Immunoglobulin free light chains in saliva: a potential marker for disease activity in multiple sclerosis.

A new procedure was developed and applied to study immunoglobulin free light chains (FLC) in saliva of healthy subjects and patients with multiple sclerosis (MS). The procedure was based on a Western blot analysis for detection and semiquantitative evaluation of monomeric and dimeric FLCs. The FLC indices accounting for the total FLC levels and for the monomer/dimer ratios of κ and λ FLC were calculated, and the cut-off values of the FLC indices were determined to distinguish healthy state from MS disease. The obtained FLC index values were statistically different in the saliva of three groups: active MS patients, MS patients in remission and healthy subjects groups. Our FLC monomer-dimer analysis allowed differentiation between healthy state and active MS with specificity of 100% and a sensitivity of 88·5%. The developed technique may serve as a new non-invasive complementary tool to evaluate the disease state by differentiating active MS from remission with sensitivity of 89% and specificity of 80%.

The frequency of CSF oligoclonal banding in multiple sclerosis increases with latitude.

BACKGROUND: With the advent of MRI scanning, the value of lumbar puncture to assess oligoclonal band (OCB) status-for the diagnosis of multiple sclerosis (MS) is increasingly uncertain. One major issue is that the reported frequency of cerebrospinal fluid (CSF)-restricted oligoclonal banding for the diagnosis of MS varies considerably in different studies. In addition, the relationship between OCB positivity and disease outcome remains uncertain, as reported studies are generally too small to assess comparative disability outcomes with sufficient power. METHODS: In order to further investigate variation of OCB positivity in patients with MS, we utilized MSBase, a longitudinal, Web-based collaborative MS outcomes registry following clinical cohorts in several continents and latitudes. We also assessed whether OCB positivity affects long-term disability outcome. RESULTS: A total of 13,242 patient records were obtained from 37 MS specialist centres in 19 different countries. OCB status was documented in 4481 (34%) patients and 80% of these were OCB positive. The presence of OCB was associated with degree of latitude (p = 0.02). Furthermore, the outcome of patients negative for CSF-specific OCB was significantly better in comparison to the OCB positive patients, as assessed by Expanded Disability Status Scale change (p < 0.001). CONCLUSIONS: The results of this study indicate that latitude could explain some of the inconsistencies in OCB status reported in different populations. The study confirms that OCB positivity in MS is associated with a worse long-term prognosis.

Familial Mediterranean fever (FMF) and multiple sclerosis: an association study in one of the world's largest FMF cohorts.

BACKGROUND AND PURPOSE: To describe and characterize the association between familial Mediterranean fever (FMF) and multiple sclerosis (MS). METHODS: The patient registry of The National Center for FMF was screened for the coexistence of FMF and MS. Tel-Hashomer criteria were used for the diagnosis of FMF, and FMF severity was evaluated, using the simplified FMF severity scale. McDonald criteria were used for the diagnosis of MS, and neurologic disability was measured using the expanded disability status scale (EDSS). RESULTS: We identified nine patients, affected with both FMF and MS. The onset of the FMF averaged 15.6 (3-37) years. Most patients suffered from abdominal and joint attacks, and 50% of the patients sustained a moderate to severe FMF. The onset of the MS was at an average age of 31.6 (17-50) years. Neurologic manifestations varied individually, without a dominant deficit, and the course was in a relapsing-remitting pattern in most. The median EDSS was in general of low score (3.0), apart from the patients who were homozygous for the M694V mutation, in whom the MS was more severe. Based on our case series, the frequency of MS in our FMF population is 0.075%, twice higher the expected rate in the general population (P=0.0057). CONCLUSIONS: Multiple sclerosis is more common in FMF than in the general Israeli population. Homozygosity for the M694V MEFV mutation may aggravate the phenotype of MS and predispose FMF patients to develop MS.

Periodic lateralized epileptiform discharges in multiple sclerosis: a case report.

