Sequencing analysis of the human glucocorticoid receptor (NR3C1) gene in multiple sclerosis patients.

Various specific human glucocorticoid receptor (NR3C1) gene polymorphisms have been described in multiple sclerosis (MS) patients and correlated with disease progression, susceptibility and aggressiveness. Herein, we investigated the presence of gene alterations in the entire coding region of the NR3C1 in MS patients of variable clinical status (CIS, RRMS and SPMS) and the association(s) of these alterations with severity of disease (EDSS), response to glucocorticoid (GC) treatment and clinical improvement. Sixty Caucasian Greek MS patients were included. Sequencing the coding sequences and intron-exon boundaries of the NR3C1 did not reveal the presence of mutation(s) in any of the MS patients. Three previously described polymorphisms were detected: p.N363S (rs6195), p.N766N (rs6196) and c.1469-16G>T (rs6188). None of the identified alleles/genotypes were found to be associated with the severity of disease, response to glucocorticoids and disease subtypes. Known polymorphism, such as ER22/23EK that has been previously detected in MS patients, was not detected. There is a considerable ethnicity-related variation in the frequency of the NR3C1 polymorphisms. Although a genetic basis of the glucocorticoid sensitivity exists in healthy population, in the presence of chronic inflammation and abundance of cytokines--such in MS patients--other factors appear to play a more important role in GC sensitivity.

Neurochemical and neuroendocrine correlates of overactive bladder at first demyelinating episode.

AIMS: Bladder dysfunction is frequent during the course of multiple sclerosis (MS), observed in up to 75% of patients. Urinary symptomatology can be a feature of the first episode of MS in a minority of cases, and most often shows characteristics of an overactive bladder (OAB), with voiding symptoms seen less frequently, often in combination with OAB. The neural control of micturition is complex, involving systems located in the brain, spinal cord, and periphery, and implicating central noradrenergic, serotonergic, and dopaminergic activities. Urinary disorders are also linked to anxiety and depression, conditions connected to hypothalamus-pituitary-adrenal axis activity. In this study we aimed to investigate neurochemical and neuroendocrine correlates of bladder dysfunction in early MS. METHODS: We included 101 patients at first demyelinating episode suggestive of MS that were drug-free at assessment. We evaluated the presence of urinary symptomatology and estimated CSF levels of the main metabolites of noradrenaline, serotonin, and dopamine, as well CSF-ACTH and serum cortisol. RESULTS: In total, 15 patients (15%) reported urinary dysfunction suggestive of OAB. Four of these had coexistent voiding symptomatology. The serotonin metabolite 5-HIAA was significantly reduced (P = 0.017) in patients with OAB syndrome, while there were no differences in the metabolites of noradrenaline (MHPG) and of dopamine (HVA). Additionally, significantly lower serum cortisol (P = 0.009) and borderline lower CSF-ACTH (P = 0.08) were found in patients with OAB. CONCLUSIONS: MS patients with OAB syndrome at the first demyelinating episode show reductions in central serotonergic activity and stress hormones. Whether the same changes persist at later disease stages remains to be investigated. Neurourol. Urodynam. 35:955-958, 2016. © 2015 Wiley Periodicals, Inc.

Body Mass Index in Multiple Sclerosis: Associations with CSF Neurotransmitter Metabolite Levels.

Body weight and height of patients with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome suggesting MS (CIS) in the age range 18 to 60 years (154 males and 315 females) were compared with those of subjects (146 males and 212 females) free of any major neurological disease. In drug-free patients, CSF levels of the metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA), neurotransmitters involved in eating behavior, were estimated in searching for associations with body mass index (BMI). Statistical evaluations were done separately for males and females. Lower BMI was found in female MS patients compared to female controls, more pronounced in RRMS. BMI was not associated with duration of illness, smoking, present or previous drug treatment, or disability score. Body height showed a shift towards greater values in MS patients compared to controls. Patients in the lower BMI quartile (limits defined from control subjects) had lower 5-HIAA and HVA compared to patients in the upper quartile. The results provide evidence for weight reduction during disease process in MS, possibly related to deficits in serotoninergic and dopaminergic activities that develop during disease course, resulting in impairments in food reward capacity and in motivation to eat.

Plasma homocysteine levels in patients with multiple sclerosis in the Greek population.

