Journal of the Neurological Sciences 336 (2014) 273–275
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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Slowly progressive folate-deficiency myelopathy: Report of a case Akinori Okada, Haruki Koike, Tomohiko Nakamura, Hirohisa Watanabe, Gen Sobue ⁎ Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
a r t i c l e
i n f o
Article history: Received 19 July 2013 Received in revised form 27 September 2013 Accepted 21 October 2013 Available online 30 October 2013 Keywords: Cobalamin Folate Folate deficiency Folic acid Myelopathy Subacute combined degeneration
a b s t r a c t Background: Folate deficiency is known to be associated with subacute combined degeneration of the spinal cord; however, reports of long-standing cases are rare. Although neurological deficits due to folate deficiency have been reported to respond to folic acid supplementation, the functional outcomes have not been fully elucidated. Objective: The aim of the study was to evaluate the clinical features and response to folate supplementation in a patient with folate deficiency manifested over 10 years as a slowly progressive myelopathy. Methods: We performed comprehensive clinical screening, electrophysiological testing, and posturography before and after folate supplementation. Results: A 49-year-old man had a slowly progressive gait disturbance for 10 years. He had not eaten fresh green vegetables for more than 10 years. Neurological examination revealed spastic paraplegia and absence of any vibration sense in the lower limbs accompanied by a positive Romberg's sign. Serum folate level was low, and plasma homocysteine level was elevated. Levels of blood thiamine and serum cobalamin were normal. We diagnosed the patient with myelopathy due to folate deficiency. Folic acid supplementation led to improvement of his symptoms; posturography and walking speed tests showed partial improvement, while the somatosensory-evoked potentials and central motor conduction time remained unchanged. Conclusions: Folate deficiency should be considered as a differential diagnosis of chronic slowly progressive myelopathy. The present case suggests the importance of early diagnosis and treatment before the adverse neurological manifestations of folate deficiency become irreversible. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Folate is a water-soluble B vitamin present in fresh green vegetables, citrus fruits, legumes, and liver [1–3]. It acts as an important cofactor in DNA synthesis and methylation pathways [4,5]. Folate deficiency can result from a variety of causes, including reduced intake of folate-rich products and impaired absorption, or increased metabolism of folate. Additional causes of folate deficiency include lactation, genetic defects, chemotherapy, antiepileptic medication, bariatric surgery, and chronic alcoholism [4,6–8]. Classically, folate deficiency has been known to cause acquired hematological and neurological complications [5]. Hematological complications are characterized by megaloblastic anemia, while acquired neurological complications are variable and include depression, psychosis, dementia, myelopathy, and neuropathy [8,9]. Of all the identified neurological complications of vitamin deficiency, subacute combined degeneration of the spinal cord is the most well-known [10]. Subacute combined degeneration is characterized by subacute progression of affected areas in the posterior and lateral columns of the spinal cord and is typically caused by cobalamin deficiency [11]. However, a few cases of subacute combined degeneration due to folate deficiency have been reported [12,13]. In addition, the functional
⁎ Corresponding author. Tel.: +81 52 741 2385, fax: +81 52 744 2384. E-mail address: [email protected] (G. Sobue). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.10.032
consequences of folate deficiency have not been fully elucidated, although neurological deficits due to folate deficiency reportedly respond well to folic acid supplementation. In this report, we describe a patient who had folate deficiency and manifested progressive spastic paraplegia over 10 years. Further, we discuss folate deficiency as a cause of chronic slowly progressive myelopathy. 1.1. Case report A 49-year-old man reported the onset of a gait disturbance 10 years before admission to our hospital. He had no noteworthy family or personal history. He had been drinking 350 ml beer per day since he was 20 years old. He had eaten only meat and polished rice for more than 10 years; importantly, he had not eaten fish or vegetables since his youth. He had been exercising daily until 13 years ago. He began to experience difficulty in walking approximately 10 years ago. At first he had trouble going down stairs quickly; later on, he began to have difficulty going up stairs quickly. An unsteadiness of gait became apparent 3 years later, and he required a cane to walk approximately 6 months before admission to the hospital. Neurological examination revealed that he was alert and welloriented. His mental status was normal, and his cranial nerves were intact. Mild weakness was observed in the distal portions of the lower
