Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS. METHODS: The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31. FINDINGS: Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ(2) on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40-1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event. INTERPRETATION: We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments. FUNDING: The Motor Neurone Disease Association of Great Britain and Northern Ireland.

The natural history of multiple sclerosis: a regional study with some longitudinal data.

A regional survey of multiple sclerosis (MS) patients in Wellington, New Zealand in 1983 identified 245 patients, giving a prevalence (all categories included) of 72 per 100,000. Retrospective review of the history and medical records identified a poorer prognosis for disability where there was progressive onset of symptoms, secondary progression after a remitting phase, older age of onset (40 years or more), or a motor syndrome involving the limbs at presentation. In 1983 follow up data were obtained on 96 patients who were seen during a previous survey in 1968. For those with definite or probable MS, progression to severe disability (Kurtzke disability status scale (DSS) 6-9) or death (DSS 10) was seen in 26/34 with moderate disability (DSS 3-5) in 1968 and in only 5/29 with mild disability (DSS 0-2). When the analysis is confined to those with symptoms for at least five years in 1968, severe disability or death from MS occurred in 22/30 with moderate and 4/19 with mild disability (chi 2 = 10.8, p = 0.001). It is concluded that the patient's established disability level after five years of illness is a useful, but not infallible, prognostic indicator. From the follow up of the 1968 patients, the probability of MS-related mortality for a given disease duration was calculated. Using this survival distribution to adjust the disability ratings in the 1983 population, it was found that the proportion with mild disability decreased steadily with increasing disease duration, reaching 14% when the disease duration was more than 25 years.

Frequent involvement of the optic radiation in patients with acute isolated optic neuritis.

Magnetic resonance imaging revealed asymptomatic lesions in white matter regions corresponding with the optic radiations in 20 of 28 patients (71%) with clinically isolated optic neuritis. In contrast to the findings with symptomatic lesions, there was no relationship between the latency of the visual evoked potential and the presence of these asymptomatic posterior visual pathway lesions.

Class II HLA antigens in multiple sclerosis.

HLA typing in Wellington revealed a stronger association of multiple sclerosis with DR2 than with DQw1. The association with DQw1 appeared to be due to linkage disequilibrium of this antigen with DR2. These results, when considered in conjunction with other studies, are most easily explained by the hypothesis that susceptibility to multiple sclerosis is influenced by multiple risk factors, with DR2 being an important risk factor in Caucasoid populations.

Comparison of mefenamic acid and propranolol with placebo in migraine prophylaxis.

The prophylactic effects of the antiprostaglandin agent mefenamic acid on migraine attacks were compared with propranolol or placebo in a double-blind crossover study of 29 patients. In the 17 patients who completed the trial the frequency of attacks and their total duration were significantly reduced during mefenamic acid therapy or propranolol therapy as compared to placebo. There were no significant effects of mefenamic acid or propranolol on average duration or severity of migraine attacks. The study suggests that mefenamic acid and propranolol are equally effective for migraine prophylaxis.

Ethnic and HLA patterns related to multiple sclerosis in Wellington, New Zealand.

A recent survey revealed 237 cases of multiple sclerosis in Wellington, New Zealand, giving an overall prevalence of 69 cases per 100,000. Two hundred and thirty-five were European with one Asian and only one Maori, confirming the rarity of the disease in Maoris. HLA A3, B7 and DR2 antigens were more frequent in multiple sclerosis patients compared with European controls. The same antigens were much less common in the Maori population. The results suggest that Maoris have a low susceptibility to multiple sclerosis despite living in a high risk area, and that genetic susceptibility may be related to the HLA system.

Gliomatosis cerebri--report of a case.

An unusual case of gliomatosis cerebri in a 37 yr-old man is reported. He presented with a variable clinical picture. Mental changes, brain stem signs, cerebellar signs and rise in intracranial pressure were the constant findings. The postmortem findings are described and the available literature is reviewed.

Studies of endemic cretinism in Papua New Guinea: digital and palmar dermatoglyphic patterns.

