A 44-month clinical-brain MRI follow-up in a patient with B12 deficiency.

We report a 51-year-old woman with vitamin B12 deficiency who presented with slight megaloblastic anemia and severe neurologic deficits associated with multiple focal and confluent T2-weighted white matter hyperintensities on brain MRI. Forty-four months after initiation of hydroxocobalamin therapy, there was clinical improvement and striking reduction in the MRI abnormalities. B12 deficiency should be considered in the differential diagnosis of neurologic disorders associated with multiple areas of white matter hyperintensities on T2-weighted brain MRI.

Progressive nuclear ophthalmoplegia associated with mental deficiency, lingua scrotalis, and other neurologic and ophthalmologic signs in a family.

Six members of a family--the mother, three daughters, and two sons--have a unique syndrome consisting of congenital external ophthalmoplegia, bilateral facial weakness, lingua scrotalis, progressive chorioretinal sclerosis, and an intellectual deficit. Bilateral ptosis and almost complete ophthalmoplegia were found in three of the family members, bilateral facial weakness in two, and Parinaud's syndrome and convergence paresis in one. Electromyographically, a lesion of the lower motor neurons--"nuclear ophthalmoplegia"--was found. Three members of the family had different stages of progressive chorioretinal sclerosis and two had myopia. All the family members had lingua scrotalis, and all of those who had ophthalmoplegia had low IQs. Electroretinographic reactions were subnormal or absent in patients with chorioretinal degeneration. It was concluded that an extensive abiotrophic process, genetically conditioned, was a possibility.

The occurrence of oligoclonal IgG in tears from patients with MS and systemic immune disorders.

Using isoelectric focusing (IEF) and immunoperoxidase staining of proteins transferred to nitrocellulose membranes, we have examined the IgG band pattern in tears and matched serum and CSF specimens of 28 patients with MS, 4 patients with optic neuritis (ON), 30 individuals with systemic, inflammatory, or other neurologic diseases, and 5 patients with tension headache. We found no evidence of positive oligoclonal IgG in tears in any MS or ON patients, while 10 out of 16 cases with systemic immune disorders or infections of the CNS had positive tear oligoclonal bands. We are thus not able to support the hypothesis that tears from MS patients reveal abnormalities in their humoral immune response.

Uric acid levels in sera from patients with multiple sclerosis.

The levels of uric acid (UA), a natural peroxynitrite scavenger, were measured in sera from 240 patients with multiple sclerosis (MS) and 104 sex- and age-matched control patients with other neurological diseases (OND). The mean serum UA concentration was lower in the MS than in the OND group, but the difference did not reach the level of statistical significance (P = 0.068). However, the mean serum UA level from patients with active MS (202.6 + 67.1 mumol/l) was significantly lower than that in inactive MS patients (226.5 + 78.6 mumol/l; P = 0.046) and OND controls (P = 0.007). We found a significant inverse correlation of serum UA concentration with female gender (P = 0.0001), disease activity (P = 0.012) and duration (P = 0.017), and a trend towards an inverse correlation with disability as assessed by EDSS score, which did not reach statistical significance (P = 0.067). Finally, multivariate linear regression analyses showed that UA concentration was independently correlated with gender (P = 0.0001), disease activity (P = 0.014) and duration of the disease (P = 0.043) in MS patients. These findings suggest that serum UA might serve as a possible marker of disease activity in MS. They also provide support to the potential beneficial therapeutic effect of radical-scavenging substances in MS.

Serum interleukin-12 levels in patients with multiple sclerosis.

Increasing body of evidence which suggests a crucial role for interleukin (IL)-12 in modulating immune responses in multiple sclerosis (MS) prompted us to analyze IL-12 in serum from MS patients. We measured the sera concentrations of IL-12, tumor necrosis factor (TNF)-alpha and transforming growth factor-beta1, in 21 MS patients and 13 patients with non-inflammatory nervous diseases. In clinically active MS, serum levels of IL-12 were detectable in 53% and TNF-alpha in 40% of patients. None of the patients with clinically inactive MS had detectable IL-12 and TNF-alpha sera levels. Analysis of serum concentrations of all three cytokines revealed no significant differences between MS patients and controls. These findings provide further evidence that both IL-12 and TNF-alpha might have an active role in immunopathogenesis of MS.

