Migration and multiple sclerosis in United Kingdom and Ireland immigrants to Australia: a reassessment. II. Characteristics of early (pre-1947) compared to later migrants.

In our recent reassessment we explored the risk of MS by age at immigration in 258 migrants from United Kingdom and Ireland (UKI) to four states of Australia (New South Wales, Queensland, South Australia, and Western Australia) in the period 1947-1981 (Group II). In the present report we have compared their characteristics with 44 cases who migrated before 1947 (Group I), divided into two subsets: Group Ia (15 cases) was rather similar to Group II in age at immigration (means of 20 and 23 years), age at onset (39 and 33 years), and duration from immigration to onset (19 and 10 years). Group Ib (29 cases) was significantly different from Group II, with mean ages of 4 years at immigration and 40 years at onset, for a mean interval of some 35 years between immigration and onset. All onsets in Group Ib occurred after 1947. We concluded that the Group Ib cases had most probably acquired their MS in Australia. Immigrants from high MS risk countries, including UKI, were modest in number before 1947, but some 770,000 entered from 1947-1981. They may have been the source of MS for the Group Ib migrants.

Migration and multiple sclerosis in immigrants to Australia from United Kingdom and Ireland: a reassessment. I. Risk of MS by age at immigration.

A previous study of the prevalence of multiple sclerosis (MS) in 1981 among immigrants from the United Kingdom and Ireland to Australia found that the prevalence for those with age at immigration (AAI) under 15 years of age did not differ from the older immigrants. We have reanalysed the original materials as well as census data for 1901-1981 for UKI and other high MS risk country immigrants. There was a highly significant trend in the prevalence rates of all Australians from New South Wales (NSW) to South Australia (SA) to Western Australia (WA) to Queensland (QLD). Rates by state among the Australian-born were almost identical to these, but there was no prevalence gradient for the UKI-born. The denominator population at risk of MS by AAI was calculated from special census tables of length of residence in Australia by age 0-79 in 1981 for UKI immigrants 1947-1981. The numerator was limited to the subset of 258 MS (Group II) also immigrating in 1947 and later, and age 0-79 in 1981. The absolute risk of MS for these migrants to the four states entering at age 0-14 was 22/100,000, significantly less than for all older age groups; age 15-39 immigrants had a risk of 54/100,000. Similar risk ratios for 0-14 versus 15-39 by state were 31 versus 61 (NSW), 29 versus 44 (QLD), 11 versus 50 (SA), 15 versus 51 (WA).

Cold-induced sweating syndrome: CISS1 and CISS2: manifestations from infancy to adulthood. Four new cases.

Cold-induced sweating syndrome (CISS), a rare autosomal recessive disorder, is genetically heterogeneous. Deficiency of the CRLF1 and the CLCF1 gene functions results in CISS1 and CISS2, respectively. So far, only a single patient with CISS2 has been reported. Here we describe four new cases of CISS, two additional patients with CISS2 (confirming locus heterogeneity) and two patients with CISS1. Their case histories are given in detail to emphasize the striking similarity of their presentation, which makes a clinical differentiation impossible. All four cases had a uniform presentation in the neonatal period, much like Crisponi syndrome - inability to suckle and swallow due to facial and bulbar weakness; excessive startle and trismus-like facial contractions when crying or being handled; apnoeic spells; episodic unexplained fevers (up to 41 degrees C) and associated seizures or even sudden death; erythematous skin rashes; and camptodactyly. Thus it is evident that Crisponi syndrome is the pediatric manifestation of both CISS1 and CISS2. Signs abate during infancy and most children have a normal psychomotor development. During the first decade all children develop scoliosis and abnormal sweating which is the most disabling symptom in adulthood. We report that cold-induced sweating can be effectively treated. Detailed clinical observations, correlated with the findings from basic science research, may serve to elucidate the role(s) of this important cytokine complex in embryonic and postnatal development.

Long-term prognosis of multiple sclerosis in Australia.

Long-term survival and progression of disability in multiple sclerosis have not been studied previously in Australia. We report the findings in a cohort of 159 patients from Newcastle. Median survival time from onset of symptoms to death was 42 years. When expected survival rates are compared with those of the Australian population, there is approximately a 10% reduction in survival time in multiple sclerosis patients, after 20 years or more from disease onset. The expected time to reach DSS 3 and DSS 6 was 7 years and 27 years respectively. Survival time of multiple sclerosis patients and rate of progression of the disease are similar in the Northern and Southern Hemispheres.

