Brain barrier dysfunction in Cuban epidemic optic neuropathy.

BACKGROUND AND PURPOSE: There are practically no references to cerebrospinal fluid (CSF) studies in tropical or nutritional neuropathies. In the present paper we present the results of CSF studies in patients with Cuban Epidemic Optic Neuropathy (CEON) during epidemic and endemic periods, with an appraisal as to the contribution of brain barriers' function in the pathophysiology of this disease. METHODS: Two hundred and five patients with CEON were studied during the epidemic period (1992-1993) and 12 patients outside the outbreak (1995-1997). CSF protein determination and electrophoresis were carried out, as well as serum and CSF albumin and immunoglobulin G (IgG) quantitation for calculating IgG and Q(alb) indexes, in order to evaluate intrathecal IgG synthesis and the permeability of the blood-CSF barrier (B-CSF B). RESULTS: One fourth of the patients had increased permeability of the B-CSF B, but damage was more frequent between 16 and 60 days from onset of disease, disappearing after 120 days. B-CSF B dysfunction was more prevalent in patients with severe neurological impairment, although it was not related to the severity of ophthalmological damage. The group of patients studied outside of the outbreak (endemic period) showed similar results. DISCUSSION: The possible association of increased permeability of the B-CSF B with oxidative stress, which lies on the basis of this epidemic outbreak, is discussed.

Réplica. Sobre diagnóstico en la epidemia de neuropatía en Cuba / Reply. Overdiagnosis in the epidemic of neuropathy in Cuba

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[Folic acid deficiency and increased concentrations of formate in serum and cerebrospinal fluid of patients with epidemic optical neuropathy]. / Deficiencia de folato y concentraciones elevadas de formato en suero y líquido cefalorraquídeo de pacientes con neuropatía óptica epidémica.

We studied 62 patients aged 48 years as an average and diagnosed with bilateral optical neuropathy during an epidemics in Pinar del Río province. Of these patients, 42 showed the optical form whereas 20 had the mixed form of optical neuropathy. We researched into the levels of formate and folate in serum and cerebrospinal fluid samples and we found a marked deficiency of folates in more than 50% of samples and high formate concentration levels in almost 25% of samples. We concluded that nutritional shortages that lead to a reduction of folates, and the intake of small amounts of methanol in alcoholic drinks could lead to lacking energetic states which would facilitate that the optical nerve be affected and the epidemic optical neuropathy appear.

[The neuropathy epidemic in Cuba: eight years of investigation and follow-up]. / La epidemia de neuropatía en Cuba: ocho años de estudio y seguimiento.

INTRODUCTION: The authors describes the past eight years, since an epidemic started in Cuba which mainly affected the nervous system, particularly the optic nerve and the peripheral nerves. It is thought to have been the biggest epidemic involving the nervous system this century, although there may be over-diagnosis. The cause is controversial but is probably nutritional imbalance with additional toxic elements also in some cases. At the present time the continuous, low, notification of new cases means that it is endemic. DEVELOPMENT: In this paper we consider the clinical and electrophysiological aspects characteristic of the disorder, the degree of involvement, evolution, incidence and annual follow-up of cases from 1992 to date and their differential diagnosis. We describe the national programme of healthcare for control of the disease in Cuba, the measures designed to reduce the number of patients, most of the results of clinical and epidemiological studies and the possible causes. We also discuss the most likely physiopathological hypotheses.

[Clinical manifestation and molecular identification of patients with Leber's hereditary optic neuropathy in a national reference center for neuro-ophthalmology in Cuba]. / Manifestaciones clínicas e identificación molecular de pacientes con neuropatía óptica hereditaria de Leber en un centro de referencia nacional para la neuroftalmología en Cuba.

INTRODUCTION: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder, confirmed at a molecular level 10 years ago. This had permitted better understanding of the condition. Since 1998, the Instituto de Neurología y Neurocirugía has used these techniques for the study of mutations which are considered to be the origin of the disorder. PATIENTS AND METHODS: We describe the characteristics of 14 cases from 10 families with LHON and the molecular confirmation found between 1994 and 1998 in the Instituto de Neurología Neurocirugía de Cuba. We also review the few cases seen in the previous 18 years. These were from only two families. They were diagnosed on clinical grounds and in view of maternal inheritance. RESULTS AND CONCLUSIONS: In 80% of the families in which the presence of primary mutations was investigated there was A117789, and in 20% A3460G. The average age of appearance was 28 years. The ages of onset were within the limits of 11 years and 48 years. There were 43% women. Two cases were considered to be sporadic. The clinical features corresponded to those described in such cases, with severe visual defects, central scotomas, very reduced colour vision and severely altered visual evoked potentials, with normal diffuse light and pattern electroretinograms. An improvement in visual acuity of 0.2 was seen in two cases. Microangiopathy, described as characteristic of the early stages of this disorder was detected in five cases, in at least one eye. The others had different degrees of optic atrophy. Two generations of one complete family, all with mutation 3460, were studied. In several families with this mutation alterations were found in the colour vision test of Farnsworth Munsell Hue 100 and also microangiospathy of the retina.

[Leber's hereditary optic neuropathy and its possible relation to a recent epidemic in Cuba]. / Neuropatía óptica hereditaria de Leber y su posible relación con la reciente epidemia de Cuba.