The effects of high-dose intravenous methylprednisolone on event-related potentials in patients with multiple sclerosis.

The aim of this study was to assess the effects of high-dose (i.e. 1000 mg per day) intravenous methylprednisolone (HDMP) on event-related potentials (ERPs), elicited by a standard auditory 'oddball' paradigm, in patients with clinically active multiple sclerosis. In a double-blind study design, forty-four consecutive inpatients were randomly assigned in two clinically similar groups of 22 subjects each; one treated with HDMP for five days, and other with placebo. ERPs were recorded before and after the treatment. After HDMP therapy the P3 peak latency was significantly shortened (P=0.006), while peak latencies of other waves (i.e. N1, P2, and N2) remained unchanged. On the other hand, ERPs were uninfluenced by placebo treatment. Our results suggest the beneficial effect of intravenous HDMP therapy on, at least some aspects of, cognitive processing capabilities (as assessed by the auditory ERPs) in patients with multiple sclerosis.

Interleukin-12 and tumor necrosis factor-alpha levels in cerebrospinal fluid of multiple sclerosis patients.

Concentrations of interleukin (IL)-12 and tumor necrosis factor-alpha (TNF-alpha) in cerebrospinal fluid (CSF) were measured in patients with multiple sclerosis (MS) and control patients with non-inflammatory neurological diseases (NIND) by an enzyme-linked immunosorbent assay. TNF-alpha was detectable in the CSF of 60% of the patients with active MS, none of those with inactive MS and 29% of patients with NIND. CSF concentrations of TNF-alpha correlated with the degree of disability in MS patients (P < 0.05). Detectable levels of IL-12 were found in 10% of the MS CSF samples and 18% of NIND CSF samples. There was a significant relationship between CSF concentrations of IL-12 and those of TNF-alpha in MS patients (P < 0.05); no relationship was observed between the presence of IL-12 and disease activity or severity. These findings further stress the involvement of T helper 1 type-response within the central nervous system in MS.

Unusual association of multiple sclerosis and tomaculous neuropathy.

We describe two cases in which multiple sclerosis (MS) occurred in association with tomaculous neuropathy, presenting as chronic, distal sensorimotor polyneuropathy. In Case 1, monoclonal gammopathy of undetermined significance with monoclonal IgG lambda reactive against GM1 ganglioside, was also detected. The diagnosis of tomaculous neuropathy was established after sural nerve biopsy. Teased fibers examination revealed focal 'sausage-like' thickenings of the myelin sheaths in intact fibers and in fibers with segmental demyelination. Electron microscopy showed them to be due, mostly, to multiple windings of redundant myelin and concentric apposition of numerous lamellae, in contact with an intact myelin sheath. These are the first reported cases of tomaculous neuropathy in patients with MS. Whether the combination of the two conditions is purely coincidental or suggests the possible causal relation between MS and tomaculous neuropathy, is not certain.

Tooth pulp evoked potentials (TPEPs) in multiple sclerosis patients.

The purpose of this study was to determine possible changes of the tooth pulp evoked potentials in patients with multiple sclerosis, and to compare these with other types of evoked potentials, in the same patients. The results showed TPEP changes in all multiple sclerosis patients. In 12 patients the changes were observed on both sides, while in 6 on one side only. It is interesting to note that the second negative wave was characterized by two peaks. The first peak possessed latency of approximately 125 ms that was significantly shorter than in the control group. The second peak appeared after about 195 ms. The significant prolonged latency of the second negative wave was observed in 100% of TPEPs, 95% VEPs and 72% AEPs. In only one case the changes were observed in TPEPs, while VEPs and AEPs were normal. It could be concluded that TPEPs, as well as other types of evoked potentials, are a sensitive indicator of the demyelination process.

