Neurol Sci DOI 10.1007/s10072-014-1902-6
BRIEF COMMUNICATION
Pyridoxine-induced sensory ataxic neuronopathy and neuropathy: revisited Kongkiat Kulkantrakorn
Received: 24 May 2014 / Accepted: 18 July 2014 Ó Springer-Verlag Italia 2014
Abstract High dose pyridoxine is neurotoxic. Previous case reports were sparse and little is known about the clinical and electrodiagnostic findings. Three patients with pyridoxine-induced sensory ataxic neuropathy were studied and a review of the involved literature was performed. Three patients, aged 80, 83 and 83 years old, presented with sensory ataxia for 3–8 months. Examination showed signs of polyneuropathy and sensory ataxia. Six hundred milligrams of pyridoxine was consumed each day for 3–10 years, in the form of vitamin B1-6-12 combination tablet. Investigations for other causes of neuropathy were unremarkable. Blood levels of vitamin B6 were markedly elevated at 104.6, 81.4 and 66.9 times of upper normal limits. Electrodiagnostic tests showed symmetric axonal sensory polyneuropathy in two patients. Two years after vitamin discontinuation, all patients showed no significant improvement in the neuropathy and gait. In conclusion, consumption of high dose pyridoxine can cause sensory neuronopathy and axonal sensorimotor polyneuropathy, leading to sensory ataxia which may not be reversible. Keywords Pyridoxine Toxicity Ataxia Neuronopathy Neuropathy
Introduction Vitamin B6 is an essential vitamin that plays an important role in amino acid metabolism. The three natural forms are pyridoxine, pyridoxal and pyridoxamine. Pyridoxine is the most common form used in pharmaceutical preparations and dietary supplements [1]. Pharmacological benefits of pyridoxine include prevention of side effect from isoniazid, treatment of pyridoxine-dependent epilepsy, prevention of cancer, stroke and cardiovascular diseases, and in the enhancement of cognitive and immune functions [2]. Even though the benefits are not clearly proven in most cases, it is widely used or sold freely as a nutritional supplement and a medication, in the form of an isolated tablet or in a formulation with other vitamins. For the past few decades, reports of vitamin B6 toxicity have re-emerged. Clinical information was briefly described, with minimal electrodiagnostic data and follow-up information. In this report, we describe three cases of pyridoxine-induced sensory neuronopathy and neuropathy in details.
Case reports Clinical information K. Kulkantrakorn (&) Neurology Division, Department of Internal Medicine, Thammasat University, Rangsit Campus, Pathumthani 12120, Thailand e-mail: [email protected] K. Kulkantrakorn Neuroscience Center, Bangkok Hospital Medical Center Bangkok Hospital Group, Bangkok 10310, Thailand
The clinical characteristics were summarized in Table 1. Three patients, aged 80, 83 and 83 years old, presented with numbness and ataxia for 3–8 months. They were not ambulatory and required great assistance in standing and walking. They took vitamin B1-6-12 combination tablet (NeurobionÒ, manufactured by Merck, Ltd.), which contained vitamin B1 100 mg, vitamin B6 200 mg and vitamin
123
Neurol Sci Table 1 Clinical characteristics Patient 1
Patient 2
Patient 3
Age (year)
80
83
83
Sex
M
M
M
Underlying diseases
Lacunar infarction, left chronic C7 radiculopathy Sensory ataxia for 6 months
Diabetes mellitus, hypertension,chronic kidney disease, dyslipidemia, lumbar radiculopathy
Diabetes mellitus, lacunar infarction, dyslipidemia, peripheral arterial disease Progressive sensory polyneuropathy and sensory ataxia for 3 months
Aspirin
Glimepiride, sitagliptin, manidipine, doxazosin, folic acid, calcium, rosuvastatin
Gliclazide, metformin, aspirin, cilostazol, simvastatin, calcium, donepezil
Clinical manifestations Concomitant medications Vitamin B6 (pyridoxine) Intake
Progressive sensory polyneuropathy for 2 years sensory ataxia for 8 months
600 mg/day for 3 years
600 mg/day for 3 years
600 mg/day for10 years
Blood level of PLP (normal 8.70–27.20 lg/l)
2,843.76
2,213.07
1,818.46
Elevation above the upper normal limits (times)
104.55
81.36
66.9
Outcome at 2 years
