Serum bilirubin concentration in patients with amyotrophic lateral sclerosis

Oxidative stress plays probably an important role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). It is known that bilirubin (BR) is an endogenous antioxidant. The aim of this study was to evaluate serum BR concentration in ALS patients. BR was determined by automated analyzer in the serum from 30 ALS and 26 healthy control group people. The study showed that serum BR concentration is significantly decreased in ALS patients with a long duration of ALS compared with patients with a short duration (P<0.05), and it is also significantly decreased in ALS patients with a moderate clinical state compared with control group patients (P<0.05). There was no significant difference in BR concentration between the groups of patients classified according to their age and sex, the clinical state, and the type of ALS onset (P>0.05). Results suggest a possibility of endogenous antioxidant system dysfunction in later phase of ALS. A decrease in BR concentration might diminish its protective effect against oxidative injury and could accelerate motor neuron degeneration.     

Affective instability and impulsivity in borderline personality and bipolar II disorders: similarities and differences

Objectives: many studies have reported a high degree of comorbidity between mood disorders, among which are bipolar disorders, and borderline personality disorder and some studies have suggested that these disorders are co-transmitted in families. However, few studies have compared personality traits between these disorders to determine whether there is a dimensional overlap between the two diagnoses. The aim of this study was to compare impulsivity, affective lability and intensity in patients with borderline personality and bipolar II disorder and in subjects with neither of these diagnoses. Methods: patients with borderline personality but without bipolar disorder (n=29), patients with bipolar II disorder without borderline personality but with other personality disorders (n=14), patients with both borderline personality and bipolar II disorder (n=12), and patients with neither borderline personality nor bipolar disorder but other personality disorders (OPD; n=93) were assessed using the Affective Lability Scale (ALS), the Affect Intensity Measure (AIM), the Buss–Durkee Hostility Inventory (BDHI) and the Barratt Impulsiveness Scale (BIS-7B). Results: borderline personality patients had significantly higher ALS total scores (P<0.05) and bipolar II patients tended to have higher ALS scores than patients with OPD (P<0.06). On one of the ALS subscales, the borderline patients displayed significant higher affective lability between euthymia and anger (P<0.002), whereas patients with bipolar II disorder displayed affective lability between euthymia and depression (P<0.04), or elation (P<0.01) or between depression and elation (P<0.01). A significant interaction between borderline personality and bipolar II disorder was observed for lability between anxiety and depression (P<0.01) with the ALS. High scores for impulsiveness (BISTOT, P<0.001) and hostility (BDHI, P<0.05) were obtained for borderline personality patients only and no significant interactions between diagnoses were observed. Only borderline personality patients tended to have higher affective intensity (AIM, P<0.07). Conclusions: borderline personality disorder and bipolar II disorder appear to involve affective lability, which may account for the efficacy of mood stabilizers treatments in both disorders. However, our results suggest that borderline personality disorder cannot be viewed as an attenuated group of affective disorders.     

Prostaglandin E2 is increased in amyotrophic lateral sclerosis patients

OBJECTIVES: Oxidative stress and glutamate-mediated excitotoxicity may play an important role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). Prostaglandin E2 (PGE2) activity can be associated with motor neuron death by inducing free radical formation and glutamate release from astrocytes. The aim of this study was to determine PGE2 concentration in the serum and cerebrospinal fluid (CSF) of ALS patients. MATERIAL AND METHODS: PGE2 concentration was measured by the enzyme-linked immunosorbent method in the serum and CSF from ALS and control group patients. RESULTS: Serum and CSF PGE2 concentration was significantly higher in the whole group of ALS patients compared with the control group patients (P < 0.05). There was no relationship between PGE2 concentration and clinical parameters of the disease, such as clinical state, type of ALS onset, and duration of the disease (P > 0.05). A significant correlation between CSF PGE2 concentration and age of control group patients was found (P < 0.05). CONCLUSIONS: A significant increase in serum and CSF PGE2 concentration, in ALS patients observed in this study, indicates that PGE2 may play a role in neurodegeneration of ALS through oxidative damage of neurons and glutamate-mediated excitotoxicity. It suggests that inhibition of PGE2 synthesis could prevent motor neuron death. However, serum and CSF PGE2 cannot be a marker of the type of ALS onset, clinical state of patients, or the duration of the disease.     

