[The use of biological markers in the diagnosis and follow-up of patients with multiple sclerosis. Test of five fluids]. / Utilidad de los marcadores biológicos en el diagnóstico y seguimiento de los pacientes con esclerosis múltiple. Test de los cinco humores.

PATIENTS AND METHODS: We studied five biological fluids which were easily accessible to immunological examination (cerebrospinal fluid, plasma, tears, saliva and urine) in 25 patients with multiple sclerosis, clinically definite according to the criteria of Cleveland, Ohio (1991) and tabulated according to the Kurztke's expanded disability status scale. The samples were obtained simultaneously during a clinical bout of the disease before any pharmacological or immunosuppressive treatment had been given. RESULTS: The soluble interleukin-2 levels were significantly raised in at least three of these fluids--always absent from the urine--when compared with normal controls. The sensitivity and specificity of this determination for diagnosis of the condition was greater than that of other immunochemical parameters--oligoclonal distribution of immunoglobulins (specifically of IgG), imbalance of the light Kappa and Lambda chains--and physiological studies (evoked potentials). The dosification and quantification of basic myelin protein of the central nervous system, rich in citruline in the urine, may be a parameter of progressiveness. CONCLUSION: This methodology (five humours test) may be used to establish an earlier, more certain diagnosis of multiple sclerosis and also monitor its biological activity together with nuclear magnetic resonance with intravenous contrast.

Test de los cinco humores / The use of biological markers in the diagnosis and follow-up of patients with multiple sclerosis. Test of the five humours

Pacientes y métodos. Se estudiaron cinco fluidos biológicos de fácil acceso a la exploración inmune (líquido cefalorraquídeo, suero, lágrimas, saliva y orina) en 25 pacientes con esclerosis múltiple clínicamente definida, de acuerdo con los criterios de Cleveland, Ohio (1991), y tabulados según la escala del estado de incapacidad ampliada de Kurtzke. Las muestras se obtuvieron simultáneamente durante un brote de la enfermedad y previo a todo tratamiento farmacológico e inmunosupresor. Resultados. El nivel de receptor soluble de interleucina-2 se encontró significativamente aumentado en, por lo menos, tres de estos fluidos -ausente siempre en la orina- en comparación con el de los controles normales. La sensibilidad y especificidad de su determinación para el diagnóstico de la afección fue mayor que la de otros parámetros inmunoquímicos -distribución oligoclonal de inmunoglobulinas (específicamente de IgG), desequilibrio de cadenas livianas kappa y lambda- y estudios electrofisiológicos (potenciales evocados). La dosificación y cuantificación de proteína básica de mielina del sistema nervioso central, rica en citrulina en orina, puede ser un parámetro de progresividad. Conclusión. Esta metodología (test de los cinco humores) podría utilizarse para establecer un diagnóstico más certero y precoz de la esclerosis múltiple así como también para monitorizar su actividad biológica junto con la resonancia magnética nuclear con contraste intravenoso (AU)

Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009 Study Group.

This multicentre randomised double-blind 3- to 5-year trial was designed to assess whether initial therapy with cabergoline alone or in combination with levodopa prevents or delays the occurrence of long term motor complications in patients with early Parkinson's disease. Patients eligible for study inclusion (n = 412) had early idiopathic Parkinson's disease (Hoehn and Yahr stages 1 to 3) and had received no previous treatment with levodopa, selegiline or dopamine agonists. Patients were randomised to receive either cabergoline (0.25 to 4 mg once daily) or levodopa (100 to 600 mg/day) titrated over a maximum period of 24 weeks. Once the optimum or maximum tolerated dose was achieved, it was maintained up to the end-point (development of motor complications confirmed at 2 consecutive 3-month visits) or up to a minimum of 3 years' treatment. Open labelled levodopa was added in both treatment arms when the improvement in motor disability [Unified Parkinson's Disease Rating Scale (UPDRS) factor III] decreased below 30% vs baseline. Both treatments improved motor disability, decreasing UPDRS factor III scores and factor II scores for activities of daily living. The development of motor complications (end-point) was significantly less frequent in patients treated with cabergoline than in levodopa recipients (22% vs 34%; p < 0.02). The relative risk of developing motor complications during treatment with cabergoline was more than 50% lower than with levodopa. Serious adverse events, either drug related or not, were slightly more frequent in cabergoline-treated patients (31%) than in those treated with levodopa (25%). The withdrawal rate in the cabergoline vs levodopa group was 16 vs 13%. In conclusion, the study shows that, in patients with early Parkinson's disease, cabergoline is effective either as monotherapy or combined with levodopa. Moreover, starting treatment with cabergoline significantly delays the development of motor complications.