We have tested the hypothesis that the abnormal development of the central nervous system seen in endemic cretinism might be accompanied by concurrent abnormal dermatoglyphic patterns. We compared digital and palmar dermatoglyphics of normal individuals and endemic cretins inhabiting the Huon Peninsula of Papua New Guinea. The population sampled from the Irumu River Valley included 118 males and 114 females with 22 male cretins and 23 female cretins. The population sampled from the Wantoat River Valley included 72 males and 38 females with 12 male cretins. No pathognomonic patterns were found that could identify the endemic cretin subpopulation. However, the occurrence of a number of differences between controls and cretins suggests that subtle changes in dermatoglyphic patterns accompany the anomalous development of the CNS secondary to maternal iodine deficiency. We discuss the significance of these findings and compare the dermatoglyphic patterns of normal Irumu and Wantoat natives and 21 other populations of Papua New Guinea.

Red cell antigen, serum protein and red cell enzyme polymorphisms in Eastern Highlanders of New Guinea.

A series of 1,187 blood samples from eight population groups in the Eastern Highlands of Papua New Guinea were tested for genetic variation in blood groups, serum proteins and red cell enzyme systems. The populations belonged to the language groups Gahuku-Asarc-Bena Bena, Kamano, Yagaria, Keiagana, Fore, Agarabe, Auyana and Tairora. Polymorphic variation was found in the ABO, MNS, P1, Rh, Hp, Tf, SEP, 6-PGD, ADA, MDH, and PGM genetic systems. East to West variation was shown in the language groups; the O, S, R2, and R0 genes increase in frequency from East to West and the A, R1, and M genes decrease in the same direction. In the East higher frequencies were found for the Du antigen, for the PGM21 gene and for a PGM second locus variant. The MDH 3 variant was found in all the populations, its highest value being in the Tairora.

Red cell antigen, serum protein and red cell enzyme polymorphisms in Karkar Islanders and inhabitants of the adjacent North Coast of New Guinea.

Blood samples from the Waskia and Takia populations of Karkar Island, Papua New Guinea, and other nearby mainland populations, were tested for genetic variation in blood group, serum protein and red cell enzyme systems. Polymorphic variation was present in the ABO, P, MNS, Rh, Lewis, Duffy, Kidd and Gerbich blood group systems, in the Hp and Tf serum protein systems, and in the acid phosphatase, 6-PGD, ADA, PGM, MDH, and G-6-PD enzyme systems. A small number of variants was found in other systems: there were 4 Lu(a+), 1 Kp(a+), 2 C variants in the acid phosphatase system, 6 LDH variants, 1 ADA3-1 and 1 AK2-1 sample. All samples were negative for the red cell antigens Cw, Vw, He, K, Jsa, Dia, Wra, Rd and Marriott, and no variation was observed in the PHI enzyme system. The results are discussed in relation to those obtained on other Papua New Guinea populations.

Genetic surveys from the Central, Morobe and Northern Districts, Papua New Guinea.

The results of blood group surveys on a number of linguistic groups inhabiting contiguous areas within the Goilala sub-district of the Central District, the southern part of the Morobe District and the Northern District are reported. Altogether about 1900 subjects were tested, but the extent of testing varied. Red cell enzyme and serum protein systems were also investigated in two groups. Similarities and dissimilarities of blood group distributions are noted, as also are some possible gene gradients among peoples living to the north of the main divide. Two groups, the Kuni/Tauade of the Goilala sub-district, and the Roro/Kovio living towards the Papuan Gulf coast seem well distinguished from the remainder. Genetic distances were calculated for five populations north of the divide, and agree with the geographical and linguistic situation. The Weri people of the middle Waria provided an example of Hp 2-1 modified, two examples of the MDH.NG.1 variant and one of AK 2-1.

Red cell antigen, serum protein, and red cell enzyme polymorphisms in inhabitants of the Jimi Valley, Western Highlands, New Guinea.

A series of blood samples from four villages in the Jimi Valley, Western New Guinea Highlands, has been tested for genetic variation in blood group, serum protein, and red cell enzyme systems. Polymorphic variation was present for the AB0, MNS, P, and Rh blood group systems, for the Hp and Tf serum protein systems, and for the acid phosphatase, 6-PGD, PGM, MDH, and ADA enzyme systems. One each of the following variants was detected: Ge(a-), G6PD deficient, AK 2-1 and PHI 7-1 or 8-1. All samples tested were Cw-, K-, Kp(a-), Wr(a-), Fy(a+ b-), Rd-, and LDH normal. Genetic distance analysis places the Jimi Valley populations closer to peoples of the Chimbu-Chuave and Wahgi-Hagen areas than to the Maring people of the Simbai Valley to the north.

Congenital nystagmus among the Red-skins of the Highlands of Papua New Guinea.

