1Department of Neurology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
2Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
3Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong, China.
Correspondence Address: Dr. Jin Jun Luo, Departments of Neurology and Pharmacology, Temple University School of Medicine, 3401 North Broad Street, Suite C525, Philadelphia, PA 19140, USA. E-mail: email@example.com
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Aim: Elevated plasma level of homocysteine (eHcy) is a recognized risk factor for dementia. However, whether the central conduction is affected in patients with an isolated eHcy is unknown. In this study, we addressed whether central conduction is altered in adults with eHcy.
Methods: Evoked potential studies including somatosensory (SSEP), visual (VEP) and brainstem auditory evoked potentials (BAEP), were performed to evaluate central conduction in patients with isolated eHcy.
Results: Nine SSEP, 7 VEP, and 6 BAEP were studied in 9 patients with eHcy (age: 63.3 ± 7.5 years old, mean ± standard deviation, male/female: 4/5). SSEP with median nerve stimulation was delayed in peak latency of N9 (5/9/55.6%, abnormal/total subjects/percentage), N13 (7/9/77.8%), N20 (6/9/66.7%), and/or interpeak latency of N9-N13 (5/9/55.6%), N13-N20 (5/9/55.6%), and N9-N20 (4/9/44.4%). There was one delayed P100 latency (1/7/14.3%) in 7 VEP. BAEP was within normal limits in all the 6 subjects tested.
Conclusion: Our pilot study provided neurophysiologic evidence of central conduction slowness in patients with eHcy, which may be due to a large diameter fiber dysfunction within the somatosensory, but not the visual and auditory, white matter pathway. The central conduction slowing in eHcy may be relevant to the pathophysiologic background for slowing the central processing.
central conduction, evoked potential, homocysteine, hyperhomocysteinemia
Homocysteine (Hcy) is an intermediary metabolite of amino acid, methionine, during methylation. Elevated plasma level of homocysteine (eHcy) have been observed in many neurologic and psychiatric disorders including stroke,[1,2] cognitive impairment, dementia,[3,4] Alzheimer’s disease,[5,6] Parkinson’s disease,[6,7] amyotrophic lateral sclerosis, depression,[6,9-12] schizophrenia and bipolar disorders and in an animal model,[13,14] indicating eHcy may adversely cause central nervous system dysfunction. -Whether eHcy interferes with central conduction as the pathophysiologic background relevant to the central processing slowness is unknown. We, therefore, studied the central conduction in patients with eHcy.
Neurophysiology laboratory databank of evoked potentials and the charts of subjects with a clinical diagnosis of eHcy-induced neuropathy seen in the Neuromuscular Clinic were initially retrospectively reviewed. The symptoms and signs of neuropathy included the presentation of numbness and tingling in the distal limbs with a decreased sensation in a glove- and/or stocking-like pattern. Data of clinical presentations, physical and neurological examinations, history of concomitant comorbidities; and laboratory findings including plasma levels of homocysteine, methyl malonic acid, vitamin B12 and folic acid were collected. Laboratory data included mean corpuscular volume of red blood cells, glucose, creatinine, glycosylated hemoglobin, thyroid stimulating hormone, lipids and liver function panels; inflammatory and infectious studies including erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, rapid plasma reagin, lyme titers, hepatitis profile, and human immunodeficiency virus. Subjects with an isolated eHcy who completed evoked potential studies were included. Subjects with an identifiable etiology, other than eHcy, such as deficiency of vitamin B12 and/or folic acid, metabolic, toxic, endocrinologic, infectious, inflammatory, renal or liver diseases were excluded. Additionally, subjects with history of degenerative or inflammatory disorders, such as dementia, Parkinson’s, amyotrophic lateral sclerosis, multiple sclerosis, lupus, sarcoidosis, seizures/epilepsies, cervical spondylosis or traumatic injury, were excluded. This study was approved by the Temple University Institutional Review Board.
Conventional evoked potential studies, including somatosensory, visual, and brainstem auditory evoked potentials (SSEP, VEP, and BAEP, respectively), were performed using Viking Select 10.0.0 (Nicolet, Madison, Wisconsin). Individual peak latency, interpeak latency, interlateral latency and amplitude were analyzed.