Low concentrations of glutamate induce apoptosis in cultured neurons: implications for amyotrophic lateral sclerosis

Evidence is accumulating that excessive glutamate concentration in the extracellular space is neurotoxic and plays a role in amyotrophic lateral sclerosis (ALS). However, the published results on glutamate levels in cerebrospinal fluid (CSF) and on glutamate-mediated toxicity of CSF in ALS disease remain controversial. In this report, we studied CSF from patients with sporadic ALS and controls to determine glutamate concentrations, and then analyzed the neurotoxic effect of glutamate at the concentrations present in CSF from ALS patients on cultured cortical neuronal cells. Our study shows that glutamate, at the concentrations found in CSF from ALS patients (5.8 microM), diminished cell viability and increased apoptosis determined by the fluorescent DNA-binding dye Hoechst 33342 as well as by Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP Nick End-Labeling (TUNEL) reaction in cultured neuronal cells. However, glutamate concentrations as those found in CSF from controls (2.8 microM or below) did not induce any effect. Both significant glutamate-induced effects were inhibited in the presence of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate-sensitive glutamate receptor antagonist. These results demonstrate that AMPA/kainate receptors are involved in the glutamate-mediated neurotoxic effects on cultured neurons, according to reports that implicate these receptors in ALS disease. We conclude that the glutamate-mediated neuronal apoptosis through AMPA/kainate receptors could occur in ALS patients who have elevated CSF glutamate concentration.     

Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive cell death of upper and lower motor neurons. In this study, we measured monocyte chemotactic protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) levels in cerebrospinal fluid (CSF) and serum by enzyme-linked immunosorbent assay (ELISA) in 42 ALS patients, and compared these levels with those of control subjects with other neurodegenerative disorders or with those of normal controls. MCP-1 levels in CSF were significantly higher in ALS patients than in the control group. VEGF levels in CSF tended to be lower in ALS patients than in the control group, but not significantly. A positive correlation was found between MCP-1 levels in CSF of ALS patients and the total Norris scale. The elevation of MCP-1/VEGF ratio in CSF was more specific to ALS patients compared to other neurological diseases such as Parkinson's disease (PD) and spinocerebellar ataxia (SCA) and to controls. Our data suggested that both MCP-1 levels and MCP-1/VEGF ratio in CSF may be useful markers for the clinical diagnosis of ALS.     

Nerve growth factor in never-medicated first-episode psychotic and medicated chronic schizophrenic patients: possible implications for treatment outcome

Nerve growth factor (NGF) has been found to play a crucial role in the neuroplasticity of predominantly cholinergic neurons in brain development, and neuronal survival following brain injury, which reflect in cognitive performance. Wide ranges of neurodevelopmental abnormalities have been reported in schizophrenic patients, who also show poor cognitive performance. We report plasma NGF levels in never-medicated first-episode psychotic (FEP; N=24) and chronic medicated schizophrenic patients (N=24). NGF levels were determined in plasma by Enzyme-Linked ImmunoSorbent Assay (ELISA). Plasma NGF levels were significantly lower in both FEP and medicated chronic patients as compared to normal subjects (P<0.001). However, NGF levels were significantly higher in chronic schizophrenic patients, which were treated with antipsychotics as compared to FEP (P<0.05). Moreover, NGF levels in chronic patients treated with atypical antipsychotics were markedly higher as compared to patients treated with typical antipsychotics (P<0.05). Lower NGF levels in FEP patients at the onset of psychosis may have implications for the neurodevelopmental abnormalities. However, higher NGF levels in chronic patients treated with atypical antipsychotics may have implications for the treatment outcome.     

Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive cell death of upper and lower motor neurons. In this study, we measured monocyte chemotactic protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) levels in cerebrospinal fluid (CSF) and serum by enzyme-linked immunosorbent assay (ELISA) in 42 ALS patients, and compared these levels with those of control subjects with other neurodegenerative disorders or with those of normal controls. MCP-1 levels in CSF were significantly higher in ALS patients than in the control group. VEGF levels in CSF tended to be lower in ALS patients than in the control group, but not significantly. A positive correlation was found between MCP-1 levels in CSF of ALS patients and the total Norris scale. The elevation of MCP-1/VEGF ratio in CSF was more specific to ALS patients compared to other neurological diseases such as Parkinson's disease (PD) and spinocerebellar ataxia (SCA) and to controls. Our data suggested that both MCP-1 levels and MCP-1/VEGF ratio in CSF may be useful markers for the clinical diagnosis of ALS.     

Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis

Excitotoxicity may play a role in certain disorders of the motor system thought to be caused by environmentally acquired toxins, including lathyrism and domoic acid poisoning. Motor neurons appear to be particularly susceptible to toxicity mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-kainate receptors. There is a body of evidence implicating glutamatergic toxicity as a contributory factor in the selective neuronal injury occurring in amyotrophic lateral sclerosis (ALS). Interference with glutamate-mediated toxicity is so far the only neuroprotective therapeutic strategy that has shown benefit in terms of slowing disease progression in ALS patients. Biochemical studies have shown decreased glutamate levels in central nervous system (CNS) tissue and increased levels in the cerebrospinal fluid (CSF) of ALS patients. CSF from ALS patients is toxic to neurons in culture, apparently via a mechanism involving AMPA receptor activation. There is evidence for altered expression and function of glial glutamate transporters in ALS, particularly excitatory amino acid transporter 2 (EAAT2). Abnormal splice variants of EAAT2 have been detected in human CNS. Mitochondrial dysfunction may contribute to excitotoxicity in ALS. Induction of neuronal nitric oxide synthase and cyclooxygenase 2 in ALS may also lead to significant interactions with regulation of the glutamate transmitter system. Certain features of motor neurons may predispose them to the neurodegenerative process in ALS, such as the cell size, mitochondrial activity, neurofilament content, and relative lack of certain calcium-binding proteins and molecular chaperones. Motor neurons appear vulnerable to toxicity mediated by calcium-permeable AMPA receptors. The relatively low expression of the glutamate receptor 2 (GluR2) AMPA receptor subunit and the high current density caused by the large number and density of cell surface AMPA receptors are potentially important factors that may predispose to such toxicity.     

Amyotrophic lateral sclerosis: unusually low content of collagen in skin

The skin tissues from patients with amyotrophic lateral sclerosis (ALS) and controls were studied by electron microscopy, and their amino acid compositions were examined. On electron microscopy, the most conspicuous findings in ALS were (1) a marked increase in amorphous material separating collagen bundles, and (2) the smaller diameter of collagen fibrils. These were more marked with longer duration of illness. Amino acid analysis showed that the levels of hydroxyproline, hydroxylysine, and glycine were significantly low (P < 0.001, < 0.01, andP < 0.001, respectively) in ALS patients as compared with those of controls, and there was a significant negative correlation between the level of hydroxyproline and duration of illness in ALS patients (r = − 0.88,P < 0.01). In addition, the collagen content per dry weight (mg) of the tissues in ALS was significantly smaller (P < 0.001) than in controls. These results indicate that the metabolism of skin collagen might be affected in the disease process of ALS.     

Collagen abnormalities in the spinal cord from patients with amyotrophic lateral sclerosis

During the last 10 years, we have demonstrated morphological and biochemical abnormalities of skin extracellular matrices in amyotrophic lateral sclerosis (ALS). However, currently little is known concerning collagen of the spinal cord in ALS. We measured the amount of collagen and characterized collagen at light and electron microscopic levels in posterior funiculus, posterior half of lateral funiculus and anterior horn of cervical enlargement of the spinal cord obtained from ten patients with ALS, 11 patients with other neurologic diseases (control group A), and ten patients without neurologic ones (control group B). In posterior half of lateral funiculus and anterior horn, (1) by light microscopy, there was no significant difference in vessel wall area between ALS patients and control groups A and B; (2) ultrastructurally, collagen bundles were more fragmented and widely separated, and the fibrils were randomly oriented in the perivascular space of capillaries in ALS patients, which were not observed in any areas of control groups or in posterior funiculus of ALS patients; and (3) the collagen contents in ALS were significantly lower (P<0.001 and P<0.001, respectively) than those in control groups A and B. Fragmented and widely separated collagen bundles in the interstitial tissue surrounding capillaries and markedly decreased amount of collagen in posterior half of lateral funiculus and in anterior horn of ALS could be related to the degeneration of the upper and lower motor neurons in the spinal cord in ALS, that is, selective neuronal vulnerability in ALS.     