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limbs but was absent in the upper limbs. Vibration sense was severely impaired in the distal portions of the lower limbs, whereas it was normal in the upper limbs. Light touch sensation was normal in both upper and lower limbs. He complained of numbness below the knee on both sides. Deep tendon reflexes, including Achilles tendon reflexes, showed hyperreflexia in both upper and lower limbs. Wartenberg and Babinski reflexes were positive for limbs on both sides. His gait was spastic, and Romberg's sign was observed. Laboratory results revealed neither anemia nor macrocytosis (Table 1). Although a reduction in the serum folate level was detected (2.0 ng/ml; normal value ≧3.2 ng/ml), his serum cobalamin level was normal (276 pg/ml; normal value ≧180 pg/ml). His plasma homocysteine level was elevated (17.2 mol/l; normal value = 3.7–13.5 mol/l). In contrast, his serum methylmalonic acid level was normal (0.12 nmol/ml; normal value = 0–0.4 nmol/ml). Thiamine level in the whole blood was also normal (3.70 μg/dl; normal value = 2.0–7.2 μg/dl). Levels of serum copper and serum angiotensin I-converting enzyme were normal (copper: 125 μg/dl; normal value = 70–132 μg/dl; angiotensin I converting enzyme: 19.4 IU/l; normal value = 7.7–29.4 IU/l). Levels of anti-HTLV-1, anti-DNA, and anti-nuclear antibodies in the serum were within normal limits. Cerebrospinal fluid examination revealed no abnormalities in protein content or cell count: protein level was 33 mg/dl (normal value = 15–45 mg/dl), and cell count was 2/mm3 (normal value ≤5/mm3). Myelin basic protein concentration was normal (40 pg/ml; normal value ≤102 pg/ml), and the oligoclonal banding result was negative. Nerve conduction experiments for the median, ulnar, tibial, peroneal, and sural nerves were performed as reported previously [14] and yielded normal results. Electromyography showed intact upper and lower extremities. In contrast, central motor conduction time was not evoked in the median and tibial nerves, as assessed using previously described methods [15]. In addition, somatosensory-evoked potentials in the median and tibial nerves were examined using previously reported methods [16] and showed increased latencies (N19 for the upper limbs was 23.6 ms, normal value = 18.63 ± 0.94 ms, [mean ± SD]; P35 for the lower limbs was 52.2 ms, normal value = 36.91 ± 2.48 ms). Posturography, performed as previously described [17], revealed a marked instability while standing with the eyes closed. Cranial and
spinal cord magnetic resonance imaging, with and without gadolinium enhancement, did not reveal any abnormality. Computed tomography of the chest, abdomen, and pelvis were also normal. Walking speed was evaluated using the timed Up and Go test [18]. This test assesses basic mobility skills as well as strength, balance, and agility. In this test, the time taken to rise from sitting in an armchair, walk 3 m, turn, walk back to the chair, then sit down using regular footwear and a walking aid, if required, is measured. For our patient, this time was 24 s (normal value ≤10 s). We thought that the spastic paraplegia shown by this patient was associated with folate deficiency due to an unbalanced diet. Thus, we instructed him to improve his eating habits and initiated daily oral folic acid supplementation (Folic Acid 10 mg per day). At 4 weeks after the initiation of folic acid supplementation, his serum folate level had increased, and his plasma homocysteine level was within the normal range. Four months later, spasticity in the lower limbs had diminished, and the timed Up and Go test showed improvement of walking time (19 s). Posturography also showed improvement in the instability while standing with the eyes closed. However, somatosensory-evoked potentials showed no change compared to the pre-treatment values (in the upper limbs, N19 was 23.1 ms and in the lower limbs P35 was 52.6 ms). Further, the central motor conduction time could not be evoked. 2. Discussion Neurological manifestations associated with folate deficiency are diverse and include both congenital and acquired neurological disorders [9,19]. After a study reported that folate deficiency can cause spina bifida in a developing fetus, many countries initiated a program of folic acid fortification [20]. Currently, more than 70 countries practice folic acid fortification. However, many countries, including Japan, have not yet instituted mandatory folic acid fortification [21]. In addition, mental retardation and epilepsy occur in cause of 5,10-methylenetetrahydrofolate reductase deficiency, a congenital abnormality of folate metabolism, if folic acid supplementation is delayed [22]. A major acquired (non-congenital) neurological disorder caused by folate deficiency is subacute combined degeneration of the spinal cord [10]. This condition has been more commonly related to cobalamin deficiency, whereas
Table 1 Clinical and laboratory findings before and after folic acid supplementation.