Stable
Stable
Stable
0
PLP pyridoxal-5 -phosphate (active form of vitamin B6), NA not available
B12 200 lg, one tablet three times a day. Therefore, the total dose of 600 mg of pyridoxine per day was consumed for 3–10 years. The second and third patient took rosuvastatin 10 mg daily for 3 years and simvastatin 10 mg daily for 1 year respectively. Their diabetic condition was diagnosed for 1 and 2 years respectively and it has been under control with glycated hemoglobin less than 7 %. Examination in all three patients showed normal motor power and absence of deep tendon reflexes in all four limbs. Impaired touch, vibratory and proprioception sensation in length-dependent and symmetric pattern were found in both lower limbs while pin-prick sensation and thermal sensation were preserved. The degree of numbness and sensory loss were moderate to severe. They were present from toes to mid-calf level in patient 1 and 2 and to ankle in patient 3. Wide-based gait, presence of Romberg’s sign and normal plantar response were noted. Lhermitte phenomenon was absent. All findings suggested sensory ataxia. Investigation Investigations for other causes of neuropathy, including blood chemistry, erythrocyte sedimentation rate, antinuclear antibody profile, anti SSA/Ro and SSB/La antibodies, serum paraneoplastic antibody profile (which included ANNA-1, ANNA-2, ANNA-3, PCA-1, PCA-2, PCA-Tr, GAD, Amphiphysin, CRMP-5, NMDA, AMPA, GABA-b, VGKC, SRP-54 antibodies), serum protein electrophoresis, serum immunofixation, anti-HIV antibody, HBsAg and
123
Anti HCV antibody were all unremarkable. Vitamin B12 level in the third patient was 1,932 pg/ml (normal 211–911 pg/ml). The blood levels of pyridoxal-50 -phosphate (PLP), the metabolically active form of vitamin B6 were measured in all three patients. They were markedly elevated at 2,843.76, 2,213.07, 1,818.46 lg/l which were 104.6, 81.4 and 66.9 times of upper normal limits (8.70–27.20 lg/l) respectively. Six months after discontinuation of pyridoxine, PLP level in the third patient was reduced to 44.25 lg/l (1.63 times of upper normal limits). Electrodiagnosis and neuroimaging The details were in Table 2. In the first patient, motor and sensory nerve conduction studies were within normal limits while EMG findings were consistent with chronic left C7 radiculopathy. Those of the second and third patients showed symmetric axonal sensorimotor polyneuropathy. In addition, chronic bilateral L5 radiculopathy was found in the third patient. Somatosensory evoked potentials were not performed. CT of whole spine in patient 1, MRI of whole spine in patient 2 and MRI of lumbar spine in patient 3 showed spondylosis without spinal cord compression or intrinsic cord lesion. Diagnosis and follow-up With all the clinical information, the first patient was diagnosed as having sensory ataxia from sensory neuronopathy. The second and third patients were diagnosed with
Neurol Sci Table 2 Electrodiagnostic and neuroimaging data Normal value
Patient 1
Patient 2
Patient 3
ND
ND
ND
ND
Motor NCS (R/L) Median DML
B4.4
3.69/3.63
Amplitude
C4.0
12.6/11.2
CV
C49
57.4/56.5
Min F-lat
B31
21.0/23.2
Ulnar DML
B3.3
6.9/8.3
Amplitude
C6.0
6.9/8.3
CV
C49
59.0,57.9/55.7,56.1
Min F-lat
B32
25.2/25/2
DML
B6.5
ND
NR/5.07
NR/4.6
Amplitude
C2.0
NR/0.6
NR/3/1
CV
C44
NR/35.2, 36.0
NR/39.1,36.4
Min F-lat
B56
NR/NR
NR/52.4
Peroneal
Tibial DML
B5.8
3.57/3.57
NR/5.44
4.60/5.07
Amplitude
C4.0
7.7/6.8
NR/0.12
2.2/1/95
CV
C41
43.5/45.0
NR/36.2
37.3/35.7
Min F-lat
B56
46.1/49.1
NR/NR
55.7/58.1
ND
ND
ND
ND
NR/NR
NR/NR
Sensory NCS (R/L) Median Amplitude
C20.0
24.2/35.5
CV
C50.0
55.1/63.9
Amplitude
C17.0
17.4/15/0
CV
C50.0
54.9/55.6
Amplitude
C6.0
12.8/9.5
CV
C40.0
53.2/54.9
Ulnar
Sural
EMG
Chronic denervation at left C7 innervated muscles
NA
Chronic denervation in both L5 innervated muscles
Neuroimaging
CT of whole spine: mild cervical and lumbar spondylosis
MRI of whole spine: cervical and lumbar spondylosis with ossified posterior longitudinal ligament without spinal cord or nerve root compression
MRI of lumbar spine: lumbar spondylosis, bilateral L5 and S1 root compression.