Elevated inflammatory parameters are associated with lower platelet density in acute myocardial infarctions with ST-elevation

Objective: Platelets and granulocytes play important roles in coronary disorders. We therefore, investigated platelet and granulocyte alterations in myocardial infarctions (MIs). Patients and study design: A total of 36 individuals having MI with raised ST-segments who were receiving thrombolytic therapy were studied. Sampling was carried out after thrombolysis within 24 h after hospital admission. After 3 to 6 months of recovery, 25 patients were reinvestigated. At the infarction, peak platelet density was determined using a special designed computerised apparatus. In addition, we did counts on platelets, neutrophils and monocytes. Moreover, plasma levels of soluble P-selectin, myeloperoxidase and interleukin 6 were determined to estimate the degree of platelet, neutrophil and monocyte activation, respectively. Peak platelet density was analysed at the MI. All other parameters were determined at the acute event and at recovery. Results: At the MI, compared to the recovery, platelet counts were lower (P<.001). In addition, increased neutrophil counts (P<.001), elevated monocyte counts (P<.001), enhanced myeloperoxidase (P<.001) and interleukin 6 (P<.001) levels were demonstrated. We failed to show elevated soluble P-selectin. Compared to individuals with ST-segment elevations and low platelet density (≤1.058 kg/l), patients having peak platelet densities >1.058 kg/l displayed lower neutrophil counts (P<.01) and decreased interleukin 6 levels (P<.01). Furthermore, we demonstrate that individuals with higher inflammatory response at the MI had higher neutrophil (r=.6; P<.01) and higher monocyte counts (r=.6; P<.001) at recovery. Conclusion: We conclude that MI is associated with an inflammatory response. However, a subgroup of patients having MI with ST-elevations and low peak platelet density was identified. Compared to subjects with higher platelet density, they had more severe inflammatory characteristics. The differences persisted during recovery.     

Albumin and immunoglobulin in plasma and cerebrospinal fluid, and blood-cerebrospinal fluid barrier function in patients with dementia of alzheimer type and multi-infarct dementia

Plasma and cerebrospinal fluid (CSF) from 20 patients with Alzheimer's dementia or senile dementia of Alzheimer type (AD/SDAT), 23 with multi-infarct dementia (MID) and 16 controls were assayed for their content of immunoglobulins (Ig) and albumin (Alb). The concentrations of IgG and Alb were used to analyze the blood-CSF barrier function in the respective group.

MID patients had significantly (P < 0.001) elevated plasma IgG levels compared to controls and AD/SDAT patients. CSF concentration of Alb was significantly higher in MID (P < 0.01) and AD/SDAT (P < 0.05) patients compared to the controls. Concentration of CSF IgG was significantly (P < 0.05) lower in AD/SDAT patients compared to the MID patients; no significant differences were found when CSF concentrations of IgG of demented patients were compared to controls. These findings may indicate a blood-CSF barrier dysfunction especially in cases with MID with significantly (P < 0.001) elevated values of transudation. Also these findings indicate a non-specific and/or specific binding of IgG in CNS tissue and/or vessel walls in both forms of dementia on the basis of low IgG ratios compared to proportionally higher Alb ratios.

There were no signs of local synthesis of IgG in CNS in either group of demented patients.     