Sixty-four people with pigmentary anomalies of the skin were examined in the Eastern Highlands of New Guinea. Thirty-one had a bronze-red skin colour which appears to be unique to New Guinea. Eighteen of the Red-skins had congenital nystagmus which was not associated with impairment of visual acuity. The fundi were normal. The pigmentary anomaly is recessively inherited, and the gene responsible for the nystagmus appears to be associated with those controlling skin colour. The condition appears to be a unique form of albinism and confers no disadvantage on those who have it.

Granulomatous angiitis of the CNS.

A 25-year-old man had granulomatous angiitis of the CNS. The disease began with symptoms of an upper respiratory tract infection; it had a relentless course, simulating viral encephalitis, with the patient dying some six months after the onset of symptoms. The lesions were confined to small intracranial arteries and veins, predominantly about the cerebellum. An unusual feature was the occurrence of a small (2 mm) aneurysm on a leptomeningeal artery deep in a cerebellar sulcus. There is a need for pooling data and pathological material by an international body to enable detailed expert analysis of large numbers of cases of cerebral angiitis that do not now constitute a homogeneous group.

Variation in blood pressure in a New Guinea population.

The contributions of age and anthropometric, biochemical and socio-economic variables to blood pressure variation in the population of Karkar Island, Papua New Guinea are examined. Blood pressure does not change with age in males; in females there is a decline from ages 21 to 40 and an increase (in systolic pressure) thereafter. Body weight and skinfold thicknesses decline with age in females; arm circumferences decline in both sexes. There were no age effects on serum cholesterol or serum sodium. Variation in ponderal index and subcutaneous fat contribute to variation in blood pressure. The correlations of blood pressure with physique are more important in males and the particular variables concerned suggest a nutritional basis. The socio-economic variables examined showed little variation and this was not associated with variation in blood pressure.

Essential tremor in Papua, New Guinea.

The clinical features of 175 cases of essential tremor are related. This disorder is prevalent among a population of the Eastern Highlands of Papua New Guinea. It affects predominantly women in middle and old age; only 27 per cent of the cases were males. The disorder is slowly progressive and significant disability appears in elderly women when the trunk muscles are involved. Epidemiological studies have shown that the presence of tremor can be correlated with linguistic distinctions between high and low prevalence populations. Although only 30 patients reported a first degree relative with tremor, the syndrome would seem to stem from a genetic predisposition. In a number of patients essential tremor appeared to be associated with Parkinson's disease.

Serum thyroglobulin in inhabitants of an endemic goiter region of New Guinea.

Serum thyroglobulin Tg(RIA) was studied in 161 residents of the Nomane region of New Guinea. The incidence of antithyroglobulin antibodies (ATA) and antimicrosomal antibodies (anti-M) was also studied to assess the role of autoimmunity in goitrogenesis. ATA were detected in only 4 sera; these sera were excluded from the study since ATA interfere in the Tg radioimmunoassay. Anti-M antibodies were undetectable in all of 105 subjects whose sera were analyzed. Mean (+/-se) serum Tg(RIA) in the 84 nongoitrous (NG) subjects was 163.1 +/- 17.2 ng/ml, whereas that in 77 goitrous (G) subjects was 208.1 +/- 19.8 ng/ml; both values were much higher (P is less than 0.001) than that (5.1 +/- 0.49 ng/ml) in normal Californian subjects. The mean serum thyroid stimulating hormone (TSH) in the NG group (12.1 +/- 2.1 muU/ml) was not statistically different from that in the G group (10.1 +/- 1.5 muU/ml). Serum Tg(RIA) correlated positively with log TSH (r equals 0.38 P is less than 0.001). Intrigued by the finding of goiters in some residents of an endemic goiter region and its absence in other residents exposed to the same environmental factors, we evaluated the possibility that the thyroid glands of subjects who develop goiters may be inherently more responsive to any given level of TSH than those of the inhabitants without goiters. However, the slope of the correlation between serum Tg(RIA) and log TSH was only slightly (0.1 is less than P is greater than .05) higher in G than in the NG group. These studies suggested that factors other than thyroidal responsiveness to TSH must also be important in goiterogenesis of endemic goiter regions. We conclude that 1) serum thyroglobulin is a sensitive parameter of chronic as well as acute thyroidal stimulation; 2) Thyroid autoimmunity and increased thyroidal response to TSH do not explain goiterogenesis in New Guinea and attention should be focused on other possibilities.