Cabergoline in the treatment of early Parkinson's disease: results of the first year of treatment in a double-blind comparison of cabergoline and levodopa. The PKDS009 Collaborative Study Group.

Cabergoline is a potent D2 receptor agonist with a half-life of 65 hours that may provide continuous dopaminergic stimulation administered once daily. In this study, we randomized de novo Parkinson's disease (PD) patients to treatment with increasing doses of cabergoline (0.25 to 4 mg/d) or levodopa (100 to 600 mg/d) up to the optimal or maximum tolerated dose. Decreases of > 30% in motor disability (Unified Parkinson's Disease Rating Scale Factor III) versus baseline were considered indicative of clinical improvement. If 30% improvement was not achieved, levodopa/ carbidopa could be added on an open basis. Of the 208 patients entered in the cabergoline group, 175 remained in the study for 1 year at a mean dose of 2.8 mg/d; in the levodopa group, 176 of the 205 patients entered were still on study after 1 year at a mean dose of 468 mg/d. The proportion of patients requiring additional levodopa/carbidopa increased in the cabergoline group from 18% at 6 months to 38% at 1 year versus 10% (p = 0.05) at 6 months and 18% (p < 0.01) at 1 year in the levodopa group. The proportion of patients showing clinical improvement did not differ significantly between the two groups, or between the subgroups on monotherapy, at any endpoint. Irrespective of levodopa/carbidopa addition, 81% of patients in the cabergoline group and 87% of patients in the levodopa group were clinically improved at 1 year (p = 0.189); the corresponding figures for the subgroup on monotherapy were 79% in the cabergoline-treated patients and 86% in the levodopa-treated patients (p = 0.199). The mean difference versus baseline in Unified Parkinson's Disease Rating Scale Factor III scores in patients who remained on monotherapy up to 1 year was 12.6 (95% confidence interval [CI]: 10.8, 14.3) in the cabergoline group and 16.4 (95% CI: 14.8, 18.0) in the levodopa group. Adverse events occurred in 76% of patients on cabergoline and in 66% of patients on levodopa. The severity profile for reported events was similar for the two agents. The results of this study indicate that cabergoline treatment for up to 1 year is only marginally less effective than levodopa in the proportion of patients who can be treated in monotherapy. More than 60% of de novo PD patients could be managed on cabergoline alone up to 1 year. In the patients in whom levodopa/carbidopa was needed, the combination therapy provided efficacy similar to that obtained with levodopa alone, with a relevant sparing of levodopa.

Long-term treatment with Madopar HBS in parkinsonians with fluctuations.

1. Of 22 parkinsonians with fluctuations under long-dating dopatherapy in whom standard Madopar was substituted by the HBS form, 16 who performed the trial longer than 1 year were particularly studied to evaluate some parameters of this long-term follow-up (30-36 months). 2. The outstanding beneficial effects were an enhancement of the antiparkinsonian response, improvement or disappearance of motor oscillations, longer "on" periods, less severe "off" periods, and a more sustained nocturnal antiparkinsonian effect with a reduction of dystonias and pain at night and decreased or absent early morning parkinsonism. 3. The decrease or disappearance of dystonia was observed since the early stages of the trial and can be explained by the more sustained dopaminergic effect. 4. Surprisingly, dyskinesias also decreased in spite of the higher dopaminergic effect. The avoidance of sharp and repeated plasmatic peaks and the lower levels of L-dopa under HBS could explain this phenomenon. 5. The negative aspects of Madopar HBS are a lower bioavailability that means a dosage increase and a longer latency for the therapeutic response in the morning. 6. The dosage increase went up by 80% to 100% in relation to standard Madopar during the long-term treatment. 7. As Madopar HBS is a sustained release preparation, we had to increase the initially reduced the number of intakes, again in order to obtain better results. In the most severe cases with poor or absent response, benefits were achieved only when administering the HBS intake every hour.(ABSTRACT TRUNCATED AT 250 WORDS)

Combination of selegiline and controlled release levodopa in the treatment of fluctuations of clinical disability in parkinsonian patients.