The split hand in ALS has a cortical basis

Loss of highly fractionated movement involving the thumb and index finger is an early characteristic of hand dysfunction in many ALS patients. These movements are largely subserved by the ‘thenar complex’ including the first dorsal interosseus muscle (FDI), whereas the ‘hypothenar complex’, innervated by the same myotome, has less ability to fractionate and is relatively spared. This suggests that in ALS, hand dysfunction and wasting is related to corticomotoneuronal representation and input. To determine whether corticomotoneuronal input to the thenar spinal pool is preferentially impaired compared to the hypothenar spinal pool in ALS, we studied 18 ALS patients and 11 normal subjects. Compound muscle action potentials (CMAPs) and motor evoked potentials (MEPs) of the thenar and hypothenar complexes were evoked by peripheral nerve stimulation and transcranial magnetic stimulation. In healthy control subjects the cortical/peripheral (MEP/CMAP) ratios were significantly larger for the thenar complex suggesting a stronger corticomotoneuronal input to this muscle complex (P<0.005). This was not the case in ALS patients. Comparing the ratios between control subjects and patients revealed a significant reduction for the thenar complex (P<0.02) in ALS patients but not for the hypothenar complex. We conclude that corticomotoneuronal input to the thenar complex is preferentially affected in ALS and that corticomotoneuronal disease may be the prime determinant of hand dysfunction and wasting.     

Paradoxical response of VEGF expression to hypoxia in CSF of patients with ALS

Vascular endothelial growth factor (VEGF) is implicated in motor neurone degeneration. In normal individuals, hypoxia is known to induce an overexpression of VEGF, as measured in CSF. We show that patients with ALS do not manifest this VEGF overexpression in the presence of hypoxia. Although VEGF gene expression is mainly stimulated by hypoxia, we have measured lower VEGF levels in cerebrospinal fluid (CSF) from hypoxaemic patients with amyotrophic lateral sclerosis (ALS) than in CSF from normoxaemic patients with ALS. In contrast, hypoxaemic neurological controls displayed higher levels than normoxaemic neurological controls. There was a negative correlation between VEGF levels and the severity of hypoxaemia in patients with ALS, suggesting deregulation of VEGF in ALS.     

An exploratory study of serum urate levels in patients with amyotrophic lateral sclerosis

Urate is a natural antioxidant, and high serum urate levels could be protective against the development of amyotrophic lateral sclerosis (ALS). To determine if serum urate concentrations were lower in ALS patients than in healthy controls, we compared serum urate levels in 132 ALS patients and 337 age/sex-matched controls. Median urate levels were lower in ALS patients compared to controls (4.2mgl/dL [range:1.4–8.2], vs. 4.7 [1.7–13.1]; p = 0.04). In univariate analysis, high urate levels were less likely to be associated with ALS (odds ratio [OR]: 0.53; 95% CI: 0.29–0.97; p = 0.04), but after adjusting for age, sex and kidney function, the association was not statistically significant (OR: 0.63; 95% CI: 0.32–1.24; p = 0.18). Urate levels were lower in bulbar-onset ALS (3.9 mg/dL), compared to limb-onset ALS (4.3; p = 0.001), and in cases with longer disease duration compared to controls (4.1 mg/dL, vs. 4.7; p = 0.01). In this cross-sectional study, lower levels of serum urate were evident in ALS cases with bulbar-onset and longer disease duration, but were likely to be related to the malnutrition induced by ALS.     

Cerebrospinal fluid Flt3 ligand level in patients with amyotrophic lateral sclerosis

OBJECTIVES: The Flt3 ligand (FL) is a cytokine with a neurotrophic and antiapoptotic activity in the central nervous system that induces the survival of neurons. The aim of the study was to measure levels of FL in amyotrophic lateral sclerosis (ALS) patients. MATERIALS AND METHODS: The study involved 23 ALS patients and 23 people in the control group. The measurement of FL in the cerebrospinal fluid (CSF) and serum was performed by the enzyme-linked immunosorbent method. RESULTS: Results showed that CSF FL levels were significantly increased in ALS patients compared with the controls (P < 0.05) but the serum levels of this cytokine did not differ from the controls (P > 0.05). There was no significant correlation between CSF and serum FL levels and clinical parameters of ALS (P > 0.05). The difference in CSF/serum ratio of FL between ALS patients and controls was not statistically significant (P > 0.05). CONCLUSION: An increase in CSF FL levels in ALS patients, observed in this study, could be a compensative response for neurodegeneration but may also reflect increased diffusion of this cytokine into the central nervous system caused by blood-CSF barrier dysfunction.     

