Macroprolactin in mothers and their babies: what is its origin?

OBJECTIVES: Macroprolactinemia is one of the major causes of hyperprolactinemia. The aim of this study was to clarify the origin of macroprolactin (macro-PRL). METHODS: We examined macro-PRL in the sera of 826 pregnant women and in those of their babies' umbilical cords at delivery. Macro-PRL was evaluated by precipitation with polyethylene glycol (PEG), gel filtration chromatography (GFC), and absorption with protein G (PG). RESULTS: We detected macro-PRL in 16 out of the 826 pregnant women (1.94 %) and in 14 of their babies, which may indicate the possibility of hereditary origin of macro-PRL. However, the macro-PRL ratios of the babies correlated positively with those of their mothers (r=0.72 for GFC, p<0.001 and r=0.77 for PG, p<0.001), suggesting that the immunoglobulin (Ig)G-type anti-PRL autoantibodies might be actively transferred to babies via the placenta and form macro-PRL by binding to their babies' PRL or PRL-IgG complexes may possibly pass through the placenta. There were two cases in which only mothers had macro-PRL, indicating that the mothers had autoantibodies that did not pass through the placenta, such as IgA, PRL bound to the other proteins or PRL aggregates. No cases were found in which only the babies had macro-PRL and their mothers did not, suggesting that macro-PRL might not arise by non-hereditary congenital causes. CONCLUSIONS: Macro-PRL in women of reproductive age might be mostly IgG-type anti-PRL autoantibody-bound PRL. The likely origin of macro-PRL in babies is the transplacental transfer of IgG-type anti-PRL autoantibodies or PRL-IgG complexes from the mothers to their babies.

Intravenous immunoglobulin for chronic residual peripheral neuropathy in microscopic polyangiitis: A multicentre randomised double-blind trial.

OBJECTIVES: We conducted a Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of intravenous immunoglobulin (IVIg) in patients with glucocorticoid-refractory neuropathy associated with microscopic polyangiitis. METHODS: Patients received immunoglobulin or placebo intravenously for 5 consecutive days at baseline and after 4 weeks. The IVIg and placebo groups received IVIg and placebo, respectively, after 8 weeks. The primary and major secondary end-points were the least squares mean of the change in the manual muscle test (MMT) sum score after 8 and 4 weeks, respectively. RESULTS: A total of 37 patients were randomised into two groups (IVIg [19] and placebo [18]). The least squares mean for the change in the MMT sum score was 9.02 for IVIg and 6.71 for placebo (difference 2.32, 95% confidence interval -2.60 to 7.23, p = .345) after 8 weeks and 6.81 and 2.83 (difference 3.99, 95% confidence interval -1.22 to 9.19, p = .129), respectively, after 4 weeks. There were no new safety concerns for IVIg. CONCLUSIONS: MMT sum scores improved with IVIg compared with placebo after 8 weeks of dosing and two courses of treatment, but the differences were not statistically significant, and the results showed no clear efficacy of IVIg in this patient population. No new safety concerns were raised.

Numerous spindle-shaped lymphoma cells in lymphomatosis cerebri: An autopsy case report.

Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma (PCNSL). It is characterized by diffuse infiltration of atypical lymphoid cells with no mass formation and little or no contrast enhancement on magnetic resonance imaging (MRI). Interestingly, some lymphoma cells form characteristic spindle shapes; these cells are found in some variants of malignant lymphoma, such as primary cutaneous follicle center lymphoma, but they have not been reported in PCNSL or LC. Here, we provide an autopsy case report of LC in a 69-year-old immunocompetent man who developed rapidly progressive cognitive decline and died on day 68 after the episode despite treatment with intravenous methylprednisolone administration. MRI revealed high signal intensities on T2-weighted images of the cerebral hemispheres, cerebellum, brainstem, and spinal cord without gadolinium enhancement on T1-weighted images. On autopsy, diffuse infiltrative atypical cells were seen; these cells were positive for CD20 and CD79a and negative for GFAP, CD3, and CD5 on immunohistochemistry, resulting in a diagnosis of diffuse large B-cell lymphoma, specifically LC. We found characteristic spindle-shaped cells, especially in the cerebral cortex. This is the first report showing that lymphoma cells in PCNSL can take on a spindle-shaped form. It is difficult to recognize these spindle-shaped cells as lymphoma cells on hematoxylin and eosin staining and diagnose them correctly with small biopsy specimens without immunohistochemistry. This case suggests that we should add atypical, spindle-shaped cells to the differential diagnosis of PCNSL.