Cold-induced sweating syndrome: a report of two cases and demonstration of genetic heterogeneity.

OBJECTIVES: To characterize the specific autonomic disturbances underlying the cold-induced sweating syndrome (CISS), and to describe a novel genetic variant of this rare recessive disorder. The two not previously reported patients had similar dysmorphic features: abnormal facial appearance, high arched palate, low set rotated ears, flexion deformities of elbows and fingers and scoliosis. Most noticeable were their paradoxical sweat responses: cold ambient temperature induced a profuse sweating over the face, arms and trunk but not over the lower limbs; while in the heat very little sweating occurred primarily on the legs. Testing of autonomic functions demonstrated normal cardiovascular reflexes and postganglionic sympathetic efferent functions. Sural nerve morphology and number of unmyelinated fibers was normal and skin biopsies showed normal appearing eccrine sweat glands. MRI scans revealed no structural brain abnormalities. Oral clonidine, prescribed in one patient, completely suppressed cold-induced sweating. Observed clinical features matched those of two sisters reported from Israel and of two brothers reported from Norway. All six cases presented a similar phenotype. The Norwegian, Israeli and Canadian cases were homozygous or compound heterozygous, respectively, for mutations in the CRLF1 gene on chromosome 19p12 (CISS1). The Australian case, however, had no pathogenic sequence variants in the CRLF1 gene, but was compound heterozygous for mutations in the CLCF1 gene on chromosome 11q13.3 (CISS2). CONCLUSION: The rare cold-induced sweating syndrome is genetically heterogeneous and is probably caused by central and peripheral impairment of sudomotor functions. This is the first detailed report on the clinical consequences of mutations in the CLCF1 gene in humans. Directions for medical therapies are outlined to achieve long term symptom control.

Autonomic nervous system function in multiple sclerosis.

Autonomic dysfunction causes significant disability in patients with multiple sclerosis (MS). Abnormalities of bladder, bowel and sexual function have been well documented in previous studies but cardiovascular and sudomotor autonomic changes have been less frequently reported. The present study has documented autonomic symptoms and results of cardiovascular and sudomotor autonomic function tests in 63 MS patients and correlated these changes with the clinical features of MS.Autonomic symptoms were common in MS patients, the most common being disorders of micturition, impotence, sudomotor and gastrointestinal disturbances, which were associated with increased MS severity. There was no significant association between autonomic symptoms and abnormalities of autonomic investigations. Abnormalities of one or more autonomic function tests, not including those of bladder, gastrointestinal or sexual dysfunction, were present in more than one half of the MS patients. Autonomic dysfunction, defined as abnormalities in two or more tests, was found in 18% of patients and was associated with increased MS severity. Postural hypotension was very uncommon. Parasympathetic cardiovascular autonomic abnormalities occurred in 16% of patients and were associated with increased MS severity. Sympathetic cardiovascular abnormalities were present in 13% of patients and showed no significant association with MS severity. The sympathetic skin response(SSR) was abnormal in nearly one half of the patients and also showed no significant association with MS severity. There was a variable and heterogenous pattern of autonomic test abnormalities found in the MS patients, which were of minor clinical significance except for postural hypotension. Cardiovascular and sudomotor autonomic abnormalities in MS patients are likely to be due to plaques distributed throughout the brainstem and spinal cord affecting anatomically widespread autonomic regulatory areas and their connections.

Amyloidoma of a spinal root.

A unique case of amyloidoma presenting as a dumbbell-shaped tumor of a spinal root without bony erosion is described. Amyloid was also present in the facial nerve. DNA analysis for transthyretin was negative. Isolated amyloid fibers contained lambda light chains, and although plasma and urine immunoelectrophoresis performed by immunofixation was normal, it is possible the tumor may have been derived from an isolated plasmacytoma.

Progressive increase in incidence and prevalence of multiple sclerosis in Newcastle, Australia: a 35-year study.