Each median nerve was stimulated at the wrist with square pulses above the motor threshold using 0.2 ms stimuli. Two independent trials were performed on either nerve. The stimulus frequency was 5.1 Hz and recording time 50 ms. Filters were set at LFF 10 Hz and HFF 3 kHz. Resultants were recorded and averaged from 2,000 responses from the montage of CPc-CPi, CPi-Epc, C5s-Epc and Epi-Epc. The generators for the waveforms of N9, N13, and N20 are believed to be ipsilateral brachial plexus at the Erb’s point, dorsal column and contralateral nucleus cuneatus, and contralateral parietal somatosensory cortex, respectively. Alteration in interpeak latency of N13-N20 reflects central conduction abnormality.
Two modalities were used in VEP study: pattern reversal full field VEP’s performed monocularly utilizing 28-inch checkerboard stimuli, and goggles fitted with a mosaic of light-emitting diodes. The stimulating reversal frequency was 1.1 Hz in 25 ms with a filter setting at LFF 0.5 Hz and HFF 100 Hz. Two separate trials were performed on each eye. The resultants were recorded for 250 ms and averaged from 150 recordings from LO-MF, MO-MF, RO-MF and MF-A1 derivations. P100 latency was obtained and analyzed.
Each ear was stimulated independently utilizing broad rarefaction and alternating clicks in a frequency of 9.7 Hz in 100 ms with a filter setting of LFF 30 Hz and HFF 3 kHz. Masking noise was delivered to the contralateral ear. For each series of responses, two trials were performed separately from each ear and resultants were recorded for 10 ms and averaged from 4000 responses from Cz referenced to ipsilateral and contralateral ears (Cz-A2 and Cz-A1). The peak latency of waves I, III and V; interpeak latency of waves I-III, III-V and I-V; the amplitudes of wave I and V; and the ratios of the amplitudes of waves V and I (V/I) were measured. The generators for waves I, III, and V of BAEP are believed to involve the structures of the cochlear nerve, superior olive complex, and lateral lemniscus nuclei the mesencephalon, respectively.
From 507 records, 9 subjects who fulfilled the inclusion criteria were included (age: 63.3 ± 7.5 years old, mean ± standard deviation, range: 51-75, male/female: 4/5). Of these 9 subjects, 9 SSEP, 7 VEP, and 6 BAEP that were simultaneously performed, were included. Their plasma level of homocysteine was elevated (16.3 ± 2.3 μmol/L, normal: < 11.4) but with normal plasma levels of B12 (621.4 ± 322.0 pg/mL; normal: 200-1100), folic acid (15.7 ± 5.2 ng/mL; normal: > 5.4), methylmalonic acid (165.1 ± 72.8 nmoI/L; normal: 73-376), and a normal mean corpuscular volume of red blood cells (90.6 ± 7.8 fl; normal: 80-100).
With respect to the recordings, delayed SSEP was observed in peak latency of N9 (5/9/55.6%, abnormal/ studied subjects/percentage), N13 (7/9/77.8%), N20 (6/9/66.7%) and in interpeak latency of N9-N13 (5/9/55.6%), N13-N20 (5/9/55.6%), and N9-N20 (4/9/44.4%). No significant difference in interlateral latency was noted. There was only one delayed VEP observed (1/7/14.3%). BAEP was within normal limits in all the 6 subjects studied [Tables 1-4].
|SSEP (n = 9)|
|VEP (n = 7)|
|BAEP (n = 6)|
Somatosensory evoked potentials
|Mean ± SD||11 ± 1.2||11.2 ± 1.2||16 ± 1.2||15.8 ± 1.5||22 ± 1.9||22.9 ± 2.9||5 ± 1.4||4.6 ± 1.5||6.1 ± 1||7.1 ± 2||10.4 ± 1.4||11.4 ± 2.7|
|Normal||≤ 11.3||≤ 11.3||≤ 14.9||≤ 14.9||≤ 22.1||≤ 22.1||≤ 5.0||≤ 5.0||≤ 6.8||≤ 6.8||≤ 10.9||≤ 10.9|
Brainstem auditory evoked potentials
|Mean ± SD||1.7 ± 0.1||1.6 ± 0.1||3.8 ± 0.2||3.8 ± 0.2||5.8 ± 0.3||5.8 ± 0.3||1.8 ± 0.6||1.5 ± 0.5||2.1 ± 0.1||2.3 ± 0.2||2 ± 0.1||2 ± 0.2||4.1 ± 0.2||4.2 ± 0.3|
|Normal||≤ 2.2||≤ 2.2||≤ 4.5||≤ 4.5||≤ 6.5||≤ 6.5||≤ 2.6||≤ 2.6||≤ 2.4||≤ 2.4||≤ 4.7||≤ 4.7|
Visual evoked potentials
|Mean ± SD||104.1 ± 8.2||105.7 ± 13.2||104.9 ± 19.5||109.8 ± 18.3|
|Normal||≤ 117||≤ 117||≤ 132||≤ 132|
In this study, we observed central conduction slowness in approximately half of the adult patients with an isolated eHcy. The central conduction slowness preferentially affected the somatosensory, but not the visual and auditory, pathways. To the best of our knowledge, there is no report on central conduction in adult patients with eHcy.