The possible role of prolactin in the immunopathogenesis of multiple sclerosis.

Multiple sclerosis is a disease of the central nervous system characterized by multiple areas of inflammation and demyelination in the white matter of brain and spinal cord. A complex mechanism of the immunopathogenesis of the disease involves mononuclear cells infiltrating multiple sclerosis plaques, as well numerous cell products, such as interleukins, interferons, certain growth factors, etc. Some recent studies have emphasized the immunoregulatory role of certain neuroendocrine peptides, including prolactin. Prolactin, a hypophyseal hormone which is also produced by activated immunocytes, has been considered in this work as a co-factor participating in the immunopathogenic mechanism of multiple sclerosis.

Single dose and steady state pharmacokinetics of valproic acid in adult epileptic patients.

The pharmacokinetics of valproic acid was studied in ten adult epileptic patients (five f + five m, 19-48 years; 28 +/- 12, mean +/- SD, and body mass 45 to 70 kg; 61 +/- 7, mean +/- SD) both after single dose and at the steady state. Sodium valproate was given in a 900 mg single oral dose on the first day of therapy, followed by 3 x 300 mg/day during the three subsequent days (at the intervals of 7, 8 and 9 h). During the first day, plasma was obtained just before the drug was given, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10 and 12 h after drug administration. On the fourth day of therapy (at steady state), plasma was obtained just before the next dose and 3 h after the drug administration. The plasma concentrations of valproic acid were measured by gas chromatography with flame ionization detection, after extraction with chloroform. The pharmacokinetic parameters, necessary to define the pharmacokinetics of valproic acid, were calculated both after single dose: Cmax, tmax, kel, t1/2, Vd, AUC and Cl, and at steady state: Cminss Cmaxss and Fl%. These parameters, as well as plasma levels of the drug, were used to describe the pharmacokinetic behaviour of valproic acid under these clinical conditions, and mainly were in agreement with the values published in the literature.

Urinary excretion of phenobarbital and its metabolite p-hydroxyphenobarbital in convulsing and non-convulsing patients.

As part of an investigation of phenobarbital (PB) pharmacokinetics in patients with status epilepticus (SE), urinary excretion of PB and its main metabolite, hydroxyphenobarbital (HPB), was studied in patients who had an episode of SE, as well as in non-convulsing ones. Eleven in-patients were studied:(group 1) five patients (4 M + 1 F; 48 +/- 28 years old; 64 +/- 6 kg body weight; mean +/- SD) with convulsive status epilepticus, and (group 2) six patients (5 M + 1 F; 37 +/- 13 years old; 71 +/- 15 kg body weight) with epilepsy, seizure-free at the moment of PB administration and without established anti-epileptic therapy. All subjects received a single intravenous dose of PB (15 mg/kg) at a rate of 100 mg/min. PB and HPB concentrations were measured by high performance liquid chromatography with UV detection at 220 nm in urine samples collected throughout 24 h. The comparison of pharmacokinetic parameters of urinary excretion of PB and HPB showed a statistically significant difference in the values of recovery of HPB and total barbiturate (higher values in the patients with SE) in 24 h urine. Differences in the excretion of PB between the two groups of patients--higher values in the patients who had had an episode of SE, and in urine flow--slightly elevated volumes in the same group, failed to reach statistical significance, probably due to the small number of participants in the study.

Electroencephalographic studies in multiple sclerosis. Specific changes in benign multiple sclerosis.