Diagnosis
Sensory neuronopathy chronic left C7 radiculopathy
Axonal sensorimotor polyneuropathy
Axonal sensorimotor polyneuropathy chronic bilateral L5 radiculopathy
Amplitude is measured in mV for motor studies and lV for sensory studies NCS nerve conduction study, DML distal motor latency (msec), CV conduction velocity (m/s), min F-lat minimal F-waves latency (msec), NR no response, ND not done
sensory ataxia from axonal sensorimotor polyneuropathy. Other causes of neuropathy, especially statin and diabetes were less likely to be the significant factors in the second and third patient due to the short duration of low-dose
statin therapy and only 1–2 years of diabetes mellitus which had been well controlled. All patients then stopped taking the vitamin but continued with other concurrent medications. Two years after vitamin discontinuation, all
123
Neurol Sci
patients showed no significant improvement in the neuropathy and gait.
Discussion Case reports of pyridoxine-induced neuropathy had emerged during 1980s. Schaumburg et al. [3] reported this syndrome in seven patients who had taken very high dose of pyridoxine (over 2 g per day) for several months. Most patients improved after discontinuation, but some patients still had significant residual symptoms. In human, the symptoms may continue to progress after cessation of pyridoxine intake (coasting effect) [4].The cause and effect of vitamin B6 neurotoxicity was confirmed by subsequent studies and experiments in patients and healthy volunteers [3, 4]. For unclear reason, there were very few reports in the past decade. Electrodiagnostic data in our cases may help to diagnose sensory neuronopathy or sensory neuropathy, but there was no special characteristic in this disease. In the first patient, the diagnosis of neuronopathy was made clinically after ruling out other possible causes. It may be explained by pure small fiber neuropathy [5]. In the second and third patients, there could be potential confounding causes of their sensorimotor polyneuropathy such as age-related sensory axonal loss and diabetes mellitus, which may explain their unfavorable outcome on long-term follow-up. After long-term follow-up, their recovery was not favorable. On the other hand, this might also be due to longstanding toxicity which causes irreversible nerve damage. The mechanism of vitamin B6 toxicity is still unknown while PLP itself is thought to be responsible [2]. The hypothesis of negative impact of vitamin B6 upon levels of other B vitamins has been proposed [6]. This toxicity seems to be dose-dependent and mainly occurs in chronic exposure in human. This may explain the time lag of symptom’s onset. The other explanation could be the unrecognizable symptoms of early ataxia in the elderly. Several animal experiments confirmed the dose-dependent peripheral nervous system toxicity of pyridoxine. It involves the selective degeneration of the largest neurons in the spinal sensory ganglia and of the associated long peripheral and central neurites performing rapid impulse transmission [7]. Subcutaneous injection of high dose pyridoxine in dogs over a period of 7 days has caused disruption of axons and myelin with vacuolization in the dorsal funiculus, degeneration of dorsal root ganglia and sensory nerves, while the ventral and lateral funiculi were unaffected [1]. In chronic exposure in rats with renal failure, the susceptibility to pyridoxine-induced neuronopathy increases
123
5- to 10- folds [8]. Moreover, in these rats, less than 1 week of protein deficient diet was able to accelerate and intensify the histological lesions and clinical signs of toxicity [9]. This may explain the vulnerability of elderly patients who are frail and suffer from renal dysfunction, diabetes mellitus and multiple systemic diseases. Despite the fact that patients with severely impaired renal function often have low vitamin B6 concentration, the caution of prescribing daily pyridoxine therapy for them should be exercised. The daily recommended dietary allowance of vitamin B6 is 1.3 mg in adult. In our cases, their daily intakes were over 400 times of recommended dietary allowance and six times of allowable intake. Together with vitamin B6 consumption from food source, the actual exposure might be higher which reflected in very high level of PLP. Because nutritional supplement and megavitamin use are becoming more common in the public, many patients may have subclinical disease or wrongly diagnosed as having other causes of neuropathy. Therefore, clinician should routinely inquire patients with neuropathy about their nutritional supplement and be aware of this side effect. Acknowledgments The author would like to thank Dr. Rawiphan Witoonpanich and Prof. Nobuhiro Yuki for their assistance in manuscript preparation. Conflict of interest
None.