[EVALUATION OF A MOTOR AND SENSORY DISTURBANCE QUESTIONNAIRE FOR PATIENTS WITH EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS].

BACKGROUND AND AIMS: It is difficult to evaluate neurological signs of multiple mononeuritis (MM) in patients with eosinophilic granulomatosis with polyangiitis (EGPA). We created a new questionnaire about motor and sensory disturbances in EGPA and investigated whether the questionnaire would be a useful tool in the management of MM in EGPA patients. METHODS: We classified 40 EGPA patients attending Hiratsuka City Hospital into two groups, namely 30 who were treated with intravenous immunoglobulin (IVIG) and 10 who achieved remission by conventional treatment without IVIG. We created a questionnaire for the evaluation of motor and sensory disturbance in EGPA (ANCA related.com). In patients who received IVIG, we evaluated motor and sensory disturbance scores at disease onset, before IVIG, 1 week and 1 month after the end of IVIG. In patients treated without IVIG, we evaluated these scores at disease onset and at the time of the latest examination. RESULTS: The total motor disturbance score at disease onset was significantly lower in EGPA patients who received IVIG than in those who did not receive it. Disease duration was significantly inversely correlated with the change in the sensory disturbance ratio, but not with the motor disturbance ratio. The motor disturbance ratio was significantly correlated with the manual muscle test improvement ratio. In patients who received IVIG, the total motor disturbance score increased significantly, and the total sensory disturbance score decreased significantly, 1 month after IVIG. CONCLUSION: By using the questionnaire we could evaluate changes in motor and sensory disturbance after IVIG treatment in patients with EGPA. The questionnaire should be useful in the management of MM in EGPA patients.

A possible cause of the variable detectability of macroprolactin by different immunoassay systems.

BACKGROUND: Macroprolactinaemia is a major cause of hyperprolactinaemia. The detectability of macroprolactin varies widely among different immunoassay systems, but the causes are not fully known. This study aimed to identify the factors influencing the detectability of macroprolactin by immunoassay systems. METHODS: The study included 1544 patients who visited an obstetric and gynaecological hospital. Macroprolactinaemia was screened using the polyethylene glycol (PEG) method and confirmed using gel filtration chromatography and the protein G method. The prolactin (PRL) values determined by enzyme immunoassay (EIA) were compared with those of a chemiluminescence immunoassay system (Centaur) that is known to cross-react the least with macroprolactin. RESULTS: Macroprolactinaemia was found in 62 of 1544 patients (4.02%) who visited an obstetric and gynaecological hospital. The ratio of EIA-determined total PRL to free PRL in the supernatant after PEG precipitation was significantly elevated in all 62 serum samples with macroprolactin compared to those in 1482 serum samples without macroprolactin. In contrast, the ratio of Centaur-determined total PRL to free PRL was significantly elevated in 32 serum samples (group 1) and was within the normal range in 30 (group 2) of 62 serum samples with macroprolactin. The prevalence of non-IgG-type macroprolactin was significantly higher in group 1 than in group 2. Centaur diagnosed hyperprolactinaemia less frequently than EIA (n=2 vs. 16) in 62 patients with macroprolactinaemia. Those two hyperprolactinaemic patients diagnosed by Centaur had non-IgG-type macroprolactin. CONCLUSIONS: Macroprolactinaemia was present in 4% of patients visiting an obstetric and gynaecological hospital. The nature of macroprolactin (IgG-type or non-IgG-type) may partly explain why macroprolactin detectability varies among different immunoassay systems.

Macro TSH in patients with subclinical hypothyroidism.

