Sequential Involvement of the Nerve System in SCD VB12 deficiency is receiving increasing interest. Diabetes mellitus is very highly prevalent in developed countries. Metformin, which has been approved for use in the United States in 1994, is the first-line drug for the treatment of type II diabetes and a recent report has stated that chronic metfor- min use leads to VB12 deficiency.5 Because it is difficult to clinically distinguish between myeloneuropathy and peripheral neuropathy, and because optic neuropathy is often subclinical, we included only electrophysiological data. MATERIALS AND METHODS We conducted a retrospective record review of patients who visited our clinic with neurological complaints and whose serum VB12 level was lower than 200 pg/mL. These inclu- sion criteria have been used in previous studies.6,7 We select- ed patients who had undergone electrophysiology studies [median nerve somatosensory evoked potential (MN-SEP), posterior tibial nerve somatosensory evoked potential (PT- SEP), visual evoked potential (VEP), and nerve conduction study (NCS)] before VB12 replacement therapy. We ob- served the electrophysiological patterns of each patient. The normal limits of the evoked potentials were P100<110 msec (VEP), N19<21.1 msec (MN-SEP), P37<40.9 msec (PT- SEP). The normal limit of NCS was determined within 2 standard deviations from the mean value.8 RESULTS We enrolled 49 patients in this study. Their mean age was 56.4 years, and their average VB12 level was 68.3 pg/mL (Table 1). Abnormal SEPs were observed in 38 patients (78%); 19 of these showed abnormal findings on both MN- SEPs and PT-SEPs, 16 showed abnormal findings on PT- SEPs only, and three showed abnormal findings on MN- SEPs only. VEP study was performed in 40 patients, of which 14 (35%) showed abnormalities; two showed abnor- mal findings on VEP only, 12 of these 14 also showed ab- normal SEPs and eight of those 12 patients, in particular, showed abnormal both MN-SEPs and PT-SEPs. NCS was performed for all 49 patients. Of these, 18 (37%) showed abnormal findings; one showed abnormal findings on NCS only, 17 of these 18 patients also showed abnormal SEPs, and 5 also showed abnormal VEPs (Table 2). DISCUSSION Most of the patients (38/49, 78%) showed abnormal find- ings on SEPs; among them, 16 showed only abnormal PT- SEPs. A large number of patients who showed abnormal VEPs or NCS responses also showed abnormal SEPs. On the basis of these electrophysiological findings, we believe that abnormal PT-SEP is the first electrophysiological sign of SCD, followed by abnormal MN-SEP. Abnormal VEPs or NCS responses were observed after abnormal SEPs, but the order of generation of abnormal VEPs and NCS responses is unknown. Based on these electrophysiological findings, it may be deduced that in SCD, spinal cord involvement occurs before peripheral nerve involvement. This result is compatible with the finding that deep tendon reflexes are preserved in SCD patients who complain of numbness in the extremities.1,2 Dementia is a known sign of SCD. In this study, we did not use any neuropsychiatric tests such as the Mini Mental State Examination. However, there was no mention of dementia on the medical charts we reviewed (data not shown). Therefore, we believe dementia to be the last sign of SCD. Because SCD is a treatable disease, it is essential to start treatment immediately upon diagnosis. Hence, the natural course of SCD cannot be followed prospectively, but a cross- sectional study affords a practical way of studying it. It is well known that the presence of VB12 deficiency alone is not enough to allow for a precise diagnosis of SCD. Therefore, for an exact diagnosis, elevated methylmalonic acid levels and decreased homocysteine levels must be ob- served. Unfortunately, there were no records of methylma- lonic acid or homocysteine levels for the patients in our study, and the lack of these data is a potential weak point. Table 1. Clinical Summary Age (yrs), mean (range) Male/Female Vitamin B12 (pg/mL), mean (range) 56.4 (16-82) 41/15 68.3 (12-186) Table 2. Electrophysiological Findings Normal Abnormal Not performed SEP 11 38 0 (PT-SEP) 14 35 0 (MN-SEP) 26 20 3 VEP 26 14 9 NCS 31 18 0 SEP, somatosensory evoked potential; PT, posterior tibial nerve; MN, me- dial nerve; VEP, visual evoked potential; NCS, nerve conduction study. Yonsei Med J http://www.eymj.org Volume 53 Number 2 March 2012 277