INTRODUCTION: This century, the greatest epidemic affecting the nervous system was notified in Cuba seven years ago. At the present time the epidemic continues although to a lesser extent. The clinical findings of the illness were mainly bilateral optic neuropathy sometimes accompanied by other symptoms and peripheral neuropathy. The similarity of the optic form of the illness with Leber's hereditary optic neuropathy, and their common risk factors, were obvious from the beginning. PATIENTS AND METHODS: Statistics from the national reference department of neuro-ophthalmology of the Instituto de Neurologia de Cuba were reviewed. From these it was evident that the number of cases of Leber's hereditary optic neuropathy had increased in recent years, coinciding with the period of epidemic and endemic Cuban neuropathy. Many of these patients had previously been diagnosed as having epidemic optic neuropathy. RESULTS: We describe the characteristics of a group of these patients and discuss the differences and possible relationship between the two conditions. In the case of epidemic optic neuropathy, there is strikingly simultaneous loss of vision, less visual changes with much smaller cecocentral scotomas, loss of ganglion fibres of the retina around the papillomacular bundle, a good response to multivitamin treatment, and increased frequency of association with peripheral sensory neuropathy. CONCLUSION: This analysis reinforces the hypothesis that many patients with Leber's hereditary optic neuropathy, which started at the time of the epidemic, were incorrectly classified as suffering from this, and also perhaps their condition worsened due to the toxic nutritional features common to both conditions.

[Amino acids as biochemical markers in epidemic and endemic optic neuropathies]. / Los aminoácidos como marcadores bioquímicos en las neuropatías ópticas epidémica y endémica.

It was studied the amino acids pattern in serum and cerebrospinal fluid of 12 and 8 patients, respectively, suffering from optic epidemic neuropathy diagnosed between 1995 and 1997 (endemic period). The cerebrospinal fluid of 16 patients diagnosed during the epidemic (1992) was also studied. The analysis of amino acids in serum and cerebrospinal fluid was made by high resolution liquid chromatography with fluorescent detection, previous derivation with orthofthallic aldehyde. As in the previous study, no important deficiencies of the essential amino acids were observed in the serum of the studied patients. Lower concentrations of threonine, aspartic acid and taurine were found in the serum of patients with epidemic optic neuropathy diagnosed in the endemic period. Taurine plays an important role in the structure and function of photoreceptors of the retina. It is synthesized in the necessary amounts in man, so it must be supplied in the diet. As it is only present in food of animal origin, it is considered that the deficiency of taurine may contribute to the development of optic epidemic neuritis in our patients. Samples of cerebrospinal fluid were analyzed during the epidemic and endemic periods and it was observed an increase of the glutamic and aspartic acid in the epidemic period and of glutamic acid during the endemic. The excess of excitotoxic amino acids in the cerebrospinal fluid supports the previous neurocognitive studies that suggested the affection of the central nervous system in these patients.

[A retrospective study of patients with epidemic optic neuropathy in a health area]. / Estudio retrospectivo de los pacientes con neuropatía óptica epidémica en un área de salud.

The sample of 104 patients who were diagnosed optic epidemic neuropathy at the health area of the "Rampa" Polyclinic in 1993 was reviewed. 50 of them were studied again. Visual acuity as well as the sensitivity to contrast by the Pelli Robson's method were explored. Ishihara's color-vision test was applied and an ophthalmological examination including fundus of the eye was made. All this was done by a group of experts who were searching temporary papillary paleness or lost of the bundles of papillomacular fibres, which are the diagnostic elements of the disease even in those cases that recover vision. 21 (42%) of the 50 studied patients fulfilled the criteria established for these cases by the Ministry of Public Health concerning visual acuity and color vision to diagnose optic epidemic neuropathy, although only 14 (28%) were ratified as cases. The typical alterations of the fundus of the eye were described, confirming the diagnosis. Cases were classified according to the initial state of visual acuity and to evolution. 3 had had an affectation of the visual acuity of 0.1 or worse (severe), and only one patient had a mild affectation with 0.8 of vision. The rest ranged between 0.2 and 0.6. Only one patient had a serious sequela. The low percentage of cases ratified as optic epidemic neuropathy does not represent what happened in the whole country, but it may be considered as a pattern of what took place at those units with the same conditions during the peak of the epidemic.

[Epidemic neuropathy: proposal and arguments to rename Strachan disease as Strachan and Madan disease]. / Neuropatía epidémica: proposición y argumentacion para renombrar a la enfermedad de Strachan, como de Strachan y Madan.

INTRODUCTION: Strachan's disease is a condition which mainly affects the nervous system. It is characterized by optic, auditory and peripheral neuropathies and lesions of the skin and mucous membranes. In 1955 Miller Fisher gave it this name, since the clinical condition described by Henry Strachan in Jamaica during the nineteenth century was similar to that seen in Canadian prisoners-of-war in Japanese concentration camps during the Second World War. DEVELOPMENT: Since there are similarities between these clinical disorders and the major neuropathic epidemic seen recently in Cuba, we have reviewed and compared the endemic and epidemic conditions of similar characteristics seen in Cuba during the nineteenth and twentieth centuries. We also make a detailed review of a similar condition described in 1898-1900 by Doctors Madan, López and Santos Fernández, during the last Cuban War of Independence. This seems to be one of the earliest descriptions of the disorder. We also consider the so-called Strachan's syndrome or disease, and descriptions from the same period of tobacco-alcohol amblyopia and beriberi. These conditions seem to have been very similar to the so-called optical and peripheral forms of the current Cuban epidemic. It is concluded that the clinical characteristics of the recent Cuban neuropathic epidemic, at least in the optical form, were seen to be endemic during the nineteenth century. In many cases this was considered to be alcoholic amblyopia or some other obscure neuropathy which became epidemic during periods of severe economic depression. CONCLUSION: Madan gave a full description of the disorder at the same time as Strachan did. In 1898 he also suggested its true cause and died trying to relieve it. We therefore consider that Strachan's syndrome should be renamed the Strachan-Madan syndrome.