OBJECTIVE: TSH is a sensitive indicator of thyroid function. In subclinical hypothyroidism, however, serum TSH concentrations are elevated despite normal thyroid hormone levels, and macro TSH is one of the causes. This study aimed to clarify the prevalence and nature of macro TSH in patients with subclinical hypothyroidism. DESIGN: We conducted a 2-year cross-sectional observational study. PATIENTS: We included 681 patients with subclinical hypothyroidism and 38 patients with overt hypothyroidism (controls). MEASUREMENTS: Macro TSH was screened by polyethylene glycol (PEG) method and analysed by gel filtration chromatography and bioassays. RESULTS: Among 681 serum samples, 117 exhibited PEG-precipitable TSH ratios greater than 75% (mean + 1·5 SD in controls) and were subjected to gel filtration chromatography. TSH was eluted at a position greater than 100 kDa in 11 patients with subclinical hypothyroidism (1·62%); these patients were diagnosed with macro TSH. The nature of macro TSH included eight anti-TSH autoantibodies of IgG class, two non-IgG-associated and one human anti-mouse antibody (HAMA). Macro TSH showed low bioactivity. CONCLUSIONS: Macro TSH was heterogeneous, but it is mostly comprised of TSH and anti-TSH autoantibodies. When PEG-precipitable TSH exceeds 90% in serum samples with TSH above 10 mU/l, clinicians should strongly suspect the presence of macro TSH and confirm it by gel chromatography. Because macro TSH exhibited low bioactivity, thyroid hormone replacement therapy may not be required in patients with subclinical hypothyroidism due to macro TSH except for those with high serum free TSH levels.

Prevalence and Pathogenesis of Macro-Thyrotropin in Neonates: Analysis of Umbilical Cord Blood from 939 Neonates and Their Mothers.

Background: Macro-thyrotropin (macro-TSH) is a large molecular weight TSH that causes elevated serum TSH concentrations due to its slow clearance. It is primarily a complex of TSH and anti-TSH autoantibodies. The aims of this study were to examine the prevalence and nature of macro-TSH in neonates and to determine how to cope with macro-TSH in neonates suspected to have congenital hypothyroidism through neonatal mass screening. Methods: The presence of macro-TSH was examined using polyethylene glycol (PEG), gel filtration chromatography (GFC), and 125I-TSH binding studies in 939 umbilical cord blood samples from neonates and their mothers. Results: Among 138 serum samples with a PEG precipitation ratio of TSH >68.9% (mean + standard deviation), human anti-mouse antibodies were found in nine samples. The presence of macro-TSH was examined in the remaining 129 serum samples using a 125I-TSH binding study and GFC. The 125I-TSH binding study revealed that four babies (0.43%) had significantly high ratios of 125I-TSH binding to their sera. Two of the babies were siblings, and their mother and the other two mothers also showed significantly high binding ratios. The 125I-TSH binding was displaced by a large amount (1 µg) of unlabeled human TSH in a similar way between babies and their mothers in all cases, suggesting the presence of anti-TSH autoantibodies in their sera. Further characterization of the autoantibodies in one baby and its mother showed a low affinity and high specificity to human TSH, and the nature was very similar between them. These findings may indicate that the anti-TSH autoantibodies that developed in the mother were transferred to the baby through the placenta and formed macro-TSH by binding to neonatal TSH. GFC revealed macro-TSH in only one baby and its mother, probably because of the dissociation of TSH from autoantibodies during the analytical procedure. Conclusions: Macro-TSH was found in 0.43% of neonates, and their mothers all had macro-TSH as well. We recommend that if a baby's serum TSH concentration is high enough to consider levothyroxine treatment suspecting congenital hypothyroidism but the free thyroxine level is normal, their mother's macro-TSH should be checked.

Demyelinating Neuropathy with Markedly Elevated Serum IgG4 Levels and Anti-Contactin 1 IgG4 Antibody.

We herein report a 77-year-old man with a 4-month history of progressive gait and sensory disturbances of the extremities. A nerve conduction study indicated demyelinating polyneuropathy. Serum IgG4 levels and anti-contactin 1 IgG4 antibodies were markedly increased. The sural nerve biopsy specimen showed IgG4-positive plasma cell infiltration in the epineurium. Treatment with steroids resulted in an amelioration of functional status, improvement of nerve conduction parameters, decreased serum IgG4 levels, and negative conversion of anti-contactin 1 antibody. Further studies are needed to clarify the significance of IgG4-positive plasma cell infiltration in anti-contactin 1 antibody-positive neuropathies.

Macroprolactinemia: diagnostic, clinical, and pathogenic significance.