Serum Folate (ng/ml) Cobalamin (pg/ml) Methylmalonic acid (nmol/ml) Plasma Total protein (g/dl) Albumin (g/dl) Homocysteine(mol/l) Whole blood White blood cell (no/mm3) Red blood cell (no/mm3) Hemoglobin (g/dl) Mean corpuscular volume (fl) Mean corpuscular hemoglobin (pg) Mean corpuscular hemoglobin concentration (g/dl) Platlet (no/mm3) Thiamine (mg/dl) Electrophysiological finding Somato-sensory evoked potential in the upper limb (ms) Somato-sensory evoked potential in the lower limb (ms) Central motor conduction time in the lower limb (ms) Posturography The environed area with eyes closed (cm2) Time up and go test (s) ND = not determined; NE = not elicited.
On admission
4 weeks later
4 months later
Normal values
2.0 276 0.12
> 20.0 233 ND
> 20.0 236 ND
3.6–12.9 233–914 0–0.40
7.2 4.8 9.6
6.5–8.0 3.7–5.0 3.7–13.5
6.6 4.0 17.2
7.3 4.8 8.0
5700 5.02 × 106 15.4 92.4 30.7 33.2 31 × 103 3.7
6700 5.19 × 106 15.7 90.0 30.3 33.6 305 × 103 3.6
7200 4.97 × 106 15.0 89.1 30.2 33.9 348 × 103 3.5
3800–8500 3.60–5.00 × 106 11–16 80–100 26–33 32–36 160–410 × 103 2.0–7.2
N19:23.6 P35:52.2 NE
ND ND ND
N19:23.1 P35:52.6 NE
18.63 ± 0.94 36.91 ± 2.48 b 15
37.68 24
ND ND
24.65 19
≦ 6.63 ≦10
A. Okada et al. / Journal of the Neurological Sciences 336 (2014) 273–275
only tens of cases caused by acquired folate deficiency have been reported thus far [12,13,22–28]. Furthermore, slowly progressive cases of this condition, which extend for years, have been only rarely observed. Subacute combined degeneration of the spinal cord due to cobalamin deficiency results in paraesthesia and loss of vibration and position sense due to impaired functioning of the posterior and lateral columns [11]. These symptoms are followed by ataxia and spastic paraplegia with positive Babinski sign [11]. The functional prognosis for subacute combined degeneration caused by cobalamin deficiency is considered good if cobalamin supplementation is provided shortly after onset [11]. Significant improvement can also be expected if treatment is started within 3 months of gait disturbance [29]. However, the neurological deficits become irreversible in the advanced stage of the condition [29]. Neurological symptoms of subacute combined degeneration caused by folate deficiency are similar to those of subacute combined degeneration caused by cobalamin deficiency [12], and likewise, the functional prognosis for subacute combined degeneration caused by folate deficiency is favorable once folic acid supplementation is initiated [9]. However, objective and comprehensive evaluation of neurological impairments before and after folic acid supplementation has not yet been reported. In this report, we describe a patient who manifested spastic paraplegia that had progressed in severity over 10 years. Our findings, which included increased deep tendon reflexes, positive pathological reflexes, normal nerve conduction, prolonged somatosensory-evoked potentials, and absence of central motor conduction time potentials, all suggested that the lesion was located in the central, rather than the peripheral nervous system. A response to folic acid, but not cobalamin, administration indicated that folate deficiency was the cause of myelopathy in our patient. An unbalanced diet, due to a lack of vegetable intake, was the cause of folate deficiency in our patient. Although the symptoms and signs observed in our case are comparable to those of subacute combined degeneration of the spinal cord, the slowly progressive clinical course is a unique characteristic feature of this case. In addition to folate deficiency, multiple sclerosis, cervical cord compression, amyotrophic lateral sclerosis, adrenoleukodystrophy, tropical spastic paraparesis, HTLV-1 associated myelopathy, paraneoplastic myelopathy, and cobalamin deficiency are included in the differential diagnoses for chronic progressive myelopathy [30]. These other conditions were excluded on the basis of our laboratory and radiological examinations. The patient did not have megaloblastic anemia, despite the presence of spastic paraplegia. The absence of anemia has been previously reported in patients with folate-responsive neurological disorders [23,26,28]. Interestingly, this discrepancy has also been frequently observed in cases of neurological deficits associated with cobalamin deficiency [31]. Factors such as genetic background may influence the susceptibility of individual organs and the appearance of certain symptoms, as has been suggested in cases of thiamine deficiency [32,33]. Although it is advisable to administer folic acid supplementation intravenously in patients with acute illness [34], we chose oral supplementation for our patient due to the slowly progressive clinical course of his condition. Neurological examination showed partial improvement after folic acid supplementation, suggesting that the chronic clinical course of his condition had induced some degree of irreversible neurological damage. Therefore, early diagnosis and initiation of treatment appear to be crucial for the successful treatment of neurological complications due to folate deficiency.