BACKGROUND: In recent years, there has been increasing interest in the role of plasma homocysteine (Hcy) as a possible risk factor for several diseases of the central nervous system. The aim of this study was to determine the plasma levels of Hcy in a group of multiple sclerosis (MS) patients from a Greek population and the possible correlation with age, disability status, activity or duration of disease, sex, and treatment. METHODS: The MS group that was studied consisted of 46 patients and a total of 42 healthy individuals served as a control group. Plasma Hcy levels were determined by means of high-performance liquid chromatography coupled with fluorescence detection, after precolumn derivatization with 4-Fluoro-7-aminosulfonylbenzofurazan (ABD-F). RESULTS: Statistical analysis revealed that, in the MS patients, Hcy levels were not significantly different as compared to those in the controls. Men presented with higher Hcy levels than women in the MS group; however, age, disease subtype, disease duration, relapse rate, and Expanded Disability Status Scale score/Multiple Sclerosis Severity Score did not significantly affect Hcy levels in MS patients. CONCLUSION: The preliminary data suggest that Hcy levels were not elevated in our sample of Greek MS patients, which does not support previous findings of a significant correlation between elevated serum Hcy levels and MS. Further studies to establish a possible association between MS and Hcy levels in the context of different ethnic groups with different habits are needed.

Evidence for involvement of central noradrenergic activity in crying proneness.

Crying as a response to emotionally-charged situations varies greatly among individuals, genders, and cultures. Information on the neural systems involved in crying behavior comes mainly from studies of pathological laughing and crying in patients after brain injury. The authors assessed crying proneness (CPR) as expressed by the score on the "crying easily" item of the SCL-90 questionnaire in 65 men and 105 women subjects in whom lumbar puncture was performed for diagnostic reasons. None of the subjects showed pathological laughing or crying. The authors estimated the levels of the main metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA) in CSF, and searched for associations to CPR score. Subjects with high CPR showed significantly lower MHPG levels than subjects with low CPR, and no differences in 5-HIAA or HVA levels. Higher frequencies of women were found in the subgroups with high CPR. The "crying easily" score was positively associated with the Interpersonal Sensitivity subscale of the SCL-90 questionnaire in female but not in male subjects, indicating the cultural dimension of crying behavior, while it was not associated with the Depression subscale score. It is suggested that central noradrenergic mechanisms control the threshold for tear production in normal crying behavior.

Serum total cholesterol correlates positively to central serotonergic turnover in male but not in female subjects.

Reduced central serotonergic activity and low total serum cholesterol have been related to increased aggression, violent behavior, and suicidality. Searching for a correlation between them, we estimated serum total cholesterol and CSF levels of the main serotonin metabolite 5-HIAA in medication free male and female subjects for whom diagnostic lumbar puncture was performed. To eliminate age influence, we included in the study subjects in the age range 26 to 45years. In a group of 62 subjects (30 males), found negative after diagnostic neurological examination, the correlation was not significant for the whole group, but after sex stratification, a significant positive correlation was revealed for males but not for females. These results were replicated in a second group of 76 subjects (31 males) with clinical and laboratory findings suggestive of multiple sclerosis (clinically isolated syndrome). The results link low cholesterol to low serotonergic activity only in males, predisposing them for violent and risky behaviors. This phenomenon could be seen as an evolutionary trait, possibly a result of the distinct role of males in a hunter-gatherer environment of evolutionary adaptedness, and may contribute to the understanding of the higher incidence of violent behavior observed in males.

Familial asymmetric distal upper limb amyotrophy (Hirayama disease): report of a Greek family.

INTRODUCTION: Hirayama disease is a rare nonprogressive, predominantly unilateral, juvenile distal upper limb amyotrophy that involves C7, C8, and Th1 innervated muscles. The etiology and pathogenesis of this focal amyotrophy is presently unknown. There is a debate as to whether Hirayama disease is an unusual neck flexion induced cervical myelopathy or an intrinsic motor neuron disease. Despite being a sporadic disorder, familial forms have been occasionally described, with either autosomal recessive or dominant inheritance. CASE SERIES: We describe a 3-generation Greek family, with 4 members affected by a benign distal upper limb amyotrophy of long duration, reminiscent of Hirayama disease, suggesting an autosomal dominant inheritance pattern. Hypothesizing that this familial amyotrophy might be related to autosomal dominant distal spinal muscular atrophy type V(dSMA-V) that is characterized by prominent involvement of the distal upper extremities, we tested the index case for glycyl tRNA synthetase and Berardinelli-Seip congenital lipodystrophy (BSCL2) N88S and S90L gene mutations (by direct sequencing) that are involved in the development of dSMA-V phenotype. Despite the phenotypical similarity of this familial amyotrophy to dSMA-V, no missense mutation in the genes presently associated with it was detected. CONCLUSION: The reported family is the first in the literature with occurrence of Hirayama amyotrophy in 3 generations of a family. Considering that familial forms of Hirayama amyotrophy are uncommon, it could be assumed that they might represent a different subtype of the same disease having the same clinical features but different pathogenesis.