Macroprolactinemia is characterized by a large molecular mass of PRL (macroprolactin) as the main molecular form of PRL in sera, the frequent elevation of serum PRL (hyperprolactinemia), and the lack of symptoms. Macroprolactin is largely a complex of PRL with immunoglobulin G (IgG), especially anti-PRL autoantibodies. The prevalence of macroprolactinemia is 10-25% in patients with hyperprolactinemia and 3.7% in general population. There is no gender difference and a long-term followup demonstrates that macroprolactinemia develops before middle age and is likely a chronic condition. Polyethylene-glycol- (PEG-) precipitation method is widely used for screening macroprolactinemia, and gel filtration chromatography, protein A/G column, and I125-PRL binding studies are performed to confirm and clarify its nature. The cross-reactivity of macroprolactin varies widely according to the immunoassay systems. The epitope on PRL molecule recognized by the autoantibodies is located close to the binding site for PRL receptors, which may explain that macroprolactin has a lower biological activity. Hyperprolactinemia frequently seen in macroprolactinemic patients is due to the delayed clearance of autoantibody-bound PRL. When rats are immunized with rat pituitary PRL, anti-PRL autoantibodies are produced and hyperprolactinemia develops, mimicking macroprolactinemia in humans. Screening of macroprolactinemia is important for the differential diagnosis of hyperprolactinemia to avoid unnecessary examinations and treatments.

[Steroids-Resistant EGPA-Induced Neuropathy with Acute Disease Progression: How to Use Mepolizumab as Novel Targeted Agent].

Eosinophilic granulomatosis with polyangiitis (EGPA), an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, is a systemic vasculitis syndrome involving inflammatory damage of predominantly small vessels. Initial treatment is extremely important because the peripheral nervous system is a major target organ that depends on long-term clinical outcomes. Moreover, detailed neurological observations are necessary during the remission period. Although corticosteroids and cyclophosphamide are used as the first-line therapy, intravenous immunoglobulin is beneficial for patients with steroid resistance. Mepolizumab administration is preferentially considered for patients with EGPA, which is refractory to treatment with corticosteroids, cyclophosphamide, and intravenous immunoglobulin.

Telmisartan is the most effective ARB to increase adiponectin via PPARα in adipocytes.

Telmisartan and irbesartan are angiotensin II receptor blockers (ARBs) and reportedly stimulate adiponectin secretion from adipocytes via partial peroxisome proliferator-activated receptor γ (PPARγ) activation. However, quantitative evaluation among different ARBs has not been performed. Adiponectin exerts strong protection against a number of pathological events by suppressing cell death, inhibiting inflammation, and enhancing cell survival, while leptin promotes inflammation, oxidative stress, atherogenesis, and thrombosis. The aim of this study was to identify the most effective ARB enhancing adiponectin secretion without raising leptin secretion from human white adipocytes (HWAs). Among seven ARBs (azilsartan, candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan), telmisartan was the most effective ARB for the increase of adiponectin secretion and irbesartan was the second, whereas the other ARBs at 1 µM had no effect on adiponectin secretion. GW9662, a PPARγ antagonist, completely blocked pioglitazone (PPARγ agonist)-induced adiponectin secretion and mRNA expression, whereas it unexpectedly blocked neither telmisartan- nor irbesartan-induced adiponectin secretion and mRNA expression but rather increased them. GW6471, PPARα antagonist, and siRNA for PPARα suppressed telmisartan- and irbesartan-induced adiponectin secretion, suggesting that PPARα is the main target of these ARBs to increase adiponectin secretion in HWAs. Leptin secretion was not affected by any ARBs at 1 µM and GW9662 significantly decreased the basal secretion of leptin, suggesting that basal leptin secretion is regulated in a PPARγ-dependent manner. We conclude that telmisartan is the most effective ARB to increase adiponectin secretion via PPARα without raising leptin secretion from HWAs.

Excessive expression of hippocampal ezrin is induced by intrastriatal injection of 6-hydroxydopamine.

Accumulating evidence in humans demonstrates that visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson's disease (PD). Ezrin, radixin, and moesin are collectively known as ERM proteins. Although ERM proteins have important implications in cell-shape determination and relevant signaling pathway, they have not been studied in the hippocampus in association with visuo-spatial memory impairments. The purpose of the present study is to examine whether the expression level of ERM proteins in the hippocampus is changed by an intrastriatal injection of 6-hydroxydopamine (6-OHDA) in mice. The intrastriatal injection of 6-OHDA induced partial dopaminergic deficits and spatial memory impairments. We also found that ezrin was increased in the hippocampus by the microinjection of 6-OHDA. On the other hand, protein levels of radixin and moesin were not influenced by 6-OHDA lesions. These results suggest that excessive ezrin may be related to visuo-spatial memory impairments.