The prevalence of multiple sclerosis (MS) in Newcastle, Australia increased significantly between 1961 and 1981 and the incidence of the disease also increased between the decades 1950-1959 and 1971-1981. The present study sought to determine whether there has been a further increase in the frequency of MS in the subsequent 15 years, and to examine the potential factors underlying this change. The incidence, prevalence and clinical profile of multiple sclerosis were therefore re-examined in Newcastle, Australia in 1996 using comparable diagnostic criteria and methods to those employed in studies in the same region in 1961 and 1981. There has been a significant progressive increase in prevalence from 19.6 to 59.1 per 100,000 population and a significant increase in incidence from 1.2 to 2.4 per 100,000 population from 1961 to 1996. The most pronounced increase in prevalence was in females and in the age-group over 60 years, and there was also an increased incidence in females aged 20-29 years. There was little change in the age of disease onset, but duration of disease in females had increased substantially. The significant increase in prevalence is attributed to increased incidence, particularly in females; and to increased survival. Although such trends in prevalence have been observed in the Northern Hemisphere, this is the first such study in the Southern Hemisphere to show a longitudinal increase in prevalence and incidence over a period of this duration.

Performance of growing-finishing pigs fed diets based on normal or low viscosity rye fed with and without enzyme supplementation.

One hundred and forty crossbred pigs (Pig Improvement Canada Ltd, Acme Alberta), weighing an average of 21.5 + 3.6 kg, were assigned on the basis of sex, weight and litter to one of five dietary treatments. The control diet was barley-based, while in the remaining four treatments, the grain component consisted of either normal or low viscosity rye fed with or without pentosanase. Digestibility coefficients for dry matter, crude protein and gross energy were significantly (P = 0.0001) higher for the rye-based diets than the barley based diet. There were no differences in digestibility coefficients between normal and low viscosity diets or between diets supplemented or unsupplemented with pentosanase. Over the entire experimental period (21.5 to 100.7 kg), pigs fed the normal viscosity rye gained better (P = 0.001) and had a higher daily intake (P = 0.001) than pigs fed the low viscosity rye. Pigs fed the low viscosity rye tended to gain slower than pigs fed barley and with lower intake while pigs fed the normal viscosity rye had similar gains and intake to the pigs fed barley. Enzyme supplementation failed to improve pig performance. Males had higher gains and intake than females (P < 0.05). Enzyme supplementation, rye viscosity or choice of cereal grain had no effect on any of the carcass traits measured. In conclusion, the results of the present experiment indicate that rye is a good alternative to barley for use in growing-finishing rations and becomes increasing attractive as the age of the pig increases. Breeding efforts directed towards reducing the viscosity of rye are unlikely to be successful in improving the nutritive value of rye for swine.

Studies on rye (Secale cereale L.) lines exhibiting a range of extract viscosities. 1. Composition, molecular weight distribution of water extracts, and biochemical characteristics of purified water-extractable arabinoxylan.

Five rye lines exhibiting a wide range of extract viscosities, along with commercial cultivars of rye and wheat, were compared with respect to their physical and chemical properties. Rye wholemeals contained significantly higher concentrations of total and soluble dietary fiber (TDF and SDF, respectively), total and water-extractable arabinoxylan (TAX and WEAX, respectively), and beta-glucan than did wheat. Significant positive correlations were obtained between rye wholemeal extract viscosity and SDF content (r = 0.90, p < 0.05) and WEAX content (r = 0.89, p < 0.05). Gel permeation chromatography (GPC) of water extracts of rye wholemeals revealed the presence of a high molecular weight fraction (HMWF), which was found in higher concentration in the ryes than in wheat. A significant positive correlation (r = 0.84, p < 0.05) was observed between HMWF content (expressed as a proportion of the total carbohydrate in water extracts) and extract viscosity of rye wholemeals. Treatment of a rye wholemeal extract with xylanase, followed by GPC, indicated that the HMWF consisted primarily of WEAX. Successive treatment of a rye wholemeal extract with alpha-amylase, lichenase, protease, and xylanase confirmed that the viscosity of the extract was primarily related to its content of WEAX. WEAX was isolated from high, intermediate, and low extract viscosity ryes. Structural differences were observed among the three arabinoxylans using H NMR and high-pressure size exclusion chromatography with triple detection. The WEAX from high extract viscosity rye was a higher molecular weight macromolecule exhibiting a higher intrinsic viscosity, a larger radius of gyration, a larger hydrodynamic radius, and a lower degree of branching compared to WEAX from low and intermediate extract viscosity ryes.

Studies on rye (Secale cereale L.) lines exhibiting a range of extract viscosities. 2. Rheological and baking characteristics of rye and rye/wheat blends and feeding value for chicks of wholemeals and breads.