Somatosensory evoked potential evaluates the integrity of the somatosensory pathway from peripheral to the cortex. The pathway initiates from peripheral segment of the large sensory fibers whose cell bodies, the pseudomonopolar neurons, reside in the dorsal root ganglia. The central processes of the pseudomonopolar neurons enter the ipsilateral posterior column of the spinal cord, decussate and synapse at the contralateral dorsal column nucleus (cuneate nucleus) at the cervico-medullary junction where the secondary order fibers start and synapse at ventro-posteriolateral nucleus of thalamus, from which the third order fibers advance to the somatosensory cortex. It is commonly accepted that SSEP evaluates only the large diameter fibers.
The current study provided evidence that the large fiber dysfunction occurs in central conduction, involving somatosensory pathway, in addition to the peripheral conduction delay.[16,18] We have recently reported that eHcy is an independent risk factor for the development of peripheral neuropathy. The estimated incidence of the isolated eHcy-induced neuropathy was as low as 1.81% of peripheral neuropathy (our unpublished data). The electrophysiologic features of the isolated eHcy-induced peripheral neuropathy are a mild, large fiber sensorimotor neuropathy with mixed neurophysiologic features of mild demyelination and distal axonal degeneration, although the involvement of small diameter fibers cannot be dismissed.
Elevated plasma level of homocysteine may result from deficiency of vitamin B12 and/or folate, and genetic predispositions such as C677T polymorphism of MTHFR.[19,20] Additionally, it may also result from various pathophysiologic conditions including aging,[21,22] obesity,[23,24] diabetes mellitus,[25-27] renal function impairment, medications and/or toxic substances such as levodopa,[7,28] anti-gastric acid agents,[29,30] anti-epileptics,[31,32]tobacco, and alcohol.[34-36] Because of its excitatory property which may promote the vulnerability of neuronal cells to excitotoxic- and oxidative-stress-induced injury, Hcy, especially eHcy, can be neurotoxic.[4,37-39]
Elevated plasma level of homocysteine has been observed in a number of neurological disorders including stroke,[1,2] Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In addition, eHcy may also play a role in psychiatric disorders, such as depression,[6,9-12] bipolar disorders and schizophrenia.[13,14] Importantly, eHcy has been linked to cognitive impairment and dementia.[3,4] The findings of slowness of the central conduction in our study may suggest an electrophysiologic background for the central process slowing relevant to memory and cognitive functions. Notably, VEP was performed using two different modalities with only one out of 7 subjects showing abnormality. It is not clear the reason why visual and auditory pathways were spared. It may be related to the susceptibility of eHcy-induced nerve fiber damage or the tolerability of the fibers to eHcy-induced insults. An alternative explanation is that there may be a yet to be determined protective mechanism against eHcy-induced toxicity in special sensory pathways.
Vitamin B12 deficiency is a well-documented etiology for both central and peripheral nervous system dysfunction. The current study provided evidence that the large fiber dysfunction occurs in central conduction, involving the somatosensory pathway. The findings combining our previous[16,18] and current observations suggest that, in addition to B12 deficiency, eHcy may be a potential risk factor in interfering with peripheral and central conduction of the somatosensory pathway. In other words, it is possible that the mechanism by which B12 deficiency causes central and peripheral nervous system dysfunction maybe partly via eHcy. A clinical observation that administration of antifolate agent such as methotrexate induced a clinical phenotype compatible with that of vitamin B12 deficiency favored this notion.[40,41] However, laboratory evidence is needed to support this claim.[3,4,19,38,39]
As the central large fiber conduction slowing is evident electrophysiologically in some patients with eHcy, it may be relevant to the central nervous system dysfunction and raise the concern regarding eHcy-related central neurodegeneration, such as dementia. Therefore, early recognition of the condition and prompt treatment may be critical. Since there is no cure currently available for neurodegenerative disorders, the best approach in clinical practice should be on prevention by modifying acquired risk factors, including eHcy. Thus, eHcy may become a therapeutic target. The efficacy of reducing eHcy with a regimen of combined vitamin B12, folate, and B6 in preventing the development of neurodegenerative disorders needs to be explored. Nevertheless, our finding of central conduction slowing in adults with eHcy suggests clinically relevant significance and warrants further investigation. The limitation of this report was a retrospective study with a small number of subjects.