The occurrence of epileptiform abnormalities on the EEG in patients with multiple sclerosis (MS) is rare. The following case correlates the clinical, EEG, MRI, and single photon emission computed tomographic (SPECT) findings in a patient with a long history of MS and acute onset of focal motor seizures and confusion. Two routine EEGs, brain MRI, and brain SPECT were performed. The patient was a 44-year-old woman with a long history of clinically definite MS of the relapsing-remitting and secondary progressive form with three events of focal motor seizures followed by generalized tonic-clonic seizures and postictal confusion. The first EEG done during admission showed periodic lateralized epileptiform discharges in the right temporal region. Brain MRI done several weeks later showed scattered T2 hyperintensities in several locations, including the periventricular and subcortical white matter bilaterally. Brain SPECT using Tc99-Neurolite demonstrated decreased perfusion on the right parietal and temporal lobes. This case suggests that focal motor seizures and a transient state of altered consciousness can be the result of an exacerbation of MS. The neurophysiologic expression of these clinical manifestations may present as periodic lateralized epileptiform discharges on the EEG and decreased regional perfusion on brain SPECT.

Comparison of glatiramer acetate (Copaxone) and interferon beta-1b (Betaferon) in multiple sclerosis patients: an open-label 2-year follow-up.

OBJECTIVE: To compare the clinical efficacy, as expressed by relapse rate and disability accumulation, and safety profile of glatiramer acetate (Copaxone; COP-1) and Interferon beta-1b (Betaferon; IFN beta - 1b) administered to multiple sclerosis patients during a 2-year follow-up on an open-label parallel design, as compared to their clinical condition in the 2-year period prior to treatment. BACKGROUND: Copaxone and IFN beta - 1b have been recently introduced for the treatment of relapsing forms of MS. Both medications have been proven to have a relatively safe profile and are used extensively world-wide. METHODS: 58 consecutive patients with relapsing forms of MS were enrolled from the MS out-patient clinic, during three months. After being informed in detail of the two approved treatment options existing at the time in Israel, the patients chose by themselves to receive either: (a) Copaxone 20 mg subcutaneously (sc) daily (Copaxone dly, 20 patients), or (b) Copaxone 20 mg sc alternate-day (Copaxone alt, 18 patients) or (c) IFN beta-1b 8 MIU sc in alternate day (20 patients). Mean relapse rate/year and mean EDSS/year were calculated for each group of patients during the 2 years prior to the onset of treatment, and during the year prior to the onset of treatment. Statistical significance was observed in the relapse rate in the year prior to the onset of treatment between the IFN beta -1b group and the two Copaxone groups (p = 0.05). This statistical difference has no effect on the overall data of the 2 years prior to starting the treatment and on the results. No statistical significance was observed in the total number of relapses, and on the 2-year relapse rate, prior to the onset of treatment. Mean relapse rate/year and mean EDSS/year were calculated for each group during the first and second year of treatment. Wilcoxon analysis for clinical data and chi-square for adverse events were applied. RESULTS: The three groups were statistically comparable concerning mean relapse/year in the 2 years before the trial started and no statistical significance was observed among the three groups. A statistically significant reduction in the mean relapse rate in the 2 years after onset of treatment was observed in the three group of patients: Copaxone daily (dly) 1.1 +/- 0.6 (p = 0.0001); Copaxone alternate (alt) 0.9 +/- 0.6 (p = 0.0004) and IFN beta -1b 1.2 +/- 0.7 (p = 0.0001). Disability as expressed by EDSS score prior to the onset of treatment and after 2 years of treatment showed deterioration in the three groups although more significant in the Copaxone groups: Copaxone dly 3.3 +/- 1.4 to 3.8 +/- 1.6 (p = 0.007); Copaxone alt 2.4 +/- 1.1 to 2.8 +/- 1.3 (p=0.04); IFN beta - 1b 3.1 +/- 1.3 to 3.3 +/- 2.0 (N.S.). The most common adverse events reported were: (1) flu-like symptoms 7 pts (35%) in the IFN beta -1b group; 10 pts (26%) of the two Copaxone groups; (2) increased spasticity of lower limbs 3 pts (15%), only in the IFN beta -1b group; (3) site injection reaction (SIR): 16 SIR (80%) in the IFN beta -1b group; 12 SIR (67%) in the Copaxone alt group; 14 SIR (70%) in the Copaxone dly group; and (4) systemic reaction 3 pts (15%) in the IFN beta -1b group; 4 pts (22%) in the Copaxone alt group; 6 pts (30%) in the Copaxone dly group. Premature termination occurred in five patients treated with Copaxone (3 in the alternate group and 2 in the daily group). CONCLUSION: The present study, despite the limitations of an open-label study, shows that Copaxone dly, Copaxone alt and IFN beta -1b treatment seem to be equally effective for the control of exacerbations in MS. The adverse event profile, as reported by the patients, was also similar. However, the adverse events profile registered indicated that Copaxone is somewhat less detrimental, whereas disability as measured by EDSS accumulation showed that the interferon beta - 1b patients demonstrated a slower progression of the disability.