Acknowledgments This work was supported by grants from the Ministry of Health, Labor and Welfare and the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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[9] Green R, Miller JW. Folate deficiency beyond megaloblastic anemia: hyperhomocysteinemia and other manifestations of dysfunctional folate status. Semin Hematol 1999;36:47–64. [10] Pincus JH. Folic acid deficiency: a cause of subacute combined system degeneration. In: Botez MI, Reynolds EH, editors. Folic acid in neurology, psychiatry, and internal medicine. New York: Raven Press; 1979. p. 427–33. [11] Scalabrino G. Cobalamin (vitaminB(12)) in subacute combined degeneration and beyond: traditional interpretations and novel theories. Exp Neurol 2005;192:463–79. [12] Lever EG, Elwes RD, Williams A, Reynolds EH. Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. J Neurol Neurosurg Psychiatry 1986;49:1203–7. [13] Pincus JH, Reynolds EH, Glaser GH. Subacute combined system degeneration with folate deficiency. JAMA 1972;221:496–7. [14] Koike H, Hirayama M, Yamamoto M, Ito H, Hattori N, Umehara F, et al. 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Subacute combined degeneration of the spinal cord due to folate deficiency in association with a psychotic illness. Ir Med J 1990;83:73–4. [20] Quinlivan EP, Gregory III JF. Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr 2003;77:221–5. [21] Flour Fortification Initiative. http://www.ffinetwork.org/index.html. [22] Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, Leeming RJ. Subacute combined degeneration of the cord, dementia and Parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatry 1986;49:920–7. [23] Botez MI, Cadotte M, Beaulieu R, Pichette LP, Pison C. Neurologic disorders responsive to folic acid therapy. Can Med Assoc J 1976;115:217–23. [24] Botez MI, Fontaine F, Botez T, Bachevalier J. Folate-responsive neurological and mental disorders: report of 16 cases. Neuropsychological correlates of computerized transaxial tomography and radionuclide cisternography in folic acid deficiencies. 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Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Slowly progressive folate-deficiency myelopathy: Report of a case Akinori Okada, Haruki Koike, Tomohiko Nakamura, Hirohisa Watanabe, Gen Sobue ⁎ Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
a r t i c l e
i n f o
Article history: Received 19 July 2013 Received in revised form 27 September 2013 Accepted 21 October 2013 Available online 30 October 2013 Keywords: Cobalamin Folate Folate deficiency Folic acid Myelopathy Subacute combined degeneration
a b s t r a c t Background: Folate deficiency is known to be associated with subacute combined degeneration of the spinal cord; however, reports of long-standing cases are rare. Although neurological deficits due to folate deficiency have been reported to respond to folic acid supplementation, the functional outcomes have not been fully elucidated. Objective: The aim of the study was to evaluate the clinical features and response to folate supplementation in a patient with folate deficiency manifested over 10 years as a slowly progressive myelopathy. Methods: We performed comprehensive clinical screening, electrophysiological testing, and posturography before and after folate supplementation. Results: A 49-year-old man had a slowly progressive gait disturbance for 10 years. He had not eaten fresh green vegetables for more than 10 years. Neurological examination revealed spastic paraplegia and absence of any vibration sense in the lower limbs accompanied by a positive Romberg's sign. Serum folate level was low, and plasma homocysteine level was elevated. Levels of blood thiamine and serum cobalamin were normal. We diagnosed the patient with myelopathy due to folate deficiency. Folic acid supplementation led to improvement of his symptoms; posturography and walking speed tests showed partial improvement, while the somatosensory-evoked potentials and central motor conduction time remained unchanged. Conclusions: Folate deficiency should be considered as a differential diagnosis of chronic slowly progressive myelopathy. The present case suggests the importance of early diagnosis and treatment before the adverse neurological manifestations of folate deficiency become irreversible. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Folate is a water-soluble B vitamin present in fresh green vegetables, citrus fruits, legumes, and liver [1–3]. It acts as an important cofactor in DNA synthesis and methylation pathways [4,5]. Folate deficiency can result from a variety of causes, including reduced intake of folate-rich products and impaired absorption, or increased metabolism of folate. Additional causes of folate deficiency include lactation, genetic defects, chemotherapy, antiepileptic medication, bariatric surgery, and chronic alcoholism [4,6–8]. Classically, folate deficiency has been known to cause acquired hematological and neurological complications [5]. Hematological complications are characterized by megaloblastic anemia, while acquired neurological complications are variable and include depression, psychosis, dementia, myelopathy, and neuropathy [8,9]. Of all the identified neurological complications of vitamin deficiency, subacute combined degeneration of the spinal cord is the most well-known [10]. Subacute combined degeneration is characterized by subacute progression of affected areas in the posterior and lateral columns of the spinal cord and is typically caused by cobalamin deficiency [11]. However, a few cases of subacute combined degeneration due to folate deficiency have been reported [12,13]. In addition, the functional
⁎ Corresponding author. Tel.: +81 52 741 2385, fax: +81 52 744 2384. E-mail address: [email protected] (G. Sobue). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.10.032
consequences of folate deficiency have not been fully elucidated, although neurological deficits due to folate deficiency reportedly respond well to folic acid supplementation. In this report, we describe a patient who had folate deficiency and manifested progressive spastic paraplegia over 10 years. Further, we discuss folate deficiency as a cause of chronic slowly progressive myelopathy. 1.1. Case report A 49-year-old man reported the onset of a gait disturbance 10 years before admission to our hospital. He had no noteworthy family or personal history. He had been drinking 350 ml beer per day since he was 20 years old. He had eaten only meat and polished rice for more than 10 years; importantly, he had not eaten fish or vegetables since his youth. He had been exercising daily until 13 years ago. He began to experience difficulty in walking approximately 10 years ago. At first he had trouble going down stairs quickly; later on, he began to have difficulty going up stairs quickly. An unsteadiness of gait became apparent 3 years later, and he required a cane to walk approximately 6 months before admission to the hospital. Neurological examination revealed that he was alert and welloriented. His mental status was normal, and his cranial nerves were intact. Mild weakness was observed in the distal portions of the lower
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limbs but was absent in the upper limbs. Vibration sense was severely impaired in the distal portions of the lower limbs, whereas it was normal in the upper limbs. Light touch sensation was normal in both upper and lower limbs. He complained of numbness below the knee on both sides. Deep tendon reflexes, including Achilles tendon reflexes, showed hyperreflexia in both upper and lower limbs. Wartenberg and Babinski reflexes were positive for limbs on both sides. His gait was spastic, and Romberg's sign was observed. Laboratory results revealed neither anemia nor macrocytosis (Table 1). Although a reduction in the serum folate level was detected (2.0 ng/ml; normal value ≧3.2 ng/ml), his serum cobalamin level was normal (276 pg/ml; normal value ≧180 pg/ml). His plasma homocysteine level was elevated (17.2 mol/l; normal value = 3.7–13.5 mol/l). In contrast, his serum methylmalonic acid level was normal (0.12 nmol/ml; normal value = 0–0.4 nmol/ml). Thiamine level in the whole blood was also normal (3.70 μg/dl; normal value = 2.0–7.2 μg/dl). Levels of serum copper and serum angiotensin I-converting enzyme were normal (copper: 125 μg/dl; normal value = 70–132 μg/dl; angiotensin I converting enzyme: 19.4 IU/l; normal value = 7.7–29.4 IU/l). Levels of anti-HTLV-1, anti-DNA, and anti-nuclear antibodies in the serum