Macroprolactinaemia in patients with hyperprolactinaemia: composition of macroprolactin and stability during long-term follow-up.

OBJECTIVE: Macroprolactin, which comprises immunoglobulin G (IgG) or anti-prolactin (PRL) autoantibody-bound PRL, is one of the causes of hyperprolactinaemia. This study evaluated the composition and stability of macroprolactin and determined whether the condition was long lasting. We also investigated whether we could predict the composition of macroprolactin based on the ratio of polyethylene glycol (PEG)-precipitable PRL. PATIENTS: Two hundred and ninety-two patients with hyperprolactinaemia (252 women and 40 men). DESIGN: We used PEG precipitation to screen for macroprolactinaemia in 625 serum samples from 292 patients with hyperprolactinaemia visiting a city hospital over the last 5·5 years. Macroprolactinaemia was defined by PEG-precipitable PRL ratio greater than 60%. IgG-bound PRL and anti-PRL autoantibodies were measured by protein G and (125) I-hPRL binding studies, respectively. We also examined the autoantibody specificity and binding characteristics. RESULTS: In 39 patients with macroprolactinaemia, IgG-bound PRL was present in 87% and anti-PRL autoantibodies in 67%. A non-IgG-bound form of macroprolactin was found mainly in sera with marginally elevated PEG-precipitable PRL. The higher the PEG-precipitable PRL ratio, the greater the likelihood that autoantibodies were involved in the composition of macroprolactin. The autoantibodies were IgG type and specific to human PRL and had a low affinity and high capacity. Long-term follow-up (2-17 years) revealed that the ratios of PEG-precipitable PRL, IgG-bound PRL and anti-PRL autoantibody-bound PRL were relatively stable. CONCLUSIONS: This study showed that higher PEG-precipitable PRL ratio in macroprolactinaemic sera might preferentially indicate the presence of anti-PRL autoantibodies and that macroprolactinaemia might be a long-lasting condition.

Re-evaluation of serum leptin and adiponectin concentrations normalized by body fat mass in patients with rheumatoid arthritis.

Leptin and adiponectin are produced mainly in adipocytes and classified as adipocytokines because of their possible involvement in inflammation and immunity. The aim of this study was to elucidate the relationships of these adipocytokines with the disease activities of RA. We examined leptin and adiponectin concentrations and inflammatory markers such as metalloproteinase-3 (MMP-3) in 136 patients with rheumatoid arthritis (RA) (26 males and 110 females, 69.6 ± 9.3 years) and 78 controls (36 males and 42 females, 66.7 ± 15.0 years). Serum leptin and adiponectin concentrations correlated positively (r = 0.565, P < 0.001) and negatively (r = -0.331, P < 0.001) to the amount of body fat, respectively. Serum leptin and adiponectin concentrations normalized by body fat mass were significantly higher in RA than those in controls [leptin, 1.24 (median) ng/mL/kg fat in RA vs. 0.76 ng/mL/kg fat in controls; adiponectin, 0.74 µg/mL/kg fat in RA vs. 0.44 µg/mL/kg fat in controls]. Normalized adiponectin concentrations correlated positively not only to the degree of bone destruction in Steinbrocker classification but also to serum MMP-3 concentrations. Normalized leptin concentrations did not correlate to the degree of bone destruction. We conclude that adiponectin but not leptin may be involved in joint damage in RA.

Macroprolactinaemia: prevalence and aetiologies in a large group of hospital workers.

OBJECTIVE: Macroprolactinaemia is one of the causes of hyperprolactinaemia and often leads to misdiagnosis and inappropriate treatment, but the aetiologies are unclear. The objective of the study was to determine the prevalence of macroprolactinaemia in a healthy population and to investigate the mechanisms underlying the development of macroprolactin. DESIGN: Observational study of the prevalence, causes, mechanisms and diagnosis of disease using excess sera after hepatitis B virus screening tests at a hospital in Japan. PARTICIPANTS: A total of 1330 hospital workers (1010 women and 320 men) participated in this study. MEASUREMENTS: Macroprolactinaemia was screened using the polyethylene glycol (PEG) precipitation method. Sera containing macroprolactin were further examined by binding studies for possible aetiologies. RESULTS: Of the 1330 subjects, 49 (3.68%) were diagnosed with macroprolactinaemia. The frequency of hyperprolactinaemia in untreated samples in subjects with macroprolactinaemia (30.6%) was significantly higher than in individuals without macroprolactinaemia (2.26%). Of the 49 subjects with macroprolactinaemia, all had a normal monomeric PRL concentration following PEG removal of macroprolactin. Of 44 hyperprolactinaemias found, 15 (34.1%) had macroprolactinaemia. IgG-bound prolactin was detected in all sera containing macroprolactin. The levels of IgG-bound prolactin positively correlated with those of macroprolactin, suggesting that IgG-bound prolactin forms macroprolactin. Approximately three quarters of the subjects with macroprolactinaemia had anti-prolactin autoantibodies. Glycosylation, aggregation and covalent/noncovalent binding were also involved in the formation of macroprolactin. CONCLUSIONS: Macroprolactinaemia is a common disorder and causes hyperprolactinaemia in a healthy population. The major aetiology of macroprolactin in our subjects was complexes of prolactin-IgG comprising mainly anti-prolactin autoantibodies, and other minor complex prolactin species.