Thirteen parkinsonians with a long duration of the disease and long-term dopa therapy, seven of them showing severe on-off oscillations and 6 an "end-of-dose impairment", were treated with a controlled release (HBS) preparation of L-DOPA/benserazide for more than 3 years. Thereafter, selegiline was added in a progressively increasing dosage up to a maximum of 10 mg/day during 4 months, with the aim of a) further improving the long-term results and b) reducing the doses of the new formula of L-DOPA. A significant decrease of early morning parkinsonism and reduction of motor disability throughout the day were observed; "wearing-off" cases showed better results compared with those presenting "on-off" oscillations. A mean reduction of 20% in the doses of levodopa was achieved. Likewise, a mild reduction of dyskinesias and a mild-moderate enhancement of dystonias were recorded. Only one patient did not tolerate selegiline and two others received lower doses due to side-effects. Selegiline was capable of enhancing the antiparkinsonian effect of the new formula of L-DOPA, while allowing a reduction of the doses administered. It must also be emphasized that such improvement was achieved in complicated patients, most of whom showed some deterioration of response in the late stages of long-term sustained-release levodopa treatment.

A combined regimen of subcutaneous lisuride and oral Madopar HBS in Parkinson's disease.

At the first stage of a pilot study involving 14 parkinsonians with motor fluctuations, treatment with standard Madopar was substituted by a sustained-release form, Madopar HBS, which attenuated fluctuations in patients with end-of-dose impairment, but achieved only moderate improvement in patients with on-off phenomena. In a second phase of the trial, 4 parkinsonians exhibiting the most severe fluctuations of mobility and the poorest response to Madopar HBS (Hydrodynamically Balanced System) were selected for treatment with a combined regimen utilizing subcutaneous lisuride infusions as the additional component. The sequence of the trial was as follows: 1. standard Madopar, 2. Madopar HBS, 3. standard Madopar combined with lisuride infusions and 4. Madopar HBS combined with lisuride infusions. Steady improvement was observed along the lines of this schedule, but the best results were obtained when Madopar HBS was combined with lisuride infusions. Subsequently motor fluctuations were less marked or disappeared, early-morning Parkinson symptoms decreased and dystonia was not recorded any longer. Even better results could be accomplished in an extended trial attempting to establish the best dosage ratio of the combination, possibly admitting increased dosage. The tolerance of the combined regimen was excellent, except in one patient who transiently exhibited delusions and postural hypotension. The combination of sustained-release Madopar and continuous infusions of the dopaminergic agonist lisuride seems to prove a more physiological and effective regimen for the treatment of severe motor fluctuations.

Substitution of standard Madopar by Madopar HBS in parkinsonians with fluctuations.

Fourteen parkinsonian patients, 10 of them showing severe and long-standing 'on-off' effects and 4 'end-of-dose impairment', received Madopar HBS instead of standard Madopar. At the end of the dosage adaptation phase (9 weeks) most patients improved; in patients with 'on-off' phenomenon, parkinsonism became less severe, on periods were longer, and fluctuations decrease; end-of-dose impairment resolved in 4 patients. However, a longer delay in the onset of the therapeutic effect was observed after the first daily drug intake in those patients still showing severe early-morning parkinsonism. With Madopar HBS, L-dopa dosage was increased by 116%. In spite of a greater dopaminergic effect, dyskinesias were reduced, and dystonias became less marked or even disappeared.

Aspectos diagnósticos y terapéuticos de los tics / Diagnostic and therapeutic aspects of tics

El diagnóstico diferencial de los tics se plantea en las etapas primeras del tic transitorio del niño y de la Enfermedad de Gilles de la Tourette dada su similitud clínica al inicio. La evolución con la remisión habitual y en definitiva total de las primeras y la asociación de nuevos síntomas algunos de ellos específicos como la coprolalia en las segundas permite aclarar el diagnóstico. A pesar de la preocupación familiar el tic transitorio benigno del niño no debe ser tratado a menos que sea intenso. En la enfermedad de los tics cuando la disquinesia es de grado leve no debe medicarse; si la intensidad es moderada puede iniciarse tratamento con clonazepam pero en los grados mediano e intenso es imperativo emplear tratamiento específico para evitar la importante repercusión social tanto del tic como de la coprolalia, que ocasionarán trastornos emocionales importantes con depresión psíquica y aislamiento. Si bien el haloperidol ha sido empleado como primera opción dada su eficacia, consideramos que debido a sus frecuentes, variados e importantes efectos adversos, deben utilizarse inicialmente otros fármacos de similar potencia antidisquinética y de mejor tolerancia. Proponemos en primera instancia el uso del triapride, antidisquinético específico con escasa capacidad parkinsonígena y que no induce disquinesias; si su efecto terapéutico no es suficiente creemos conveniente la administración de pimozide o flufenazina que poseen similar eficacia a la del haloperidol con mejor tolerancia. Además del uso de...