were within normal limits. Cerebrospinal fluid examination revealed no abnormalities in protein content or cell count: protein level was 33 mg/dl (normal value = 15–45 mg/dl), and cell count was 2/mm3 (normal value ≤5/mm3). Myelin basic protein concentration was normal (40 pg/ml; normal value ≤102 pg/ml), and the oligoclonal banding result was negative. Nerve conduction experiments for the median, ulnar, tibial, peroneal, and sural nerves were performed as reported previously [14] and yielded normal results. Electromyography showed intact upper and lower extremities. In contrast, central motor conduction time was not evoked in the median and tibial nerves, as assessed using previously described methods [15]. In addition, somatosensory-evoked potentials in the median and tibial nerves were examined using previously reported methods [16] and showed increased latencies (N19 for the upper limbs was 23.6 ms, normal value = 18.63 ± 0.94 ms, [mean ± SD]; P35 for the lower limbs was 52.2 ms, normal value = 36.91 ± 2.48 ms). Posturography, performed as previously described [17], revealed a marked instability while standing with the eyes closed. Cranial and
spinal cord magnetic resonance imaging, with and without gadolinium enhancement, did not reveal any abnormality. Computed tomography of the chest, abdomen, and pelvis were also normal. Walking speed was evaluated using the timed Up and Go test [18]. This test assesses basic mobility skills as well as strength, balance, and agility. In this test, the time taken to rise from sitting in an armchair, walk 3 m, turn, walk back to the chair, then sit down using regular footwear and a walking aid, if required, is measured. For our patient, this time was 24 s (normal value ≤10 s). We thought that the spastic paraplegia shown by this patient was associated with folate deficiency due to an unbalanced diet. Thus, we instructed him to improve his eating habits and initiated daily oral folic acid supplementation (Folic Acid 10 mg per day). At 4 weeks after the initiation of folic acid supplementation, his serum folate level had increased, and his plasma homocysteine level was within the normal range. Four months later, spasticity in the lower limbs had diminished, and the timed Up and Go test showed improvement of walking time (19 s). Posturography also showed improvement in the instability while standing with the eyes closed. However, somatosensory-evoked potentials showed no change compared to the pre-treatment values (in the upper limbs, N19 was 23.1 ms and in the lower limbs P35 was 52.6 ms). Further, the central motor conduction time could not be evoked. 2. Discussion Neurological manifestations associated with folate deficiency are diverse and include both congenital and acquired neurological disorders [9,19]. After a study reported that folate deficiency can cause spina bifida in a developing fetus, many countries initiated a program of folic acid fortification [20]. Currently, more than 70 countries practice folic acid fortification. However, many countries, including Japan, have not yet instituted mandatory folic acid fortification [21]. In addition, mental retardation and epilepsy occur in cause of 5,10-methylenetetrahydrofolate reductase deficiency, a congenital abnormality of folate metabolism, if folic acid supplementation is delayed [22]. A major acquired (non-congenital) neurological disorder caused by folate deficiency is subacute combined degeneration of the spinal cord [10]. This condition has been more commonly related to cobalamin deficiency, whereas
Table 1 Clinical and laboratory findings before and after folic acid supplementation.
Serum Folate (ng/ml) Cobalamin (pg/ml) Methylmalonic acid (nmol/ml) Plasma Total protein (g/dl) Albumin (g/dl) Homocysteine(mol/l) Whole blood White blood cell (no/mm3) Red blood cell (no/mm3) Hemoglobin (g/dl) Mean corpuscular volume (fl) Mean corpuscular hemoglobin (pg) Mean corpuscular hemoglobin concentration (g/dl) Platlet (no/mm3) Thiamine (mg/dl) Electrophysiological finding Somato-sensory evoked potential in the upper limb (ms) Somato-sensory evoked potential in the lower limb (ms) Central motor conduction time in the lower limb (ms) Posturography The environed area with eyes closed (cm2) Time up and go test (s) ND = not determined; NE = not elicited.