Five rye lines exhibiting a wide range of extract viscosities were evaluated for the rheological and baking properties of their flours, individually and in blends with hard red spring wheat flour. Commercial cultivars of rye and triticale were included in the study as controls. Extract viscosities of rye flours were higher than those of corresponding wholemeals, indicating shifting of water-extractable arabinoxylan into flour during roller milling. Falling numbers of the rye flours correlated positively with their extract viscosities in the presence (r = 0.73, p < 0.05) or absence (r = 0.65, p < 0.05) of an enzyme inhibitor. Farinograms revealed the weakness of rye and triticale flours compared to wheat flour. Extract viscosities of rye flours were negatively correlated (r = -0.65, p < 0.05) with mixing tolerance index and positively correlated (r = 0.64, p < 0.05) with dough stability, suggesting a positive impact of extract viscosity on dough strength. Extract viscosity was negatively correlated (r = -0.74, p < 0.05) with loaf volume and specific volume (r = -0.73, p < 0.05) and positively correlated (r = 0.73, p < 0.05) with loaf weight of rye/wheat bread. Overall, the results indicated that 30% of flour from high or low extract viscosity rye could be incorporated into rye/wheat breads without seriously compromising bread quality. Inclusion of rye, particularly high extract viscosity rye, in chick diets seriously impeded growth performance and feed efficiency. Part of the arabinoxylan survived bread-making and exerted an effect on chicks, although substantially lower digesta viscosities were observed in chicks fed rye bread diets than in those fed rye wholemeals.

Multiple sclerosis in Australia: prognostic factors.

In order to determine the influence of age of onset, sex, onset symptoms, clinical course and interval from onset to first relapse on the subsequent outcome of multiple sclerosis (MS), data from 2934 cases of MS documented in a large population based study undertaken in Australia have been analysed. Disability on prevalence day (30 June 1981) was defined on the Kurtzke disability scale as mild (DSS 0-3), moderate (DSS 4-6) and severe (DSS 7-9). Prognostic factors associated with mild vs moderate/severe, and moderate vs severe disability on prevalence day were identified by logistic regression analysis. A worse prognosis was significantly associated with older age of onset, progressive disease course, onset symptoms that were multiple, pyramidal or cerebellar, and a short interval between onset and first relapse.

The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia.

The prevalence of multiple sclerosis in the Australian-born population in five different regions of Australia has a strong correlation with latitude, the disease becoming increasingly prevalent with increasing south latitude. In this study, the prevalence in the migrant population from the UK and Ireland (UKI) in the different regions also showed a significant correlation with latitude, but this relationship was strongly influenced by the high prevalence in Hobart. Except for Hobart, the prevalence in migrants was considerably less than that in their countries of origin. The prevalence of multiple sclerosis among those migrating before the age of 15 years from the high-risk UKI to lower-risk Australia was not significantly different to that among those migrating at or after that age, and this finding was confirmed in a case-control study which demonstrated little association between age at migration and risk of developing multiple sclerosis. These findings suggest that the risk from environmental factors in multiple sclerosis may operate over a period of many years and not only in childhood and early adult life.

Clinical syndromes associated with tomacula or myelin swellings in sural nerve biopsies.

OBJECTIVES: To describe the neuropathological features of clinical syndromes associated with tomacula or focal myelin swellings in sural nerve biospies and to discuss possible common aetiopathological pathways leading to their formation in this group of neuropathies. METHODS: Fifty two patients with sural nerve biopsies reported to show tomacula or focal myelin swellings were reviewed, light and electron microscopy were performed, and tomacula were analysed on teased fibre studies. Molecular genetic studies were performed on those patients who were available for genetic testing. RESULTS: Thirty seven patients were diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), four with hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1), four with HMSN with myelin outfolding (CMT4B), three with IgM paraproteinemic neuropathy, three with chronic inflammatory demyelinating polyneuropathy (CIDP), and one with HMSN III (CMT3). CONCLUSIONS: Most of these syndromes were shown to be related to genetic or immunological defects of myelin components such as peripheral myelin protein 22 (PMP22), myelin protein zero (P0), or myelin associated glycoprotein (MAG). These proteins share the HNK-1 epitope which has been implicated in cell adhesion processes. Impaired myelin maintenance may therefore contribute to the formation of tomacula and subsequent demyelination.

Prevalence of chronic inflammatory demyelinating polyneuropathy in New South Wales, Australia.