Anti-prolactin (PRL) autoantibodies suppress PRL bioactivity in patients with macroprolactinaemia.

OBJECTIVE: Macroprolactinaemia, mainly caused by anti-prolactin (PRL) autoantibodies, is frequently found in patients with hyperprolactinaemia. Characteristically, these patients lack clinical symptoms of hyperprolactinaemia, but the serum bioactive PRL concentrations in vitro measured by the Nb2 bioassay are usually high. In this study, we investigated the causes of the discrepancy and the true biological features of macroprolactin. SUBJECTS AND METHODS: Sixteen patients with macroprolactinaemia due to anti-PRL autoantibodies were studied. PRL bioactivity was determined by the phosphorylation of signal transducer and activator of transcription (Stat)5 in T47D human breast cancer cells and the proliferation of Nb2 rat lymphoma cells. RESULTS: PRL bioactivity by the T47D bioassay, expressed as the density of the band of phosphorylated Stat5/immunoreactive PRL, was significantly lower in sera containing anti-PRL autoantibodies (2.4 +/- 1.1) than in control sera (7.2 +/- 3.1). Dissociation of PRL from the autoantibodies by acidification resulted in an increase in phosphorylated Stat5. PRL bioactivity by the Nb2 bioassay was not significantly different between sera with and without anti-PRL autoantibodies, and free PRL in the medium gradually increased during the incubation in a time-dependent manner in sera containing anti-PRL autoantibodies. CONCLUSIONS: We conclude that the level of bioactivity of macroprolactin in the Nb2 bioassay is normal due to dissociation of PRL from the autoantibodies as a result of the longer incubation and more dilute assay conditions than in the T47D bioassay. The bioactivity of macroprolactin is low in vivo due to anti-PRL autoantibodies, but monomeric PRL dissociated from the autoantibodies retains full biological activity in patients with macroprolactinaemia.

Electrophysiological features of late-onset transthyretin Met30 familial amyloid polyneuropathy unrelated to endemic foci.

BACKGROUND: Through the development of gene diagnostic techniques, late-onset transthyretin Met30-associated familial amyloid polyneuropathy (FAP TTR Met30) has been shown to be more prevalent than is generally believed. OBJECTIVE: To examine the electrophysiological features of late-onset FAP TTR Met30 unrelated to endemic foci. METHODS: Nerve conduction findings in 44 cases with an onset of more than 50 years of age in a non-endemic area were assessed and compared with findings from 21 earlier-onset cases related to endemic foci. RESULTS: The extent of the reduction of the compound muscle action potential and, especially, the sensory nerve action potential was more profound in the late-onset group even when the decline of these indices with aging in normal control subjects was taken into account. The feature of predominant lower-limb involvement seemed to be more conspicuous in the late-onset group. Electrophysiological indices tended to be aggravated as the duration of neuropathic symptoms increased in the early-onset group, while most of these indices in the lateonset group did not show this correlation. A slowing of conduction velocity and a prolongation of distal latency, which suggests demyelination, were conspicuous in some patients. Pathologically, a predominant loss of small-fibers was not conspicuous in sural nerve biopsy specimens from late-onset patients. Large myelinated fiber density showed a negative correlation with the disease duration in early-onset cases, but not in late-onset cases. CONCLUSIONS: Electrophysiological differences between late- and early-onset cases were present, probably reflecting the different underlying pathogenic mechanisms of neuropathy. The demyelinating feature does not exclude the possibility of this disease.