EEG changes were analysed in a group of 260 patients with definite multiple sclerosis, 156 women and 104 men, average age 38.8, at different stages of the disease. Among 103 patients with an evolution up to 5 years, 34% had significantly abnormal EEG'S while in 157 patients with an evolution from 5 to 45 years abnormal records were obtained in 47.8%. The larger group showed EEG differences between benign (66 patients), malignant (23 patients) and moderate courses (68 patients) patients. The frequency of abnormal and doubtful EEGs was highest in the benign group (80.4%) and largest in the malignant group (24.1%). The main characteristic in malignant multiple sclerosis in the steadily progressive stage was a flat EEG. There was also a significant correlation between a flat EEG and intellectual deficit. In benign multiple sclerosis the dominant activities were slow (6-10 c/sec) and high voltage (80-180 muV) alpha-theta rhythms spreading all over the cortex, usually associated with "centrencephalic" discharges. A self-limiting effect of lesions around the 3rd ventricle on auto-agressive immunological processes is proposed.

Comparative analysis of the therapy of acute transverse myelitis.

Three methods of treatment of acute transverse myelitis are presented. The first group of 16 patients were treated with antibiotics (average age 32.1). Three patients died, 11 remained unrecovered, while in two cases remarkable improvement was recorded. The second group of 15 patients, whose average age was 32.4, were treated with corticosteroid per os or instrumuscularly. Four of the patients died (three of them with ascendent course of disease), there was no change in five cases, while marked improvement ("cured" and "walking with assistance") was recorded in the remaining six cases. The third group of ten patients, eight women two men, ranging from 15 to 47 years of age (average age 26.9) was treated with methylprednisolone acetate intrathecally. Five patients were practically cured after 3 to 4 weeks. Two patients were cured to an extent that they could walk with assistance. In two cases no improvement was recorded, while one of the patients, who in addition suffered from serum myelitis, died of bilateral bronchopneumonia. In all these cases the drug was administered comparatively late, on the 6th or 7th day ofthe disease.

Psychiatric disorders associated with corticosteroid therapy.

Psychiatric disorders accompanying corticosteroid therapy are reported. They are much more frequently encountered than is generally believed. Moreover, they seem to correlate with the dosage applied. For more convenient clinical approach, we suggest classification of the disorders into four groups. The authors report two of their cases suffering from multiple sclerosis with associated steroid-induced psychosis. Besides the review of etiological mechanisms, the approach to treatment of psychiatric complications induced by steroid therapy is also suggested.

[The clinical picture of Lyme disease in neurology]. / Klinicki oblici lajmske bolesti u neurologiji.

Neuroborreliosis of central and peripheral nervous system was found in 24 patients with typical and atypical clinical syndromes. Information about tick bite was obtained in only 1/3 of our patients. Specific antibodies were found in 3/4 by flourescent antibody test, oligoclonal bands in 1/2, and signs of inflammation in cerebrospinal fluid in 1/3 of patients. The majority had favourable reaction to antibiotic therapy. It is necessary to investigate every case of suspected neuroborreliosis because it can imitate many neurological diseases. One must insist on information about the tick bite and/or erythema migrans and search for specific antibody production, both in blood and cerebrospinal fluid.

The disturbance of nonverbal functions in dysphasia.

Various modalities of six neuropsychological functions (graphia, calculia, finger gnosis, right-left orientation, praxia and constructive praxia) referred to as parietal or nonverbal have been investigated in the light of speech disorders. We examined 20 patients with brain lesion of vascular origin, who met the diagnostic criteria of mild and moderate dysphagia, 13 patients with Wernicke's and 7 with Broca's dysphasia. Verbal and nonverbal functions in patients with ischemic focuses of the speech area of the left hemisphere were investigated the Boston Diagnostic Aphasia Examination (BDAE). The investigation revealed that the presence and the type of mild and moderate dysphasia had a noteworthy role in pathoplasticity of correlated signs, thus implying in clinical practice a parietal lesion. Generally, poorer and at the same time more heterogeneous results were obtained in patients with Wernicke's dysphasia, mostly on calculia and right-left orientation. Finger agnosia was not considered as an authentic parietal sign, while each modality of graphia was impaired to a varying extent in speech disorders caused by presylvian and retrosylvian lesions. The paper also deals with the significance of lobulus parietalis inferior in speech.

[Dr. John Baptiste Edouard Gélineau]. / Doktor Zan Baptist Eduar Zelino.