On admission
4 weeks later
4 months later
Normal values
2.0 276 0.12
> 20.0 233 ND
> 20.0 236 ND
3.6–12.9 233–914 0–0.40
7.2 4.8 9.6
6.5–8.0 3.7–5.0 3.7–13.5
6.6 4.0 17.2
7.3 4.8 8.0
5700 5.02 × 106 15.4 92.4 30.7 33.2 31 × 103 3.7
6700 5.19 × 106 15.7 90.0 30.3 33.6 305 × 103 3.6
7200 4.97 × 106 15.0 89.1 30.2 33.9 348 × 103 3.5
3800–8500 3.60–5.00 × 106 11–16 80–100 26–33 32–36 160–410 × 103 2.0–7.2
N19:23.6 P35:52.2 NE
ND ND ND
N19:23.1 P35:52.6 NE
18.63 ± 0.94 36.91 ± 2.48 b 15
37.68 24
ND ND
24.65 19
≦ 6.63 ≦10
A. Okada et al. / Journal of the Neurological Sciences 336 (2014) 273–275
only tens of cases caused by acquired folate deficiency have been reported thus far [12,13,22–28]. Furthermore, slowly progressive cases of this condition, which extend for years, have been only rarely observed. Subacute combined degeneration of the spinal cord due to cobalamin deficiency results in paraesthesia and loss of vibration and position sense due to impaired functioning of the posterior and lateral columns [11]. These symptoms are followed by ataxia and spastic paraplegia with positive Babinski sign [11]. The functional prognosis for subacute combined degeneration caused by cobalamin deficiency is considered good if cobalamin supplementation is provided shortly after onset [11]. Significant improvement can also be expected if treatment is started within 3 months of gait disturbance [29]. However, the neurological deficits become irreversible in the advanced stage of the condition [29]. Neurological symptoms of subacute combined degeneration caused by folate deficiency are similar to those of subacute combined degeneration caused by cobalamin deficiency [12], and likewise, the functional prognosis for subacute combined degeneration caused by folate deficiency is favorable once folic acid supplementation is initiated [9]. However, objective and comprehensive evaluation of neurological impairments before and after folic acid supplementation has not yet been reported. In this report, we describe a patient who manifested spastic paraplegia that had progressed in severity over 10 years. Our findings, which included increased deep tendon reflexes, positive pathological reflexes, normal nerve conduction, prolonged somatosensory-evoked potentials, and absence of central motor conduction time potentials, all suggested that the lesion was located in the central, rather than the peripheral nervous system. A response to folic acid, but not cobalamin, administration indicated that folate deficiency was the cause of myelopathy in our patient. An unbalanced diet, due to a lack of vegetable intake, was the cause of folate deficiency in our patient. Although the symptoms and signs observed in our case are comparable to those of subacute combined degeneration of the spinal cord, the slowly progressive clinical course is a unique characteristic feature of this case. In addition to folate deficiency, multiple sclerosis, cervical cord compression, amyotrophic lateral sclerosis, adrenoleukodystrophy, tropical spastic paraparesis, HTLV-1 associated myelopathy, paraneoplastic myelopathy, and cobalamin deficiency are included in the differential diagnoses for chronic progressive myelopathy [30]. These other conditions were excluded on the basis of our laboratory and radiological examinations. The patient did not have megaloblastic anemia, despite the presence of spastic paraplegia. The absence of anemia has been previously reported in patients with folate-responsive neurological disorders [23,26,28]. Interestingly, this discrepancy has also been frequently observed in cases of neurological deficits associated with cobalamin deficiency [31]. Factors such as genetic background may influence the susceptibility of individual organs and the appearance of certain symptoms, as has been suggested in cases of thiamine deficiency [32,33]. Although it is advisable to administer folic acid supplementation intravenously in patients with acute illness [34], we chose oral supplementation for our patient due to the slowly progressive clinical course of his condition. Neurological examination showed partial improvement after folic acid supplementation, suggesting that the chronic clinical course of his condition had induced some degree of irreversible neurological damage. Therefore, early diagnosis and initiation of treatment appear to be crucial for the successful treatment of neurological complications due to folate deficiency.
Acknowledgments This work was supported by grants from the Ministry of Health, Labor and Welfare and the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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