A double blind, randomised, parallel group study to investigate the dose equivalence of Dysport and Botox in the treatment of cervical dystonia.

OBJECTIVE: This study was designed to establish whether a ratio of three units of Dysport is equivalent to one unit of Botox for the treatment of cervical dystonia. METHODS: Patients with predominantly rotational cervical dystonia, and a minimum of four previous Botox treatments, were randomised to receive either the clinically indicated dose of Botox or three times that dose in Dysport units. Study botulinum toxin was administered in a double blind fashion, to one or more clinically indicated muscles, at one or more sites per muscle. Patients returned for assessment two, four, eight, and 12 weeks after treatment. RESULTS: A total of 73 patients (Dysport, 38; Botox, 35) were entered. The Dysport group received a mean (SD) dose of 477 (131) (range 240-720) Dysport units, and the Botox group received a mean (SD) dose of 152 (45) (range 70-240) Botox units. The mean (SEM) post-treatment Tsui scores for the Dysport group (4.8 (0.3)) and the Botox group (5.0 (0.3)) were not statistically different (p=0.66). The study had 91% power to detect a clinically significant difference of two points. Both groups showed substantial improvement in Tsui score by week 2 (mean (SD); Dysport, 46 (28)%; Botox, 37 (28)%), with a peak effect at week 4 (mean (SD); Dysport, 49 (29)%; Botox, 44 (28)%). A similar response profile was seen for other assessments of efficacy. The duration of effect, assessed by time to retreatment, was also similar (mean (SD); Dysport, 83.9 (13.6) days; Botox, 80.7 (14.4) days; p=0.85). During the study 22 of 38 (58%) Dysport patients reported 39 adverse events, and 24 of 35 (69%) Botox patients reported 56 adverse events (p=0.35). A global assessment of efficacy and safety considered that 29 of 38 (76%) Dysport patients and 23 of 35 (66%) Botox patients were treatment successes (p=0.32). CONCLUSION: Patients with predominantly rotational cervical dystonia treated with the clinically indicated dose of Botox or three times that dose in Dysport units show similar improvements and do not have significantly different safety profiles.

Focal epilepsy and exposure to organic solvents: a case-referent study.

Organic solvent exposure was studied in 104 cases of idiopathic focal epilepsy and 312 matched referents. Exposure to solvents was classified as O, I, II, or III on the basis of occupational codes. The relative risk (RR) of epilepsy for those in exposure class I, II, or III, relative to O, was estimated using conditional logistic regression. An increasing trend in RR was observed with higher exposure classes. The attributable risk for cases with focal epilepsy of deep hemispherical origin was estimated to be 8%.

Ferritin concentration in cerebrospinal fluid.

15 patients with psychosomatic disease, 26 patients with miscellaneous neurological diseases, and 16 patients with cerebrovascular disease were investigated with regard to concentrations of ferritin in serum and cerebrospinal fluid (CSF). The mean CSF ferritin concentration in the psychosomatic group was 6.2 micrograms/l +/- 2.4 (1 S.D.). Patients with recent cerebral infarction had similar values while 2 patients with intracerebral hematomas had very high CSF ferritin concentrations. There was a positive correlation between serum and CSF ferritin levels and between CSF total protein and ferritin in patients with a damaged blood-CSF barrier only. At present, the practical value of analysing ferritin in the CSF is very small.

Effect of experimental folate deficiency on lipid metabolism in liver and brain.

1. Rats were given a purified folate-deficient diet containing 5 g succinylsulphathiazole/kg for 4-5 months in two experiments. Control rats were supplemented with folic acid in the drinking-water. 2. Weight gain was much below normal in the folate-deprived rats after the first month. Very low folate levels were recorded in blood, liver and peripheral nerve (12-33% of control). In the central nervous system, including the cerebrospinal fluid, the folate depletion was less conspicuous (50-80% of control). Only marginal signs of anaemia were found and no signs of neurological dysfunction were detected, using nerve conduction velocity measurement and co-ordination tests. 3. Light and electron microscopy of the folate deficient liver revealed fatty infiltration, and enlargement of liver parenchymal cells, nuclei and nucleoli. There was often a considerable amount of bile ductular cells in the lobuli but no cirrhosis. The morphological changes resembled those observed in choline deficiency. 4. Phospholipid N-methylation in liver was depressed in folate-deficiency. This was probably due to a decreased availability of S-adenosylmethionine caused by the low concentrations of methylated folate in liver. Intraperitoneal administration of methionine did not normalize phospholipid methylation. 5. In folate deficiency the proportion of ethanolamine phosphoglyceride in liver was increased at the expense of choline phosphoglyceride, which is consistent with a decreased phospholipid methylation. Also an increase in liver triacylglycerol was noted, in accordance with the morphological observations. Brain lipid composition was unchanged. 6. After the injection of labelled ethanolamine, isotope accumulated in liver phosphoethanolamine in folate deficiency, probably due to an impairment of the CTP:ethanolaminephosphate cytidylyltransferase (EC 2.7.7.14) reaction. The mechanism of this impairment is discussed. 7. Although the low concentrations of folate was the main nutritional change in the deprived animals, changes with respect to vitamin B12 and maybe also choline cannot be excluded. We conclude that some of the changes in folate deficiency, i.e. fatty liver and decreased biosynthesis of liver phospholipids may be due to a precipitated deficiency of lipotropic agents, whereas other differences may be specific for deficiency of folate per se, such as changes in liver phospholipid fatty acids and some of the morphological aberrations.