With this brief review we honor the memory of the great French doctor Jean Baptiste Edouard Gélineau. Dr. Gélineau was born on December 23, 1828 at Blaye, Gironde, close to the Bordeaux region. His name is connected with the first clinical description of the disease for which he, both by the right of the primacy as well as ad valorem of his first two names, coined the name "narcolepsy". He was the first to notice the intrinsically evanescent symptoms of narcolepsy, such as excessive daytime somnolence, imperative sleep habits and cataplexy or "astasia" as he called it, and incorporate them into a single clinical syndrome. In 1881 Gélineau discussed Kaffe's case of "maladie du sommeil" as a proof of the existence of the new disease described a year before. As a good clinical observer Gélineau noticed the close relation of emotional engagement and astasia. His attitude was that narcolepsy was a nosologic entity, a disease sui generis, but admitted that it could appear purely as a symptom only. This was in discordance with the views in England where (in 1928) Dr. Samuel Alexander Kinnier Wilson repudiated such convictions; in 1930 Lhermitte still shared the same opinion. Gélineau differentiated narcolepsy from epilepsy with the elegance of clinical reasoning. Overall, Gélineau described three elements of the narcoleptic pentade. Sleep paralyses were first described by Mitchell in 1876, and were first attributed to narcolepsy by Wilson in 1928; in 1930 Lhermitte first described hypnapompic, and Daniels, in 1934, hypnagogic sleep paralysis. Hypnagogic hallucinations were described by Maury in 1848 and subsequently by de Saint Denis in 1867. In twenties they were thoroughly studiesed during the epidemic encephalitis and after the Big War in 1922 by Levy. The life story of Dr. Gélineau covers multivarious activities. As a young student of the Rochefort Navy Medical School he took part in the fight against colera which deluged the city of La Rochelle. In 1849 he became the "Intern" of the Navy Hospital and next year a "Surgeon of the Third Class". As a Navy surgeon he visited French colonies in the Indian ocean: first the Reunion island and then Mayotte island of the Commores Archipelago. Of this period he wrote "Voyage a i'lle de la Réunion", memoirs published much later, in 1905, in which he described colonial life and abolition of slavery. The story of Elise, a beauteous Creole woman, a concubine of a young naval Commander, who delivered a child that soon died, inexorably points to the autobiographic character of his work. He defended a doctoral thesis "Aperçu Medical de I'lle de Mayotte" at Montpellier University School of Medicine in 1858, using the data collected during his year-and-a-half stay on a Mayotte island; at that time he was a "Navy Surgeon of the Second Class". For his dedication in fighting against epidemics that broke out during the French-German war in 1870 he was nominated for the Legion of Honor, but received it only later. In 1871 Gélineau introduced "Doctor Gélineau's tablets" for the treatment of epilepsy (contained bromide and arsenic). He was a member of the Société de Médicine, Société d' Hypnologie, La-Société Française d' Hygiène, and a few others. After retirement at the age of 72, Gélineau switched to wine production, continuing the family tradition; for the quality of his Bordeaux wines he was awarded gold medals at the Anvers and Paris Exhibitions. Dr. Gélineau died on March 2, 1906, at Argeles Gazost in Pyrnees honored by the titles of Chevalier de la Légion d' Honneur, Officier d'Academie and Commander of Nichan of the Ottoman Empire.

Circulating autoantibodies in multiple sclerosis.

By using indirect immunofluorescence method, we analyzed the presence of antinuclear, anticardiac, microsomal, parietal-cell, smooth-muscle and mitochondrial antibodies in sera of 33 patients with definite multiple sclerosis (MS), without clinical evidence of associated autoimmune disorder, and 14 patients with other neurological disorders (OND). In MS patients, the prevalence of both organ-specific and non-organ-specific antibodies was significantly higher (p less than 0.05) than in OND patients. In both groups, the titers of circulating antibodies were low. The presence of low levels of autoantibodies in sera of MS patients might be the result of immunodysregulation in MS.