References 1. Chung JY, Choi JH, Hwang CY, Youn HY (2008) Pyridoxine induced neuropathy by subcutaneous administration in dogs. J Vet Sci 9:127–131 2. Bender DA (1999) Non-nutritional uses of vitamin B6. Br J Nutr 81:7–20 3. Schaumburg H, Kaplan J, Windebank A et al (1983) Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med 309:445–448 4. Berger AR, Schaumburg HH, Schroeder C, Apfel S, Reynolds R (1992) Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: a prospective study of pyridoxine neurotoxicity. Neurology 42:1367–1370 5. Camdessanche JP, Jousserand G, Ferraud K et al (2009) The pattern and diagnostic criteria of sensory neuronopathy: a casecontrol study. Brain 132(Pt 7):1723–1733 6. Head KA (2006) Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern Med Rev 11:294–329 7. Schaeppi U, Krinke G (1985) Differential vulnerability of 3 rapidly conducting somatosensory pathways in the dog with vitamin B6 neuropathy. Agents Actions 16:567–579 8. Levine S, Saltzman A (2002) Pyridoxine (vitamin B6) toxicity: enhancement by uremia in rats. Food Chem Toxicol 40:1449–1451 9. Levine S, Saltzman A (2004) Pyridoxine (vitamin B6) neurotoxicity: enhancement by protein-deficient diet. J Appl Toxicol 24:497–500
BRIEF COMMUNICATION
Pyridoxine-induced sensory ataxic neuronopathy and neuropathy: revisited Kongkiat Kulkantrakorn
Received: 24 May 2014 / Accepted: 18 July 2014 Ó Springer-Verlag Italia 2014
Abstract High dose pyridoxine is neurotoxic. Previous case reports were sparse and little is known about the clinical and electrodiagnostic findings. Three patients with pyridoxine-induced sensory ataxic neuropathy were studied and a review of the involved literature was performed. Three patients, aged 80, 83 and 83 years old, presented with sensory ataxia for 3–8 months. Examination showed signs of polyneuropathy and sensory ataxia. Six hundred milligrams of pyridoxine was consumed each day for 3–10 years, in the form of vitamin B1-6-12 combination tablet. Investigations for other causes of neuropathy were unremarkable. Blood levels of vitamin B6 were markedly elevated at 104.6, 81.4 and 66.9 times of upper normal limits. Electrodiagnostic tests showed symmetric axonal sensory polyneuropathy in two patients. Two years after vitamin discontinuation, all patients showed no significant improvement in the neuropathy and gait. In conclusion, consumption of high dose pyridoxine can cause sensory neuronopathy and axonal sensorimotor polyneuropathy, leading to sensory ataxia which may not be reversible. Keywords Pyridoxine Toxicity Ataxia Neuronopathy Neuropathy
Introduction Vitamin B6 is an essential vitamin that plays an important role in amino acid metabolism. The three natural forms are pyridoxine, pyridoxal and pyridoxamine. Pyridoxine is the most common form used in pharmaceutical preparations and dietary supplements [1]. Pharmacological benefits of pyridoxine include prevention of side effect from isoniazid, treatment of pyridoxine-dependent epilepsy, prevention of cancer, stroke and cardiovascular diseases, and in the enhancement of cognitive and immune functions [2]. Even though the benefits are not clearly proven in most cases, it is widely used or sold freely as a nutritional supplement and a medication, in the form of an isolated tablet or in a formulation with other vitamins. For the past few decades, reports of vitamin B6 toxicity have re-emerged. Clinical information was briefly described, with minimal electrodiagnostic data and follow-up information. In this report, we describe three cases of pyridoxine-induced sensory neuronopathy and neuropathy in details.
