Current research in neuro-epidemiology. Some main trends.

Recent epidemiological research has contributed to the understanding of the nature of common neurological disorders like multiple sclerosis, Parkinsonism, and amyotrophic lateral sclerosis. Viral etiology constitutes the most probable environmental factor in multiple sclerosis, but host-related genetic factors are also involved and determine susceptibility. In disorders like Parkinsonism, amyotrophic lateral sclerosis, and epilepsy, heredity seems to play a more important role than earlier believed, and segregation analyses indicate polygenic inheritance patterns. The subacute spongiform encephalopathies fit into a similar concept, and here the hunt for infectious agents has succeeded. Polygenic traits and dominantly inherited disorders seem to aggregate in genetic isolates, as shown through studies from different parts of the world. The reason for this is not quite clear, but selection through assortative matings or other mechanisms may be operating in these populations.

The clinical effect and the effect on serum IgG antibodies to peripheral nerve tissue of plasma exchange in patients wit Guillain-Barré syndrome.

The mixed haemagglutination technique was used to demonstrate IgG antibodies to peripheral nerve tissue in sera from patients with the Guillain-Barré syndrome. The clinical effect and the effect on the antibodies of plasma exchange were examined in 18 patients. Neurological examination with muscle testing and neurophysiological examination of the patients were performed before and immediately after plasma exchange. Before the exchange antibodies were detected in sera from 11 of the patients. These patients showed clinical improvement during the treatment. After plasma exchange, antibodies were detected in sera from only two of the patients. The seven patients without detectable antibodies showed no clinical improvement.

Plasma exchange in patients with Guillain-Barré syndrome: clinical improvement in patients with serum IgG antibodies to peripheral nerve tissue.

The mixed hemagglutination technique was used to demonstrate IgG antibodies to peripheral nerve tissue in sera from patients with Guillain-Barré syndrome. The clinical effect and the effect on the antibodies of plasma exchange (PE) were examined in 24 patients, 16 patients with acute form and 8 patients with the chronic form of the disease. Neurological examination with muscle testing and neurophysiological examination of the patients were performed before and immediately after the PE. Before PE antibodies were detected in sera from 15 of the patients. These patients showed clinical improvement during the treatment, however in one of the patients only after a time interval of 2 weeks. After PE, antibodies were detected in sera from only 3 of the patients. The 9 patients without detectable antibodies showed no clinical improvement.

Friedreich's ataxia in Western Norway.

Friedreich's ataxia (FA) was investigated in Western Norway, an area comprising several isolated communities and with a population of 725,000 as at 1 January 1968. The prevalence of FA was estimated to be 1/100,000 in this population. An autosomal recessive mode of transmission appeared likely in all instances. The gene frequency was only 7-9.10 minus 5, but the consanguinity rate was high in the families observed. The mutation rate was relatively high at 1-6.10 minus 5. The clinical features displayed by the 10 examined patients agreed well with those observed by other investigators. Spinal and cerebellar ataxia dominated the clinical picture. In most cases signs of peripheral neuropathy were also observed. Epilepsy was seen in some cases, and also dementia. Unspecific neuropathy, defined according to a scoring system may represent disease manifestation in FA heterozygotes.

The significance of "unspecific neuropathy" in hereditary ataxias and related disorders.

Neurological findings such as polyneuropathy, hyporeflexia, deformities, ataxic signs, and inverted plantar responses were found more frequently in unaffected sibs and other close relatives of people with hereditary ataxias or allied disorders (HA) than in a normal population sample. Introduction of a scoring system for neurological signs allowed the degree of neurological impairment to be estimated. The number of people with scores exceeding the limit of normality (sum score higher than 3.4) was counted among the members of HA families. This number was found to be greater in families where HA segregated as a recessive trait than those where it segregated as an autosomal dominant trait. The frequency of cases with high scores ("unspecific neuropathy" (Un)) observed in 1st and 2nd degree relatives of patients with dominant HA, suggested a hereditary basis for Un. The ratios were not compatible with simple Mendelism, but the observations fitted well with a hypothesis of polygenic inheritance. Un clustering in families with autosomal dominant HA could be due to a selection phenomenon through a negative assortative mating. Un cases observed in families with recessive HA may, in several instances, reflect disease manifestations in heterozygotes.

A study of certain traits accompanying some inherted neurological disorders.

Feeblemindedness, dementia, mental disorders, and epilepsy, as well as optic atrophy, tapeto-retinal degenerations, cataract, ophthalmoplegias, and neural hearing loss were found more frequently in patients suffering from hereditary ataxias (HA) and allied disorders than in the general population. Mental disorders and squints, and in certain instances also ocular myopathy, feeblemindedness, and cataract were found also in non-HA family members. These traits were particularly frequent in subjects with minor neurological signs previously defined as having an "unspecific neuropathy" (Un), and belonging to kindreds in which autosomal dominant HA segregated. Un clustering in such families is probably caused by other genetic (or other) mechanisms different from that governing the classical HA in the family. These presumably polygenic conditions are thought to be introduced into the HA kindreds by a negative selection. Optic atrophy, tapeto-retinal degenerations, surdity, epilepsy, and possibly also dementia, were found together with monomeric disease, as well as in the Un subjects, particularly in families with recessive HA. Such traits were equally rare in unaffected family members and controls. Un in such families as well as the traits mentioned may reflect manifestation of HA genes in heterozygotes. They could also reflect the presence of genes linked to the HA genes.

Linkage studies on Marinesco-Sjøgren syndrome and hypergonadotropic hypogonadism.