Luteinizing hormone-releasing hormone gene expression differs in young and middle-aged females on the day of a steroid-induced LH surge

LHRH mRNA levels were examined in young and middle-aged female rats at 4 times (10:00 h, 14:00 h, 18:00 h and 20:00 h) on the day of a steroid-induced LH surge by in situ hybridization with a digoxigenin-labeled riboprobe. Young, but not middle-aged females, exhibited dynamic temporal changes in the number of LHRH mRNA positive neurons detected in the organum vasculosum of the lamina terminalis–preoptic area (OVLT–POA) continuum. Specifically, fewer LHRH mRNA positive neurons were detected at 18:00 h compared with the number detected at 14:00 h and 20:00 h (P<0.01) in the OVLT–POA of young females. All LHRH mRNA positive neurons present in 4 anatomically matched sections through the rostral POA of young and middle-aged animals were digitized for detailed computer-assisted analysis of the hybridization reaction product. The mean hybridization area (P<0.00025) and integrated optical density per cell (P<0.006) were reduced in middle-aged compared to young females consistent with a relative age-related decline in LHRH mRNA levels. Moreover, an age-related reduction in cellular and/or regional hybridization area was noted at each of the time points examined (P<0.05–P<0.001). These data confirm earlier reports of dynamic changes in LHRH mRNA levels on the day of an LH surge. Furthermore, they support a role for age-related alterations in LHRH gene expression in the disruption of regular estrous cyclicity in middle-aged females.     

Beneficial effect of ginseng root in SOD-1 (G93A) transgenic mice

Many patients with amyotrophic lateral sclerosis (ALS; motor neuron disease) use natural or traditional therapies of unproven benefit. One such therapy is ginseng root. However, in some other disease models, ginseng has proven efficacious. Ginseng improves learning and memory in rats, and reduces neuronal death following transient cerebral ischemia. These effects of ginseng have been related to increases in the expression of nerve growth factor and its high affinity receptor in the rat brain, and antioxidant actions, inter alia. Since such actions could be beneficial in ALS as well, we studied the effect of ginseng (Panax quinquefolium), 40 and 80 mg/Kg, in B6SJL-TgN(SOD1-G93A)1Gur transgenic mice. The ginseng was given in drinking water, from age 30d onwards. We measured the time to onset of signs of motor impairment, and survival. There was no difference between the two ginseng groups (n=6, 6) in either measure. However, compared to controls (n=13), there was a prolongation in onset of signs (116d vs. 94d, P<0.001), and survival (139d vs. 132d, P<0.05). These experiments lend support to the use of ginseng root in ALS. Future experiments using this model could examine for symptomatic effects of ginseng, measure the effect of specific ginsenosides (which differ between ginseng species), and elucidate their mechanisms of action.     

Differences in clinical features between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of 227 published cases

To compare the clinical features of patients with the Lambert-Eaton myasthenic syndrome (LEMS) associated with carcinoma, with patients having LEMS but no cancer, reports on LEMS patients were analyzed systematically. Cancer was detected (CD group) in 62% of the 227 included cases. This CD group showed a male predominance (70%). No sex difference was found in patients in whom no cancer was detected (NCD group). Median age at onset of LEMS in the CD group was higher than in the NCD group (58 and 49.5 years, P<0.01). Median interval between onset of symptoms and diagnosis of LEMS was longest in NCD cases (P<0.001). CD patients had additional immunological disorders less frequently than NCD cases (6 and 27%, P<0.001). Symptoms distinguishing the CD group from the NCD group were weight loss (P<0.001) and need for prolonged artificial ventilation after anaesthesia (P<0.05). This analysis shows significant differences between CD and NCD cases of LEMS. The male predominance and higher age at onset in patients with a tumor probably reflects the characteristics of patients with small cell lung cancer. The high frequency of additional immunological disorders in patients without malignancy, together with the younger age at onset suggests a similar etiology as other non-paraneoplastic autoimmune diseases.