Aspectos diagnósticos y terapéuticos de los tics / Diagnostic and therapeutic aspects of tics

El diagnóstico diferencial de los tics se plantea en las etapas primeras del tic transitorio del niño y de la Enfermedad de Gilles de la Tourette dada su similitud clínica al inicio. La evolución con la remisión habitual y en definitiva total de las primeras y la asociación de nuevos síntomas algunos de ellos específicos como la coprolalia en las segundas permite aclarar el diagnóstico. A pesar de la preocupación familiar el tic transitorio benigno del niño no debe ser tratado a menos que sea intenso. En la enfermedad de los tics cuando la disquinesia es de grado leve no debe medicarse; si la intensidad es moderada puede iniciarse tratamento con clonazepam pero en los grados mediano e intenso es imperativo emplear tratamiento específico para evitar la importante repercusión social tanto del tic como de la coprolalia, que ocasionarán trastornos emocionales importantes con depresión psíquica y aislamiento. Si bien el haloperidol ha sido empleado como primera opción dada su eficacia, consideramos que debido a sus frecuentes, variados e importantes efectos adversos, deben utilizarse inicialmente otros fármacos de similar potencia antidisquinética y de mejor tolerancia. Proponemos en primera instancia el uso del triapride, antidisquinético específico con escasa capacidad parkinsonígena y que no induce disquinesias; si su efecto terapéutico no es suficiente creemos conveniente la administración de pimozide o flufenazina que poseen similar eficacia a la del haloperidol con mejor tolerancia. Además del uso de...(AU)

Parkinsonism, tardive dyskinesia, akathisia, and depression induced by flunarizine.

12 subjects, 8 women and 4 men, presented with extrapyramidal motor signs and psychic depression after treatment with flunarizine for between 3 weeks and 15 months. One woman presented with severe symptoms and 20 months after stopping flunarizine she still had dyskinesia and akathisia. The other patients showed partial or complete improvement after withdrawal of the drug.

Familial spastic ataxia associated with Ehlers-Danlos syndrome with platelet dysfunction.

Four members of a family with consanguineous relationships, the proband and his three children (2 sons and 1 daughter) are affected with Familial Spastic Ataxia and with Ehlers-Danlos' Syndrome with platelet aggregation dysfunction. In the four cases, this exceptional association appears remarkably homogeneous both in clinical and laboratory studies. The two syndromes are of dominant-autosomic transmission and probably originated in a new mutation which presumably maintained a genetic linkage. Spastic ataxia is characterized by a precocious onset and a slow evolution. The first-born son shows a dominant pyramidal syndrome with mild ataxia suggesting that it is a transitional form of familial spastic paraplegia. The Ehlers-Danlos syndrome pertains to form II or "mitis" with moderate skin hyperelasticity and joint hypermobility. The abnormal platelet aggregation curves have the same profile in all the patients. The first-born son also presents a mitral valve prolapsus as we may find either in Ehlers-Danlos syndrome or in spastic ataxia. The neurophysiological, tomographical, histological, ultrastructural and biochemical studies attempt to accomplish a better definition of these associated nosological entities.

Visual evoked potentials and brain stem auditory potentials in Friedreich's ataxia--a longitudinal study.

Six patients with Friedreich's ataxia, 4 males and 2 females, their ages ranging from 13 to 33 years, were studied. The early manifestations started between age 7 and 13 with an evolution time between 6 and 20 years. Serial visual and brain stem auditory evoked potential recordings were made. A progressive increase in latency, reduction in amplitude and in latency inter-ocular difference of P100 were observed. The pattern of the reversal checker-board visual evoked potential was preserved. A disorganized BAEP pattern, a well defined potential I, a very small potential V and a delay in the interpeak latency were constant findings. The assumption is made of a progressive involvement of both visual and central auditory pathways. Pathophysiological mechanisms are discussed.

Pilot study of threonine supplementation in human spasticity.

Threonine supplementation (500 mg/day) was given to 6 patients with genetic spasticity syndromes for a period of 12 months, followed by a 4-month observation period without medication. All 6 patients showed partial improvement of spasticity, intensity of knee jerks and muscle spasms without changes in true pyramidal tract signs. The improvement in motor performance, objectively measured, averaged 29% (19% in upper limbs and 42% in lower limbs). The range of overall improvement was 19--35% (7--30% for upper limbs; 25--67% for lower limbs). No toxic clinical or biochemical side effects were encountered. Thus threonine, a precursor of glycine, produced the same effect on spasticity than that previously observed with glycine. It is concluded that threonine supplementation is feasible and safe and that it deserves a controlled trial in well defined (preferably genetic) cases of spasticity.