Hermann_edit_new.qxp 8/1/09 10:50 am Page 10
Current Issues
the requirements for SAM.
39
This is supported by the finding that L-dopa related to inhibiting glutamate formyl transferase and changing the
induces activity of COMT and methionine adenosyl transferase.
40
If food intake balance between various forms of folate.
61
Finally, valproate may induce
of labile methyl groups (methionine, choline) remains unchanged, L-dopa will methionine synthase and methylenetetrahydrofolate reductase (MTHFR)
cause SAM depletion. SAM, or its precursor methionine, can ameliorate the activity in the liver and can inhibit serine hydroxymethyltransferase
neurotoxicity of L-dopa to dopamine neurons by providing sufficient methyl activity, thus causing lower folate status and increased concentrations of
groups for COMT.
41
The effect of combining COMT inhibitors with L-dopa to Hcy. Valporate has also been found to cause DNA hypomethylation and
avoid HHcy is inconclusive.
42–44
The available evidence suggests that folate, to show teratogenic effects.
62
vitamin B
6
, and vitamin B
12
, but not COMT inhibitors, are the most important
modifiers of the effect of L-dopa on Hcy levels.
45–47
Folic acid supplementation (1mg/day orally) significantly reduced plasma
Hcy after six and 12 weeks in children with elevated Hcy (>10.4µmol/l).
59
It seems that higher concentrations of Hcy in PD patients are generally Treating epileptic patients who were folate-deficient with 5mg folic acid
associated with poor progression of the disease. An association between daily for one to three years caused a marked improvement in cognition,
plasma Hcy concentrations >14µmol/l and depression, as well as mood and social behavior.
63
Folate deficiency is known to be associated
cognitive impairment, has been reported in PD patients.
48
Moreover, an with depressive syndrome. In line with this, patients treated with
increased risk of vascular disease in PD patients with Hcy 17.7µmol/l has antiepileptics developed not only low folate status, but also depressive
been reported.
49
Elderly women with PD and high baseline Hcy symptoms.
64,65
There is strong evidence suggesting that Hcy
(>21.0µmol/l) were more likely to develop hip fracture during 4.9 years concentrations should be tested in patients treated with antiepileptics.
59
of follow-up than those with lower Hcy.
50
Hip fracture is frequent in PD Folate supplementation for subjects on chronic treatment with such
patients,
51
and HHcy is a risk factor for hip fracture.
52,53
Other studies medications has been recommended.
59
failed to detect an association between vitamin intake or plasma Hcy and
the incidence or clinical course of PD.
54,55
However, these studies were Mechanisms of Homocysteine Neurotoxicity
limited by a low number of participants, a short-term follow-up, or the The mechanisms by which Hcy may damage the brain are not fully
fact that vitamin intake does not reflect vitamin status, especially in understood. Data from experimental in vitro studies have shown that Hcy
elderly subjects, in whom malabsorption commonly occurs. may induce neurological dysfunction via oxidative stress.
66,67
Hcy is a
glutamate receptor agonist that actvates N-methyl-D-aspartate (NMDA)
Taken together, the above evidence suggests that reducing plasma Hcy receptor.
68,69
HHcy is associated with hypomethylation, which in turn
may be an important measure for secondary prevention in PD patients. affects DNA methylation, phospholipid homeostasis, and activity of
Plasma concentrations of Hcy should be maintained at low levels in PD several SAM-dependent methyltransferases. In addition, some studies
patients, especially in those patients receiving L-dopa. A causal role for documented that the effect of folate or vitamin B
12
deficiency may be
Hcy in the onset of PD has not yet been tested in large studies, despite the independent of HHcy in the etiology of neurological diseases. Therefore,
consistent association between PD and HHcy. There are several vitamin it is highly recommended to test vitamin B status in patients at risk of
intervention studies in patients with PD,
46,47
but there is no information certain neurological diseases. Because Hcy is more sensitive for folate
currently available about clinical outcome in treated patients. deficiency, this marker may not be sufficient to rule out vitamin B
12
deficiency, at least in the early stages. For this reason, testing
Homocysteine in Patients with Epilepsy holotranscobalamin and/or methylmalonic acid may be essential for the
Several in vivo studies have suggested that Hcy can cause epilepsy.
56
In prevention and treatment of vitamin B
12
deficiency.
addition, most classic antiepileptic drugs (carbamazepin, phenytoin,
valproate, phenobarbital) can induce HHcy in approximately 13–40% of Conclusions
patients.
57–59
Furthermore, multidrug treatment and longer duration of To sum up, retrospective and prospective studies have shown a consistent
the therapy increase the risk of HHcy.
59
association between HHcy and several neurological diseases. Treatment
with B vitamins is an important, safe, and inexpensive approach to
Antiepileptics can increase concentrations of Hcy, probably by reducing modulate the risk. Results from a few treatment trials have shown slight
concentrations of the B vitamins.
57,59
Accordingly, antiepileptics may but significant risk reduction after vitamin treatment. We presented
impair folate absorption and gastrointestinal transport by altering several confounding factors and issues to be considered when planning
gastrointestinal pH. Moreover, increased activity of liver enzymes that and analysing future trials. Longer duration (>5 years), selection of the
catabolize folate (i.e. cytochrome P450) can result from chronic use of patients, and standard medications might be considered. B-vitamin trials
antiepileptics. For example, phenytoin, phenobarbital, and should aim at primary prevention and not treatment of dementia and
carbamazepine induce and valproate inhibits cytochrome P450.
60
other central nervous system diseases. Until the results of such studies
Antiepileptic drugs that do not induce P450 are not associated with a become available, everyone is recommended to meet at least the daily
low concentration of folate. Valproate’s effect on folate seems to be intake of the B vitamins. ■
1. Obeid R, Schorr H, Eckert R, Herrmann W, Vitamin B
12
status in animal model, Acta Neurol Scand Suppl, 1994;154:27–31. Northern Manhattan Study, Stroke, 2005;36:1207–11.
the elderly as judged by available biochemical markers, Clin 3. Sachdev PS, Homocysteine and brain atrophy, Prog 5. Lehrner J, Gufler R, Guttmann G, et al., Annual conversion to
Chem, 2004;50:238–41. Neuropsychopharmacol Biol Psychiatry, 2005;29:1152–61. Alzheimer disease among patients with memory complaints
2. Scott JM, Molloy AM, Kennedy DG, et al., Effects of the 4. Wright CB, Paik MC, Brown TR, et al., Total homocysteine is attending an outpatient memory clinic: the influence of
disruption of transmethylation in the central nervous system: an associated with white matter hyperintensity volume: the amnestic mild cognitive impairment and the predictive value of
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