In summary, our pilot study on adults with isolated eHcy showed neurophysiologic evidence of slow central conduction involving the large fibers in the somatosensory, but not the visual and auditory, white matter pathways. The neurophysiologic changes may occur in parallel to eHcy-induced central processing decline. Additional large cohort studies may be needed to validate the finding.
This article is dedicated to Mrs. Ethel Lombard for her outstanding service to the Department of Neurology at Temple University Hospital for 60 years.
There are no conflicts of interest.
1. Hankey GJ, Eikelboom JW. Homocysteine and stroke. Curr Opin Neurol 2001;14:95-102.DOIPubMed
2. Hankey GJ, Eikelboom JW. Homocysteine levels in patients with stroke: clinical relevance and therapeutic implications. CNS Druigs 2001;15:437-43.DOIPubMed
3. Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 2006;580:2994-3005.DOIPubMed
4. Loscalzo J. Homocysteine and dementias. N Engl J Med 2002;346:466-8.DOIPubMed
5. Hooshmand B, Solomon A, Kåreholt I, Leiviskä J, Rusanen M, Ahtiluoto S, Winblad B, Laatikainen T, Soininen H, Kivipelto M. Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. Neurology 2010;75:1408-14.DOIPubMed
6. Sui R, Zhang L. Depression, Parkinson disease, Alzheimer disease. The homocysteine hypothesis. Neurosciences (Riyadh) 2010;15:211-3.PubMed
7. Postuma RB, Lang AE. Homocysteine and levodopa: should Parkinson disease patients receive preventative therapy? Neurology 2004;63:886-91.DOIPubMed
8. Zoccolella S, Simone IL, Lamberti P, Samarelli V, Tortelli R, Serlenga L, Logroscino G. Elevated plasma homocysteine levels in patients with amyotrophic lateral sclerosis. Neurology 2008;70:222-5.DOIPubMed
9. Fraguas R Jr, Papakostas GI, Mischoulon D, Bottiglieri T, Alpert J, Fava M. Anger attacks in major depressive disorder and serum levels of homocysteine. Biol Psychiatry 2006;60:270-4.DOIPubMed
10. Gariballa S. Extending the homocysteine-induced neurotransmitter deficiency and depression of mood hypothesis to quality of life in older patients. Int J Geriatr Psychiatry 2013;28:878-9.DOIPubMed
11. Folstein M, Liu T, Peter I, Buell J, Arsenault L, Scott T, Qiu WW. The homocysteine hypothesis of depression. Am J Psychiatry 2007;164:861-7.DOIPubMed
12. Gariballa S. Testing homocysteine-induced neurotransmitter deficiency, and depression of mood hypothesis in clinical practice. Age Ageing 2011;40:702-5.DOIPubMed
13. Levine J, Sela BA, Osher Y, Belmaker RH. High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1181-91.DOIPubMed
14. Brown AS, Susser ES. Homocysteine and schizophrenia: from prenatal to adult life. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1175-80.DOIPubMed
15. Ansari R, Mahta A, Mallack E, Luo JJ. Hyperhomocysteinemia and neurologic disorders: a review. J Clin Neurol 2014;10:281-8.DOIPubMedPMC
16. Luo JJ, Sivaraaman K, Nouh A, Dun NJ. Elevated plasma level of homocysteine is an independent risk factor for peripheral neuropathy. Br J Med Med Res 2014;4:161-9.DOI
17. Aminoff MJ. Aminoff's Electrodiagnosis in Clinical Neurology. 6th ed. Philadelphia: Saunders; 2012 .
18. Luo JJ, Bumanlag F, Dun NJ. Electrophysiologic features of peripheral neuropathy in adults with an isolated elevated plasma level of homocysteine. J Neurol Transl Neurosci 2013;2:1027-31.