Electroencephalographic abnormalities in aseptic meningitis and noninfectious headache. A comparative study.

BACKGROUND: The finding of abnormalities on electroencephalogram (EEG) during the course of aseptic meningitis is often considered to be indicative of parenchymal brain involvement, even in absence of clinical signs of encephalitis. OBJECTIVE: To investigate if patients with aseptic nonherpetic meningitis who have abnormal EEG recordings during the acute stage of the disease differ in clinical characteristics or cerebrospinal fluid findings from patients with aseptic meningitis and normal EEG recordings. METHODS: The EEG records of 82 patients with aseptic meningitis were reviewed. A comparative group consisted of 41 age-matched patients with severe headaches without evidence of meningeal inflammation. RESULTS: Significantly more patients with aseptic meningitis (28%) demonstrated abnormalities on EEG than controls (12%) (P =.048). Patients with aseptic meningitis and abnormal EEG findings (n = 23) did not differ in age, duration of symptoms, clinical course, cerebrospinal fluid cell count, or protein level from those with normal EEG findings (n = 59). However, all patients with aseptic meningitis who were confused (n = 5) also revealed EEG abnormalities (P<.00012). Patients with headache with normal EEG recordings did not differ from those with abnormal EEGs in age, sex, or duration of symptoms. Nevertheless, patients with common migraine (n = 9) showed abnormalities on EEG (P =.06) more frequently. CONCLUSIONS: The finding of an abnormal EEG in patients with aseptic meningitis, clear mental state and absence of focal neurological signs should not be used as proof of encephalitis. Because pathological examination is usually not performed, it remains unclear if EEG abnormalities in patients with aseptic meningitis indicate a silent parenchymal inflammation, or reflect an infectious encephalopathy.

The central nervous system-specific myelin oligodendrocytic basic protein (MOBP) is encephalitogenic and a potential target antigen in multiple sclerosis (MS).

Uncovering primary target antigens in multiple sclerosis (MS) is of major significance for understanding the etiology and pathophysiology of the disease, and for designing immunospecific therapy. In this study, a synthetic peptide representing a predicted T cell epitope on myelin oligodendrocytic basic protein (MOBP) was found to be encephalitogenic in C3H.SW mice, inducing experimental autoimmune encephalomyelitis with an abrupt onset. Two separate preliminary studies with MOBP peptides indicated that autoreactivity to MOBP occurs in MS. These data strongly suggest that MOBP is a highly relevant target in MS and further point to the complexity of antigen specificities in MS.

Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: reactivity to the extracellular domain of MOG is directed against three main regions.

