hypointense on T1W and FLAIR images.
Acknowledgments
The authors declare that there were no conflicts of interest. The authors acknowledge Jaume Martorell for assistance in preparing the images.
References
- 1. ↑
Simpson K, Battersby I, Lowrie M. Suspected acquired hypocobalaminaemic encephalopathy in a cat: resolution of encephalopathic signs and MRI lesions subsequent to cobalamin supplementation. J Feline Med Surg 2012;14:350–355.
- 2. ↑
Brismar J, Ozand PT. CT and MR of the brain in disorders of the propionate and methylmalonate metabolism. AJNR Am J Neuroradiol 1994;15:1459–1473.
- 3. ↑
Radmanesh A, Zaman T, Ghanaati H, et al.. Methylmalonic acidemia: brain imaging findings in 52 children and a review of the literature. Pediatr Radiol 2008;38:1054–1061.
- 4. ↑
Enns GM, Barkovich AJ, Rosenblatt DS, et al.. Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin. J Inherit Metab Dis 1999;22:599–607.
- 5. ↑
Işikay S, Temel L, Keskin M. Imaging findings associated with methylmalonic aciduria. Pediatr Neurol 2014;50:435–436.
- 6. ↑
Kocaoglu C, Akin F, Çaksen H, et al.. Cerebral atrophy in a vitamin B12-deficient infant of a vegetarian mother. J Health Popul Nutr 2014;32:367–371.
- 8. ↑
Sachdev P. Homocysteine, cerebrovascular disease and brain atrophy. J Neurol Sci 2004;226:25–29.
- 9. ↑
McMichael MA, Freeman LM, Selhub J, et al.. Plasma homo-cysteine, B vitamins, and amino acid concentrations in cats with cardiomyopathy and arterial thromboembolism. J Vet Intern Med 2000;14:507–512.
- 10. ↑
Ruaux CG, Steiner JM, Williams DA. Relationships between low serum cobalamin concentrations and methlymalonic acidemia in cats. J Vet Intern Med 2009;23:472–475.
- 11. ↑
Simpson KW, Fyfe J, Cornetta A, et al.. Subnormal concentrations of serum cobalamin (vitamin B12) in cats with gastrointestinal disease. J Vet Intern Med 2001;15:26–32.
- 12. ↑
Cook AK, Suchodolski JS, Steiner JM, et al.. The prevalence of hypocobalaminaemia in cats with spontaneous hyperthyroidism. J Small Anim Pract 2011;52:101–106.