A prevalence study of chronic inflammatory demyelinating polyneuropathy (CIDP) was performed in New South Wales (NSW), Australia, with a prevalence day of August 6, 1996, which coincided with a national census. The population of NSW was 5,995,544, and the crude prevalence of CIDP was 1.9 per 100,000 population. It was higher in male patients than in female patients, and the age-specific prevalence reached a maximum of 6.7 per 100,000 population in the 70- to 79-year-old age group. The prevalence in the city of Newcastle, with a population of 448,663, was 2.0 per 100,000 population and is representative of the whole of NSW. The estimated crude annual incidence was 0.15 per 100,000 population. The mean age of onset was 47.6 years (median, 53.5 years), 51% of patients had a relapsing-remitting course, the mean duration on prevalence day was 7.1 years (median, 5 years), and 87% of patients were able to walk without walking aids or other assistance.

Activated non-neural specific T cells open the blood-brain barrier to circulating antibodies.

Previous studies have shown that activated T cells can successfully cross endothelial barriers and will accumulate in tissue which contains their specific antigen. Myelin specific T cells (e.g. myelin basic protein specific) are recognized to play an important role in the induction of experimental autoimmune demyelinating disease of the CNS and have been shown to induce blood-brain barrier breakdown effectively. In this study we injected T cells reactive to a non-neural antigen (ovalbumin) systemically into Lewis rats and caused them to accumulate in the thoracic dorsal column by a prior injection of ovalbumin. Selected rats were given systemic demyelinating antibody, antimyelin oligodendrocyte antibody (anti-MOG antibody), to provide evidence of permeability changes to the blood-brain barrier. These animals were compared with control rats given systemic anti-P0 monoclonal antibody and to other rats given a direct micro-injection (3 microliters) of anti-MOG antibody into the thoracic dorsal column. All animals were monitored by serial neurophysiological studies and by histological examination. Direct anti-MOG antibody injection produced a focal block in conduction at the injection site and a large circumscribed area of primary demyelination with axonal preservation within the dorsal column. An even more profound conduction block and more extensive plaque-like region of demyelination were seen in animals given antigen, activated T cells and systemic antibody. However, animals given antigen and T cells without relevant antibody did not show conduction impairment or demyelination, except when very large numbers of T cells were given; such rats developed severe irreversible axonal damage. This study demonstrates the blood-brain barrier is disrupted by activated T cells of non-neural specificity and allows large plaque-like regions of demyelination to form in the presence of circulating antimyelin antibody. The relevance of this finding to multiple sclerosis is discussed.

Spinal root and plexus hypertrophy in chronic inflammatory demyelinating polyneuropathy.

MRI was performed on the spinal roots, brachial and lumbar plexuses of 14 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Hypertrophy of cervical roots and brachial plexus was demonstrated in eight cases, six of whom also had hypertrophy of the lumbar plexus. Of 11 patients who received gadolinium, five of six cases with hypertrophy and one of five without hypertrophy demonstrated enhancement. All patients with hypertrophy had a relapsing-remitting course and a significantly longer disease duration. Gross onion-bulb formations were seen in a biopsy of nerve from the brachial plexus in one case with clinically evident nodular hypertrophy. We conclude that spinal root and plexus hypertrophy may be seen on MRI, particularly in cases of CIDP of long duration, and gadolinium enhancement may be present in active disease.

Cyclosporin A in resistant chronic inflammatory demyelinating polyradiculoneuropathy.

The role of cyclosporin A (CsA) in the treatment of resistant chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was retrospectively reviewed in 19 patients who had failed to respond adequately to corticosteroids, plasmapheresis, intravenous immunoglobulin, and in some cases other immunosuppressive agents. Patients were subdivided into progressive or relapsing types according to the course of disease and response to therapy graded at follow-up by clinical and electrophysiological criteria. In the progressive group, the mean disability status declined from 3.8+/-0.7 to 1.8+/-1.1 grades on a 5-grade scale following CsA therapy (P<0.001). In the relapsing group, the mean annual incidence of relapse declined from 1.0+/-0.5 to 0.2+/-0.4 after commencement of CsA (P<0.05). Dose-dependent, reversible nephrotoxicity was the most serious complication of therapy, and necessitated cessation of CsA in 2 patients. In conclusion, CsA is an efficacious and, with appropriate monitoring, safe therapy for patients with CIDP.