Our previous analysis of the T cell reactivity to myelin antigens in a group of 24 patients with multiple sclerosis (MS) and 16 control individuals revealed that the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) predominates in MS over that to myelin basic protein (MBP), proteolipid protein or myelin-associated glycoprotein, suggesting a prevalent role for the autoimmune response to MOG in the pathogenesis of MS. Using a recombinant human MOG (rhMOG) preparation corresponding to the extracellular immunoglobulin-like domain of the MOG molecule, we have now analyzed another group of 52 MS patients and 49 control individuals for reactivity of their peripheral blood lymphocytes (PBL) to rhMOG and to MBP concomitantly. Of the 52 MS patients tested 24 responded to MOG and 10 out of 49 responded to MBP, whereas only 5 MOG-reactive and 4 MBP-reactive control individuals were detected out of the 49 tested. These results are therefore highly confirmatory of the predominant reactivity to MOG in MS. The analysis of the primary proliferative response to 11 synthetic overlapping peptides (phMOG) spanning the extracellular domain of human MOG by PBL from 9 MS patients and 15 control individuals (9 healthy controls and 6 patients with neurological diseases other than MS) further supports a prevalent role for the autoimmune response to MOG in MS, as only 1 of the 15 controls tested showed reactivity to any of the phMOG, whilst 5 out of the 9 patients studied reacted to at least 1 of the phMOG. PBL from 10 MS patients, and from 4 controls, were selected in vitro with each of the phMOG. Of the 10 patients studied 7 reacted to at least 1 phMOG upon secondary stimulation and the reactivity was mostly directed to epitopes localized within three main regions (amino acids 1-22, 34-56 and 64-96), as was observed for the primary response of PBL. The predominant response to MOG of PBL from MS patients as demonstrated in two separate studies using native MOG and rhMOG as antigens, and the high incidence of reactivity of these PBL compared to the lack of response to phMOG by control PBL, emphasize the relevance of MOG in MS pathogenesis and support a primary role for the autoimmune T cell response to MOG in disease development.

Malignant cystic meningioma with spike and wave EEG pattern.

A 23 year old woman suffering from grand mal epilepsy showed generalized spike and wave activity on her EEG. The CT showed a cystic tumor in the cortex and the white tissue of the right parietal region. On operation the tumor was diagnosed as malignant infiltrating cystic meningioma. After removal of the tumor the spike and wave pattern disappeared. Cortical localized tumors are rarely associated with a generalized spike and wave pattern.

In vitro presynaptic modulation of cholinergic hippocampal activity by pituitary-adrenocortical hormones.

In vivo studies have shown that high blood concentrations of pituitary-adrenocortical hormones can activate the hippocampal cholinergic terminals. Incubation of hippocampal synaptosomal preparations with methylprednisolone, or with ACTH at concentrations comparable to stress-induced high concentrations in plasma, did not have any significant effects on the cholinergic parameters measured under unactivated conditions. In the presence of either high K+ or of ACh, choline uptake was decreased. This decrease was not affected by methylprednisolone. However, methylprednisolone did enhance ACh release both after a previous increase (induced by K+) or a decrease (induced by ACh) of ACh release. In contrast, ACTH had no direct effects on either unactivated or K+-stimulated synaptosomes. Thus, a differential effect was exerted by methylprednisolone on the two presynaptic regulatory mechanisms: choline uptake (no change) and ACh release (increase). We suggest that the activation, observed in vivo, resulted mainly from indirect action of the hormones on the hippocampal cholinergic terminals, in view of the fact that the direct effect in vitro was partial.

Selective regional effect of various neuroactive drugs on bromocriptine concentration in the brain of rats.

Bromocriptine (2-Br-alpha-ergocryptine), a partial ergoline derivative, is a dopamine agonist which has been used successfully in the treatment of hyperprolactinemia, acromegaly and Parkinson's disease. The main targets for the action of the drug are the hypothalamic, hypophyseal pathway and the striatum. These regions contain different populations of neurons which interact with each other in a complex way. In order to check the mechanism of these interactions in rats, we administered different neuroactive drugs together with bromocriptine. After a single intraperitoneal injection, bromocriptine concentration in the striatum was 13.1 +/- 2.9 ng/mg protein, and in the hypothalamus 13.9 +/- 0.8 ng/mg protein. The largest increase in the bromocriptine content in the striatum was found after the concomitant administration of naloxone, an opiate receptor blocker (21.2 +/- 2.5 ng/mg protein). The largest increase of the bromocriptine content in the hypothalamus was found after the concomitant injection of methysergide, a serotonin receptor blocker (27.8 +/- 2.6 ng/mg protein). Amantadine, diazepam and haloperidol caused the largest decrease in the two regions. The mechanism of interaction and therapeutic implication of these findings are discussed.