CSF neurotransmitter metabolites and neuropsychiatric symptomatology in patients with normal pressure hydrocephalus.

Patients with normal pressure hydrocephalus (NPH) may exhibit certain neuropsychiatric symptomatology, possibly related to alterations in central neurotransmitter activity. The aim of this study was to relate psychiatric distress, as expressed by the scores in the SCL-90 subscales, to CSF levels of the main metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA) in NPH patients. The metabolite levels were estimated in CSF samples taken during the tap test in 19 patients with probable NPH, and compared to 19 sex- and age-matched controls. Cognitive impairment was evaluated by the MMSE. Compared to controls, NPH patients had similar MHPG and 5-HIAA levels, and significantly elevated HVA levels, a notable difference from patients with dementias. There were no significant correlations of metabolite levels to the scores in the nine SCL-90 subscales. MMSE score was not related either to metabolite levels, or to the SCL-90 subscale scores. Patients scored higher than controls in most SCL-90 subscales, more pronounced being the difference in obsessive-compulsive symptomatology. Serotonergic neurotransmitter activity seems not to be altered in NPH patients, and this may explain the reported lack of beneficial effect of serotonergic drugs for obsessive-compulsive symptoms in NPH patients.

A novel heterozygous mutation in the NOTCH3 gene causing CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an identifiable cause of inherited stroke among young adults, characterised by diffuse leukoencephalopathy with prominent involvement of the temporal poles and external capsule. The disease is caused by mutations in the NOTCH3 gene encoding a NOTCH3 receptor protein. The clinical course is relentlessly progressive with early transient ischaemic attacks (TIA) or strokes, dementia and finally death in the mid-60s. We describe a 40-year-old patient with clinical features of CADASIL and a positive family history who was a carrier of a new mutation at the exon 4 of the NOTCH3 gene: C162R. Regardless of the distinctive clinical and neuroimaging features one of his siblings had been mistakenly diagnosed as suffering from multiple sclerosis (MS), suggesting that the disease can occasionally be misdiagnosed as MS.

Increased plasma homocysteine levels in patients with multiple sclerosis and depression.

BACKGROUND: The aim of the study was to assess the plasma levels of homocysteine in patients with multiple sclerosis (MS) and to investigate whether an association with depression exists. METHODS: Plasma homocysteine (Hcy), vitamin B12 and plasma folate were measured in 65 moderately disabled patients with relapsing/remitting MS (RR-MS) and 60 healthy controls. All subjects were assessed with the Beck Depression Inventory (BDI). RESULTS: Hcy levels were significantly increased in MS patients compared to controls (13.5 +/- 4.7 mumol/l vs 8.5 +/- 3.1, p < 0.001). A significant correlation was found between Hcy levels and BDI scores (Pearson r = 0.3025, p < 0.05). Plasma Hcy was not related to Extended Disability Status Scale (EDSS) score, age, disease duration or vitamin B12 and folate. CONCLUSION: Moderately disabled MS patients with elevated Hcy levels are particularly prone to develop depressive symptomatology. Further study is warranted in order to elucidate the prognostic and therapeutic implications of this novel finding.

Benign Raeder syndrome evolving into indomethacin-responsive hemicranial headache.

Benign Raeder syndrome is characterized by a self-limiting unilateral continuous headache associated with ipsilateral ptosis, miosis, and frequently, facial hypohydrosis. Hemicrania continua is a chronic, strictly unilateral continuous headache associated with ipsilateral cranial autonomic symptoms. We report a 50-year-old man who presented with benign Raeder syndrome, which evolved into an indomethacin-responsive hemicranial headache that resembled hemicrania continua.

Plasma glutamate and glycine levels in patients with amyotrophic lateral sclerosis.