5-S-Cysteinyldopa in ganglion stellatum.

5-S-Cysteinyldopa, an amino acid formed by nucleophilic addition of cysteine to dopaquinone, has been detected in the ganglion stellatum of the cow in amounts varying between 21 and 35 ng/g ganglionic tissue. Dopa was present in slightly higher quantities. Cysteinyldopa has previously been regarded as a substance unique for the melanocytes, where it forms melanin after oxidation and polymerization. At present only hypothetical explanations of our finding can be offered. The content of 5-S-cysteinyldopa in ganglion stellatum may be the result of dopa oxidation in ganglionic cells. An uptake mechanism for circulating cysteinyldopa may exist. Localization of cysteinyldopa to aberrant melanocytes or to aged SIF-cells in the ganglia should also be borne in mind.

Lipid composition and metabolism in liver and brain of vitamin B12-deficient rat sucklings.

1. Rat sucklings (18-d-old) bred from vitamin B12-deprived dams were compared with vitamin B12-supplemented dams' offspring, which were considered normal rat sucklings. 2. The vitamin B12-deficient rat sucklings had lower body-weight, liver weight and brain weight. 3. Vitamin B12 deficiency was also evident from the tenfold lower concentrations of vitamin B12 in liver and cerebellum. 4. The concentration of liver lipid was markedly increased in vitamin B12-deficient rats; triacylglycerol accounted for most of the increase. In brain the lipid concentration was slightly decreased (less than 0.05). 5. The methylation of ethanolamine phosphoglyceride to choline phosphoglyceride was reduced in both liver and brain in vitamin B12-deficient rats, as measured after the administration of [14C]ethanolamine. A slight decrease in choline phosphoglyceride concentration could be a consequence of this finding. The composition of phospholipids was otherwise normal. 6. Odd-chain fatty acids (pentadecanoate and heptadecanoate) accumulated in both liver and brain of the vitamin B12-deficient rat sucklings and constituted approximately 1% of total fatty acid. 7. The biosynthesis of fatty acid and cholesterol from intraperitoneally-injected 3H2O and [14C]propionate was unchanged in vitamin B12 deficiency.

Effect of vitamin B12 deficiency on phosphatidylethanolamine methylation in rat liver.

1. In vitamin B12 deficiency the activity of tetrahydropteroylglutamate methyltransferase (EC 2.1.1.13) is depressed and the synthesis of methionine is reduced. Because the methyl group of methionine is largely utilized for the methylation of phosphatidylethanolamine, we investigated the effects of vitamin B12 deficiency on phosphatidylcholine synthesis. 2. The incorporation of injected [14C]formaldehyde into liver phosphatidylcholine was reduced by approximately 50% in vitamin B12-deficient rats. Also the corresponding incorporation of 5-[14C]methyltetrahydrofolic acid tended to decrease. The findings are consistent with a lower conversion of these precursors to methionine. 3. The effect of the deficient methyl-group supply on phosphatidylcholine synthesis was also investigated by the injection of [14C]ethanolamine. The amount (%) of lipid-14C recovered in phosphatidylcholine was significantly reduced in vitamin B12 deficiency. 4. Chemical analysis of liver phospholipids showed that the vitamin B12-deficient rats had a higher proportion of phosphatidylethanolamine and a lower proportion of phosphatidylcholine, indicating that the impaired synthesis of phosphatidylcholine by methylation leads to changes in membrane phospholipid composition.

Effects of vitamin B12 deficiency on lipid metabolism of the rat liver and nervous system.