Oligoclonal IgG bands in the CSF of a patient with progressive familial myoclonus.

An oligoclonal IgG pattern was found in the CSF of a patient who is known to suffer from progressive familial myoclonus. In view of this finding the possibility arises that immunological mechanisms participate in the etiopathogenesis of this disease.

Thymectomy and chronic relapsing experimental allergic encephalomyelitis in guinea pigs.

Chronic relapsing experimental allergic encephalomyelitis (EAE) was induced in young Dunkin Hartley guinea pigs by a single sensitization with guinea pig spinal cord homogenate. The effect of either newborn thymectomy or young adult thymectomy on the clinical course of chronic and relapsing EAE was studied and evaluated statistically by Student's t test. All the animals that underwent thymectomy showed a significant delay in the onset of the disease compared with control groups. In addition, in the young adult guinea pigs in which thymectomy was done, the incidence of clinical disease was decreased. No substantial differences, however, were observed in the severity of the disease and number of remissions or relapses between guinea pigs in which thymectomy was done and in which clinical symptoms developed and controls.

Effect of various neuroactive drugs on bromocriptine concentration in the striatum of rats.

Parkinsonian patients are usually given several drugs concomitantly with bromocriptine, with variable results. The possibility of interference of these drugs with the availability of bromocriptine in the brain was investigated by measuring bromocriptine concentrations in the striatum in rats. After a single injection, bromocriptine concentration in the striatum was 13.1 +/- 2.9 ng/mg protein. Naloxone, an opiate receptor blocker, was found to produce the largest increase in bromocriptine content (21.7 +/- 2.5 ng/mg protein). Amantadine, diazepam and haloperidol produced the largest decreases (3.2 +/- 0.9, 3.3 +/- 0.8 and 4.4 +/- 1.2 ng/mg protein, respectively). Rats given L-dopa or benzodiazepine also showed slightly lower levels of bromocriptine.

Acute embolic bilateral renal artery occlusions in an elderly patient--case report: importance of early diagnosis.

Acute bilateral renal artery occlusion by emboli is a rare event and diagnosis is very often delayed. There is a high mortality rate because of anuria and controversy exists concerning an appropriate therapeutic regimen. We present the case of an elderly patient with bilateral artery occlusion, treated conservatively with anticoagulants, fibrinolytic agents and dialysis, and a review of the pertinent literature.

Convulsive attacks due to antidepressant drug overdoses: case reports and discussion.

Antidepressant drug overdoses have been reported to induce seizures, but the etiology of this phenomenon is still unclear. Recently we treated three patients who suffered from epileptic seizures after acute overdoses of three antidepressant drugs: (a) Dibenzepin HCl (Noveril), (b) Maprotiline HCl (Ludiomil), and (c) Clorimipramine (Anafranil). After a review of the pertinent literature, the possible role of antidepressant drugs in the genesis of epileptic seizures is discussed.

The behavioral effect of salbutamol (a beta-adrenergic receptor stimulant) on reserpine- and propranolol-treated rats.

Reserpine- and propranolol-treated rats were given salbutamol, a beta-adrenergic stimulant, intra-peritoneally in an open control study. The results suggest that salbutamol has a therapeutic effect on the depressive behavior of reserpine- and propranolol-treated rats.

Plasma dopamine beta hydroxylase activity in chronic schizophrenic patients tested with single dose of 2-bromo-alpha ergocriptine (Parlodel).

Plasma dopamine beta hydroxylase (D.B.H) activity was measured in 6 chronic schizophrenic patients. Treated with phenothiazine and butyrophenone derivatives after administering a single dose of bromocriptine (7,5 mg) orally, and compared to a matched group of 6 chronic treated schizophrenic patients without bromocriptine loading, and to a control matched group loaded with 7.5 mg of bromocriptine. A significant difference was observed in D.B.H. plasma levels of the schizophrenic patients group who received bromocriptine, by comparison with the other two control groups.