Defective glutamate (Glu) metabolism and glutamate excitotoxicity have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Glycine (Gly), the main inhibitory neurotransmitter, has been shown to potentiate excitatory transmission. In the present study, the levels of Glu and Gly in fasting plasma were measured by high performance liquid chromatography (HPLC) in 20 healthy volunteers and in 65 untreated ALS patients. Increased plasma Glu levels were observed in ALS (p=0.05), correlating with longer disease duration (p=0.03, beta=0.34) and male gender (p=0.02). Furthermore, the increase was found only in the spinal subtype of the disease (p=0.03), while in the bulbar subtype, no significant increase was noted. As regards plasma Gly, no difference was observed between patients and controls; however female patients had higher levels than males. The above results are compatible with the "glutamate hypothesis" of ALS and suggest that the spinal and bulbar-onset subtypes of the disease may be biochemically different.

Plasma glutamate and glycine levels in patients with amyotrophic lateral sclerosis: the effect of riluzole treatment.

OBJECTIVES: Defective glutamate (glu) metabolism and excitotoxicity have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Moreover, glycine (gly) has been shown to potentiate excitatory transmission. The "antiglutamatergic" agent riluzole has been shown to prolong survival in ALS. The aim of the study was to investigate a possible effect of riluzole on plasma glu and gly levels, correlating with clinical response to treatment. PATIENTS AND METHODS: Plasma concentrations of glu and gly were measured in 20 healthy volunteers and 22 ALS patients before treatment and after 6 months on riluzole. RESULTS: At baseline, increased plasma glu correlated with spinal onset and male gender whereas gly levels did not differ between patients and controls. No significant change was observed for both amino acids post-treatment, despite a lower rate of disease progression. CONCLUSION: These results suggest that riluzole may affect disease progression without a significant impact on plasma glu and gly levels, possibly indicating different mechanisms of drug action.

Cerebrospinal fluid tau protein is increased in neurosyphilis: a discrimination from syphilis without nervous system involvement?

OBJECTIVE: The objective of this study was to investigate the levels of tau protein in neurosyphilis. STUDY DESIGN: Total tau protein in the cerebrospinal fluid of 12 patients with neurosyphilis, 17 with syphilis without nervous system involvement, 14 controls, and 14 patients with Alzheimer disease of comparable age were analyzed. Double-sandwich enzyme-linked immunosorbent assay was used for measurements. RESULTS: Increased levels of cerebrospinal fluid total tau were observed in neurosyphilis (median [25th-75th percentile]: 349 pg/mL [312-429]) and in Alzheimer disease (543 [441-1017]) as compared with the controls (189 [106-220]) and syphilis without nervous system involvement (190 [160-223]). Using a cutoff level of 300 pg/mL, increased tau discriminated cases of neurosyphilis from syphilis without nervous system involvement with a sensitivity and specificity of 83% and 94%, respectively. CONCLUSIONS: These results indicate that increased total tau may be useful in the discrimination of neurosyphilis from syphilis without nervous system involvement.

Occipital neuralgia as an isolated symptom of C2 myelitis.

Occipital neuralgia has been attributed to lesions at a peripheral nerve or radicular level. On rare occasions, it has been associated with cervical cord lesions. We report a 55-year-old woman who presented with an isolated occipital neuralgia and was found on further investigation to have a restricted, isolated myelitis at C2 level. This represents the second reported case of occipital neuralgia due to C2 myelitis and should alert clinicians to considering cervical MRI in patients with occipital neuralgia.

Serum ferritin, transferrin and soluble transferrin receptor levels in multiple sclerosis patients.

Over the last few years, increased evidence has supported the role of iron dysregulation in the pathogenesis of multiple sclerosis (MS), as iron is essential for myelin formation and oxidative phosphorylation. We studied indices of iron metabolism, such as serum iron, ferritin, transferrin and soluble transferrin receptor (sTFR) levels in 27 MS patients. Seven patients had chronic progressive active disease (CP-A), six had chronic progressive stable (CP-S), ten had relapsing remitting active (RR-A) and four had relapsing-remitting stable (RR-S) disease. sTFR levels were found to be significantly higher in CP-A (P = 0.021) and RR-A (P < 0.004) patients than in controls. sTFR levels were also elevated in CP-S patients but did not reach significance (P = 0.064). sTFR values in RR-S patients were comparable to those found in controls (P = 0.31). Ferritin levels were significantly elevated only in CP-A patients (P < 0.002). Patients of the CP group had significantly higher ferritin values than the RR patients (P < 0.004). Haemoglobin values as well as iron and transferrin levels were within normal limits in all patients. In conclusion, the increased serum sTFR and ferritin levels in nonanaemic MS patients with active disease reflect the increased iron turnover. The mild elevation of sTFR levels in CP-S patients may indicate active inflammation with ongoing oxidative damage that is not detectable by history or examination.