Case reports Clinical information K. Kulkantrakorn (&) Neurology Division, Department of Internal Medicine, Thammasat University, Rangsit Campus, Pathumthani 12120, Thailand e-mail: [email protected] K. Kulkantrakorn Neuroscience Center, Bangkok Hospital Medical Center Bangkok Hospital Group, Bangkok 10310, Thailand
The clinical characteristics were summarized in Table 1. Three patients, aged 80, 83 and 83 years old, presented with numbness and ataxia for 3–8 months. They were not ambulatory and required great assistance in standing and walking. They took vitamin B1-6-12 combination tablet (NeurobionÒ, manufactured by Merck, Ltd.), which contained vitamin B1 100 mg, vitamin B6 200 mg and vitamin
123
Neurol Sci Table 1 Clinical characteristics Patient 1
Patient 2
Patient 3
Age (year)
80
83
83
Sex
M
M
M
Underlying diseases
Lacunar infarction, left chronic C7 radiculopathy Sensory ataxia for 6 months
Diabetes mellitus, hypertension,chronic kidney disease, dyslipidemia, lumbar radiculopathy
Diabetes mellitus, lacunar infarction, dyslipidemia, peripheral arterial disease Progressive sensory polyneuropathy and sensory ataxia for 3 months
Aspirin
Glimepiride, sitagliptin, manidipine, doxazosin, folic acid, calcium, rosuvastatin
Gliclazide, metformin, aspirin, cilostazol, simvastatin, calcium, donepezil
Clinical manifestations Concomitant medications Vitamin B6 (pyridoxine) Intake
Progressive sensory polyneuropathy for 2 years sensory ataxia for 8 months
600 mg/day for 3 years
600 mg/day for 3 years
600 mg/day for10 years
Blood level of PLP (normal 8.70–27.20 lg/l)
2,843.76
2,213.07
1,818.46
Elevation above the upper normal limits (times)
104.55
81.36
66.9
Outcome at 2 years
Stable
Stable
Stable
0
PLP pyridoxal-5 -phosphate (active form of vitamin B6), NA not available
B12 200 lg, one tablet three times a day. Therefore, the total dose of 600 mg of pyridoxine per day was consumed for 3–10 years. The second and third patient took rosuvastatin 10 mg daily for 3 years and simvastatin 10 mg daily for 1 year respectively. Their diabetic condition was diagnosed for 1 and 2 years respectively and it has been under control with glycated hemoglobin less than 7 %. Examination in all three patients showed normal motor power and absence of deep tendon reflexes in all four limbs. Impaired touch, vibratory and proprioception sensation in length-dependent and symmetric pattern were found in both lower limbs while pin-prick sensation and thermal sensation were preserved. The degree of numbness and sensory loss were moderate to severe. They were present from toes to mid-calf level in patient 1 and 2 and to ankle in patient 3. Wide-based gait, presence of Romberg’s sign and normal plantar response were noted. Lhermitte phenomenon was absent. All findings suggested sensory ataxia. Investigation Investigations for other causes of neuropathy, including blood chemistry, erythrocyte sedimentation rate, antinuclear antibody profile, anti SSA/Ro and SSB/La antibodies, serum paraneoplastic antibody profile (which included ANNA-1, ANNA-2, ANNA-3, PCA-1, PCA-2, PCA-Tr, GAD, Amphiphysin, CRMP-5, NMDA, AMPA, GABA-b, VGKC, SRP-54 antibodies), serum protein electrophoresis, serum immunofixation, anti-HIV antibody, HBsAg and
123