1. Rats bred from vitamin B12-depleted dams were fed on a vitamin B12-deficient diet for 12-15 months and developed a severe vitamin B12 deficiency, as judged from methylmalonic acid excretion and tissue vitamin B12 levels at slaughter. Control rats were supplemented with vitamin B12 in the drinking-water. 2. Neurological signs were recorded after 7 months but the motor nerve conduction velocities remained normal. Neuropathological examination revealed mild changes in the peripheral nerves but no changes in the central nervous system. 3. The amounts of total lipids and phospholipids were normal, but in all examined tissues the proportions of pentadecanoate (C15 fatty acid) and heptadecanoate (C17 fatty acid) were considerably increased in vitamin B12 deficiency. 4. 3H2O was incorporated to the same extent into the fatty acids of nervous tissue from vitamin B12-deficient and control rats after 48 h. Less 3H was found in the liver fatty acids of the vitamin B12-deficient rats. 5. Neurological dysfunction can be demonstrated in the vitamin B12-deficient rat; the relation of the biochemical and neuropathological changes to the neurological signs needs further study.

Lipid metabolism in the vitamin-B12-deprived rat.

Rats were deprived of vitamin B12 in order to study the effect of this deprivation on the metabolism of lipids in the liver and the nervous system. Serum vitamin B12 concentrations of 102.7 and 78 pg/ml were found at sacrifice after 5 and 6 months, respectively. Neurological testing failed to reveal signs of neuropathy. The total liver lipids were decreased in the vitamin-B12-deprived animals, but no changes were detected in the lipid concentration or in the phospholipid composition of the nervous system. Some animals were given propionate, and in these, contrary to expectations, pentadecanoic acid and heptadecanoic acid were found in smaller amounts in the liver triglycerides of the vitamin B12-deprived rats than in the control rats. This could be due to the inhibitory effect of methylmalonyl CoA on fatty-acid synthesis, demonstrated by others in vitro.

Vitamin B12 deprivation in the rat: effects on folate metabolism with emphasis on the nervous system.

Rats were subjected to deprivation of vitamin B12 in order to induce neuropathy and to study effect on folate metabolism. Plasma vitamin B12 concentrations were maintained at about 100 pg/ml for 5 months. Neurological testing failed to reveal signs of neuropathy. Vitamin B12 deprivation induced high plasma folate levels but had no effects on the levels of total folate in the liver or the nervous system, probably because of an adequate methionine supply. If the rats were starved, a smaller proportion of 5-methyltetrahydrofolate was found both in liver and brain of the vitamin-B12-deprived animals. The folate concentration in the cerebrospinal fluid was lower than in the plasma but the values were correlated. There was a striking similarity between the liver and the brain in the way of handling 3H-folic acid and 14C-methyltetrahydrofolic acid. However, both substances showed a higher specific activity in the brain than in the liver, indicating a more dynamic state of brain folate.

Focal reflex epilepsy with myoclonus; electrophysiological investigation and therapeutic implications.

A middle-aged man suffering from myoclonic jerks of the right arm and leg and occasional grand mal seizures was investigated electrophysiologically. The EEG showed a left central spike focus which could be activated by any stimulus which distorted the biceps, triceps or brachioradialis muscles but skin stimulation was ineffective. Electrical nerve stimulation subthreshold to the alpha motoneurone fibres evoked cortical spikes and myoclonic jerks. The evidence supports the hypothesis that the myoclonus was triggered by muscle spindle afferent fibres (Ia) which projected to an epileptogenic focus in the sensori-motor area. A marked improvement of symptoms was achieved by a combination of baclophen and dipropylacetate.

Reduction of folate levels in the rat: Difference in depletion between the central and the peripheral nervous system.

1. Rats were deprived of dietary folate for 12 and 9.5 months in two experiments; one with and one without succinylsulfathiazole added to the diet. Folate levels decreased faster in the former experiment and the final blood values were lower. Tissue folate was examined in the latter experiment only. 2. The animals were repeatedly examined with neurological tests and compared with a control group supplemented with folic acid. Every test proved normal. Measurement of motor nerve conduction velocities after 12 months in the experiment where succinylsulfathiazole was given revealed lower velocities in the non-supplemented group. There was no difference between the groups in the experiment without succinylsulfathiazole. 3. In the latter experiment brain folate was reduced by only 16% in the non-supplemented animals compared with the controls, whereas whole blood folate fell by 60%, liver folate by 50% and sciatic nerve folate by 59%. 4. The central nervous system is resistant to systemic folate depletion, whereas the peripheral nerves are depleted to the same degree as the extra-neural tissues.