Marinesco-Sjøgren syndrome and hypergonadotropic hypogonadism were observed in two kindreds, and they were found to occur togetherin 9 out of 10 affected individuals. The last patient had Marinesco-Sjøgren syndrome without manifestations of hypogonadism, and similar findings were observed in two affected sisters from a third kindred. On the hypothesis that the concurrence of Marinesco-Sjøgren syndrome and hypergonadotropic hypogonadism was caused by linkage, a lod score analysis was conducted. Four sibships in the two kindreds were informative with respect to linkage. At the recombination fraction 0.05, the lod score exceeded 3. If linkage causes the concurrence of Marinesco-Sjøgren syndrome and hypergonadotropic hypongonadism in these kindreds, the linkage is close. No linkage was observed between the clinical syndromes and 17 marker systems.

Cerebral calcinosis with late onset encephalopathy. Unusual type of pseudo-pseudohypoparathyreoidism.

A family from Western Norway is described in which 5 out of 9 members in one generation developed a progressive encephalopathy in middle life. Massive, symmetrical calcifications located in basal ganglia, dentate nuclei and cerebral sulci of the brain were seen on roentgenograms of the skull. All affected members exhibited a clinical syndrome which included mental deterioration, extrapyramidal motor deficit, cerebellar ataxia and tremor. The biochemical investigation showed normal serum calcium and phosphorous and concentration of immunoreactive parathyroid hormone was normal. The Ellsworth-Howard test with exogenously administered parathyroid extract revealed a subnormal phosphorous diuresis while urinary excretion of cyclic AMP was normal. Thus, the defect appears to be an insufficient intracellular response to cyclic AMP. The late onset of symptoms is compatible with the slight disturbance in calcium-phosphorous metabolism we have demonstrated. The family probably represents an unusual type of pseudo-pseudohypoparathyroidism of which only one other family has been reported earlier. The investigations and pedigree analysis of the present kindred is suggestive of an autosomal recessive inheritance of the disorder.

Transient cerebral ischemic attacks in the young and middle aged. A population study.

During an investigation of coronary risk factors, a population 20 to 54 years old in Tromsø, Northern Norway was screened for transient ischemic cerebral attacks. Three simple screening questions were used. Sixteen thousand six hundred and twenty-one subjects participated in the study. Among the responders, a sample of 501 were evaluated neurologically and 10 men and 16 women identified as TIA cases. Mean age for men was 41.3 years, for women 33 years. Five women (mean age 24.4) had the events during pregnancy, pointing to pregnancy as a period of risk. Five-year incidence was found to be 2.5. per 1000. Clinical expressions and ratio carotid to vertebral-basilar TIA hardly differed from that found in materials of older patients. All 26 remained stroke-free during a mean observation period of 55 months. Known risk factors like hypertension, carotid stenosis and cardiac disease were found in only a few. Five women had low blood pressure. It is suggested that TIA in younger age groups may constitute a separate entity where, among other, haemodynamic factors and pregnancy play a role.

Creutzfeldt-Jakob disease. Infection of infancy or childhood?

A 51-year-old man who died of Creutzfeldt-Jakob disease (CJD), had transient dyskinesias with intention myoclonus and exaggerated startle reaction in early life. This may suggest a link between myoclonic encephalopathy of infants and CJD, and an incubation period of more than 40 years of the transmissible agent of CJD.

Autosomal recessive non-progressive ataxia with an early childhood debut.

The case histories and clinical studies are given of 7 consanguineous patients, 4 adults and 3 children, with a rather uniform clinical picture of nonprogressive cerebellar ataxia manifesting in early childhood. Most patients have in addition slight spastic signs, short stature and normal intelligence. There are no signs of other organ pathology, biochemical aberrations, endocrine- or immunopathology. CT-scan and PEG show cerebellar atrophy. The pedigree analysis indicates an autosomal recessive mode of inheritance. The condition falls between the ataxic syndromes in the cerebral palsy range and the heredo-ataxias. Until now, no similar disorders seems to have been described.

Unusual type of neural muscular atrophy with a possible X-chromosomal inheritance pattern.

In a large family five affected males belonging to four different kinships exhibited a muscle wasting of varying degree and with a predominantly proximal distribution. The index case had a facio-scapulo-humeral and peroneal muscular atrophy, whereas one of his cousins suffered a more generalized involvement starting in infancy and similar to Werdnig-Hoffman disease. The other affected family members had only slight changes. The index case and his affected brother had a positive Babinski sign. In enzyme histochemical preparations, specimens from the index case showed small group atrophy of type 2 fibers along with pseudomyopathic changes (whorled and coiled fibers, splitting) of type 1 fibers. Similar findings were observed in his cousin. Ultrastructural investigation gave no further information. Since all patients were males and the offspring of unaffected sisters, an X-chromosomal mode of transmission is proposed for this illness.

Cerebellar ataxia and hypergonadotropic hypogonadism in two kindreds. Chance concurrence, pleiotropism or linkage?

Two kindreds with Marinesco-Sjögren's syndrome in three sibships are described. In five of the six affected, but in none of the unaffected sibs, a hypergonadotropic hypogonadism was observed. In one of the kindreds a high degree of inbreeding was revealed, and inbreeding likely also existed in the other kindred. The two families were not related. Marinesco-Sjögren's syndrome is known to be a distinct clinical entity, governed by autosomal recessive inheritance, and this also applies to hypergonadotropic hypogonadism. Several heredo-degenerative nervous disorders are accompanied by a hypogonadotropic hypogonadism, which is believed to be secondary to the neurological disorder, as in traumatic paraplegia. A hypergonadotropic hypoganadism cannot readily be explained in this way. We consider genetic linkage between two independent disorders as the most likely explanation for the observed concurrence.