Anti HCV antibody were all unremarkable. Vitamin B12 level in the third patient was 1,932 pg/ml (normal 211–911 pg/ml). The blood levels of pyridoxal-50 -phosphate (PLP), the metabolically active form of vitamin B6 were measured in all three patients. They were markedly elevated at 2,843.76, 2,213.07, 1,818.46 lg/l which were 104.6, 81.4 and 66.9 times of upper normal limits (8.70–27.20 lg/l) respectively. Six months after discontinuation of pyridoxine, PLP level in the third patient was reduced to 44.25 lg/l (1.63 times of upper normal limits). Electrodiagnosis and neuroimaging The details were in Table 2. In the first patient, motor and sensory nerve conduction studies were within normal limits while EMG findings were consistent with chronic left C7 radiculopathy. Those of the second and third patients showed symmetric axonal sensorimotor polyneuropathy. In addition, chronic bilateral L5 radiculopathy was found in the third patient. Somatosensory evoked potentials were not performed. CT of whole spine in patient 1, MRI of whole spine in patient 2 and MRI of lumbar spine in patient 3 showed spondylosis without spinal cord compression or intrinsic cord lesion. Diagnosis and follow-up With all the clinical information, the first patient was diagnosed as having sensory ataxia from sensory neuronopathy. The second and third patients were diagnosed with
Neurol Sci Table 2 Electrodiagnostic and neuroimaging data Normal value
Patient 1
Patient 2
Patient 3
ND
ND
ND
ND
Motor NCS (R/L) Median DML
B4.4
3.69/3.63
Amplitude
C4.0
12.6/11.2
CV
C49
57.4/56.5
Min F-lat
B31
21.0/23.2
Ulnar DML
B3.3
6.9/8.3
Amplitude
C6.0
6.9/8.3
CV
C49
59.0,57.9/55.7,56.1
Min F-lat
B32
25.2/25/2
DML
B6.5
ND
NR/5.07
NR/4.6
Amplitude
C2.0
NR/0.6
NR/3/1
CV
C44
NR/35.2, 36.0
NR/39.1,36.4
Min F-lat
B56
NR/NR
NR/52.4
Peroneal
Tibial DML
B5.8
3.57/3.57
NR/5.44
4.60/5.07
Amplitude
C4.0
7.7/6.8
NR/0.12
2.2/1/95
CV
C41
43.5/45.0
NR/36.2
37.3/35.7
Min F-lat
B56
46.1/49.1
NR/NR
55.7/58.1
ND
ND
ND
ND
NR/NR
NR/NR
Sensory NCS (R/L) Median Amplitude
C20.0
24.2/35.5
CV
C50.0
55.1/63.9
Amplitude
C17.0
17.4/15/0
CV
C50.0
54.9/55.6
Amplitude
C6.0
12.8/9.5
CV
C40.0
53.2/54.9
Ulnar
Sural
EMG
Chronic denervation at left C7 innervated muscles
NA
Chronic denervation in both L5 innervated muscles
Neuroimaging
CT of whole spine: mild cervical and lumbar spondylosis
MRI of whole spine: cervical and lumbar spondylosis with ossified posterior longitudinal ligament without spinal cord or nerve root compression
MRI of lumbar spine: lumbar spondylosis, bilateral L5 and S1 root compression.
Diagnosis
Sensory neuronopathy chronic left C7 radiculopathy
Axonal sensorimotor polyneuropathy
Axonal sensorimotor polyneuropathy chronic bilateral L5 radiculopathy
Amplitude is measured in mV for motor studies and lV for sensory studies NCS nerve conduction study, DML distal motor latency (msec), CV conduction velocity (m/s), min F-lat minimal F-waves latency (msec), NR no response, ND not done
sensory ataxia from axonal sensorimotor polyneuropathy. Other causes of neuropathy, especially statin and diabetes were less likely to be the significant factors in the second and third patient due to the short duration of low-dose
statin therapy and only 1–2 years of diabetes mellitus which had been well controlled. All patients then stopped taking the vitamin but continued with other concurrent medications. Two years after vitamin discontinuation, all
123
Neurol Sci
patients showed no significant improvement in the neuropathy and gait.