19. Kruman II, Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L, Mattson MP. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000;20:6920-6.PubMed
20. Lipton SA, Kim WK, Choi YB, Kumar S, D'Emilia DM, Rayudu PV, Arnelle DR, Stamler JS. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A 1997;94:5923-8.DOIPubMedPMC
21. Tsivgoulis G, Spengos K, Karandreas N, Panas M, Kladi A, Manta P. Presymptomatic neuromuscular disorders disclosed following statin treatment. Arch Intern Med 2006;166:1519-24.DOIPubMed
22. Ammendola A, Gemini D, Iannaccone S, Argenzio F, Ciccone G, Ammendola E, Serio L, Ugolini G, Bravaccio F. Gender and peripheral neuropathy in chronic alcoholism: a clinical-electroneurographic study. Alcohol Alcohol 2000;35:368-71.DOIPubMed
23. Aaberg ML, Burch DM, Hud ZR, Zacharias MP. Gender differences in the onset of diabetic neuropathy. J Diabetes Complications 2008;22:83-7.DOIPubMed
24. Mathew PG, Dun EC, Luo JJ. A cyclic pain: the pathophysiology and treatment of menstrual migraine. Obstet Gynecol Surv 2013;68:130-40.DOIPubMed
25. Pirart J, Lauvaux JP, Rey W. Blood sugar and diabetic complications. N Engl J Med 1978;298:1149.DOIPubMed
26. Factors in development of diabetic neuropathy. Baseline analysis of neuropathy in feasibility phase of Diabetes Control and Complications Trial (DCCT). The DCCT Research Group. Diabetes 1988;37:476-81.DOIPubMed
27. The effect of intensive diabetes therapy on the development and progression of neuropathy. The Diabetes Control and Complications Trial Research Group. Ann Intern Med 1995;122:561-8.DOIPubMed
28. Liu XX, Wilson K, Charlton CG. Effects of L-dopa treatment on methylation in mouse brain: implications for the side effects of L-dopa. Life Sci 2000;66:2277-88.DOI
29. Hofmann MA, Kohl B, Zumbach MS, Borcea V, Bierhaus A, Henkels M, Amiral J, Schmidt AM, Fiehn W, Ziegler R, Wahl P, Nawroth PP. Hyperhomocyst (e) inemia and endothelial dysfunction in IDDM. Diabetes Care 1998;21:841-8.DOI
30. Kulkarni K, Richard BC. Lifestyle, homocysteine, and the metabolic syndrome. Metab Syndr Relat Disord 2003;1:141-7.DOIPubMed
31. Giltay EJ, Hoogeveen EK, Elbers JM, Gooren LJ, Asscheman H, Stehouwer CD. Insulin resistance is associated with elevated plasma total homocysteine levels in healthy, non-obese subjects. Atherosclerosis 1998;139:197-8.PubMed
32. Munshi MN, Stone A, Fink L, Fonseca V. Hyperhomocysteinemia following a methionine load in patients with non-insulin-dependent diabetes mellitus and macrovascular disease. Metabolism 1996;45:133-5.DOI
33. Kawasaki A, Purvin VA, Burgett RA. Hyperhomocysteinaemia in young patients with non-arteritic anterior ischaemic optic neuropathy. Br J Ophthalmol 1999;83:1287-90.DOIPubMedPMC
34. Kim WK, Pae YS. Involvement of N-methyl-d-aspartate receptor and free radical in homocysteine-mediated toxicity on rat cerebellar granule cells in culture. Neurosci Lett 1996;216:117-20.PubMed
35. Outinen PA, Sood SK, Liaw PC, Sarge KD, Maeda N, Hirsh J, Ribau J, Podor TJ, Weitz JI, Austin RC. Characterization of the stress-inducing effects of homocysteine. Biochem J 1998;332:213-21.DOIPubMedPMC
36. Huang RF, Huang SM, Lin BS, Wei JS, Liu TZ. Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells. Life Sci 2001;68:2799-811.DOI
37. Maler JM, Seifert W, Hüther G, Wiltfang J, Rüther E, Kornhuber J, Bleich S. Homocysteine induces cell death of rat astrocytes in vitro. Neurosci Lett 2003;347:85-8.DOI
38. Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 2003;26:137-46.DOI
39. Smith AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull 2008;29:S143-72.DOIPubMed
40. Savage DG, Lindenbaum J. 11 Neurological complications of acquired cobalamin deficiency: clinical aspects. Baillieres Clin Haematol 1995;8:657-78.DOI
41. Yi Y, Kang HJ, Shin HY, Kim K. Progressive myelopathy mimicking subacute combined degeneration after intrathecal chemotherapy. J Child Neurol 2014. Epub ahead of print.PubMed
42. Luo JJ, Dun NJ. Should homocysteine be a therapeutic target for neurological disorders? Brain Disord Ther 2013;2:e107.
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