Discussion Case reports of pyridoxine-induced neuropathy had emerged during 1980s. Schaumburg et al. [3] reported this syndrome in seven patients who had taken very high dose of pyridoxine (over 2 g per day) for several months. Most patients improved after discontinuation, but some patients still had significant residual symptoms. In human, the symptoms may continue to progress after cessation of pyridoxine intake (coasting effect) [4].The cause and effect of vitamin B6 neurotoxicity was confirmed by subsequent studies and experiments in patients and healthy volunteers [3, 4]. For unclear reason, there were very few reports in the past decade. Electrodiagnostic data in our cases may help to diagnose sensory neuronopathy or sensory neuropathy, but there was no special characteristic in this disease. In the first patient, the diagnosis of neuronopathy was made clinically after ruling out other possible causes. It may be explained by pure small fiber neuropathy [5]. In the second and third patients, there could be potential confounding causes of their sensorimotor polyneuropathy such as age-related sensory axonal loss and diabetes mellitus, which may explain their unfavorable outcome on long-term follow-up. After long-term follow-up, their recovery was not favorable. On the other hand, this might also be due to longstanding toxicity which causes irreversible nerve damage. The mechanism of vitamin B6 toxicity is still unknown while PLP itself is thought to be responsible [2]. The hypothesis of negative impact of vitamin B6 upon levels of other B vitamins has been proposed [6]. This toxicity seems to be dose-dependent and mainly occurs in chronic exposure in human. This may explain the time lag of symptom’s onset. The other explanation could be the unrecognizable symptoms of early ataxia in the elderly. Several animal experiments confirmed the dose-dependent peripheral nervous system toxicity of pyridoxine. It involves the selective degeneration of the largest neurons in the spinal sensory ganglia and of the associated long peripheral and central neurites performing rapid impulse transmission [7]. Subcutaneous injection of high dose pyridoxine in dogs over a period of 7 days has caused disruption of axons and myelin with vacuolization in the dorsal funiculus, degeneration of dorsal root ganglia and sensory nerves, while the ventral and lateral funiculi were unaffected [1]. In chronic exposure in rats with renal failure, the susceptibility to pyridoxine-induced neuronopathy increases
123
5- to 10- folds [8]. Moreover, in these rats, less than 1 week of protein deficient diet was able to accelerate and intensify the histological lesions and clinical signs of toxicity [9]. This may explain the vulnerability of elderly patients who are frail and suffer from renal dysfunction, diabetes mellitus and multiple systemic diseases. Despite the fact that patients with severely impaired renal function often have low vitamin B6 concentration, the caution of prescribing daily pyridoxine therapy for them should be exercised. The daily recommended dietary allowance of vitamin B6 is 1.3 mg in adult. In our cases, their daily intakes were over 400 times of recommended dietary allowance and six times of allowable intake. Together with vitamin B6 consumption from food source, the actual exposure might be higher which reflected in very high level of PLP. Because nutritional supplement and megavitamin use are becoming more common in the public, many patients may have subclinical disease or wrongly diagnosed as having other causes of neuropathy. Therefore, clinician should routinely inquire patients with neuropathy about their nutritional supplement and be aware of this side effect. Acknowledgments The author would like to thank Dr. Rawiphan Witoonpanich and Prof. Nobuhiro Yuki for their assistance in manuscript preparation. Conflict of interest
None.
References 1. Chung JY, Choi JH, Hwang CY, Youn HY (2008) Pyridoxine induced neuropathy by subcutaneous administration in dogs. J Vet Sci 9:127–131 2. Bender DA (1999) Non-nutritional uses of vitamin B6. Br J Nutr 81:7–20 3. Schaumburg H, Kaplan J, Windebank A et al (1983) Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med 309:445–448 4. Berger AR, Schaumburg HH, Schroeder C, Apfel S, Reynolds R (1992) Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: a prospective study of pyridoxine neurotoxicity. Neurology 42:1367–1370 5. Camdessanche JP, Jousserand G, Ferraud K et al (2009) The pattern and diagnostic criteria of sensory neuronopathy: a casecontrol study. Brain 132(Pt 7):1723–1733 6. Head KA (2006) Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern Med Rev 11:294–329 7. Schaeppi U, Krinke G (1985) Differential vulnerability of 3 rapidly conducting somatosensory pathways in the dog with vitamin B6 neuropathy. Agents Actions 16:567–579 8. Levine S, Saltzman A (2002) Pyridoxine (vitamin B6) toxicity: enhancement by uremia in rats. Food Chem Toxicol 40:1449–1451 9. Levine S, Saltzman A (2004) Pyridoxine (vitamin B6) neurotoxicity: enhancement by protein-deficient diet. J Appl Toxicol 24:497–500
