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Six candidate gene studies report a genetic association of DNA variants within the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). However, several other large studies, including five genome-wide association studies, have not duplicated this finding.

The histochemical silver amplification technique autometallography (AMG), was used to trace bismuth in the testis of Wistar rats injected intraperitoneally with bismuth subnitrate. In the seminiferous tubules, bismuth was located in lysosomes of Sertoli cells closely associated with heads of spermatids in the late stages of the spermatogenesis, i.e. shortly before the release of Step 19 spermatids in Stage XIII. No bismuth-specific AMG silver grains were detected in the spermatogenic cell line. However, tails of free sperm cells located in the tubular lumen showed autometallographic grains in close contact to the nine outer microtubule doublets in the axonema. Leydig cells concentrated huge amounts of AMG-bismuth in their lysosomes. Furthermore, parallel exposure to selenium significantly increased the amount of histochemically traceable bismuth in the rat testis.

The location and number of brain stem serotonin-synthesizing neurons were analyzed in 11 patients with Alzheimer's disease (AD) and 5 agematched controls using immunohistochemical techniques. In addition, the number of neuritic plaques and neurofibrillary tangles in the cortex and brain stem raphe was evaluated, as was the number of Nissl-stained raphe neurons. AD patients could be classified into two groups based on their raphe pathology; patients with such pathology (AD+) and those without (AD-). The number of large raphe neurons correlated significantly with the number of serotonin-synthesizing neurons in control material, indicating that all large neurons were serotonergic. This relationship was not apparent in AD+ patients, in whom the number of serotonin-synthesizing neurons correlated with the number of neurofibrillary tangles in the raphe of these patients. This indicates that in AD+ patients the serotonin-synthesizing neurons were selectively affected. There was no correlation between raphe and cortical pathology or raphe pathology and patient sex, age, mini-mental score or depression score, even when such scores were weighted for the interval between testing and death. There was a trend for the raphe pathology to correlate with the age of onset and duration of dementia and the Blessed dementia score in AD+ patients. Most AD+ patients with severe raphe lesions had clinical dementia only, while AD- patients had additional clinical features. The raphe lesions were more dramatic in AD+ patients with a rapid progression of symptoms.

A brother and sister developed a slowly progressive neurological disorder with cerebellar and pyramidal signs and mild dementia. The brother developed symptoms at 6 months and died aged 11 years; the sister developed symptoms at 3 years and died aged 18 years. At post-mortem both had severe widespread central nervous system demyelination with islands of preserved myelin, and small amounts of sudanophilic lipid products. Metachromatic material, globoid cells, and adrenal abnormalities were not seen. The features were those of Pelizaeus-Merzbacher disease (PMD). It has been proposed, on the basis of only a few family studies, that PMD is an X-linked recessive disorder. These cases suggest that autosomal recessive inheritance may occur.

Abstract: Inorganic mercury has been proposed as a neurotoxin that could cause sporadic motor neuron disease (SMND). We were therefore interested to see if mercury could be detected in the upper and lower motor neurons of SMND patients, and if mercury accumulated within motor neurons during life. Paraffin sections of formalin-fixed spinal cord (22 control adults, 20 SMND adults, 25 infants) and frontal primary motor cortex (9 control adults, 18 SMND adults, 20 infants) were stained with silver nitrate autometallography to detect ionic mercury. Mercury was found in the spinal motor neurons of 36% of adult control cases and 45% of adult SMND cases, with no significant difference between groups. No mercury was seen in infant spinal motor neurons, or in any adult or infant corticomotoneurons. In conclusion, many humans appear to accumulate mercury in their spinal motor neurons by the time they are adults, but mercury does not appear to play a major role in the loss of upper or lower motor neurons in SMND.

Abstract: It has been suggested that delayed development in either the peripheral or central nervous system could underlie the sudden infant death syndrome (SIDS). We studied the phrenic nerve in an attempt to find if maturation in this nerve was delayed in SIDS, and to see if fiber size differences could explain the paucity of type I muscle fibers described in SIDS diaphragms. Samples of phrenic nerves were taken at post mortem from 11 SIDS and 10 control infants. Myelinated fibers were quantitated in 1-μm silver-stained resin sections using a semi-automatic image analysis system. The numbers and sizes of all myelinated fibers in the right phrenic nerve were compared between SIDS and control groups. The proportion of small (less than 6-μm diameter) phrenic nerve fibers was similar in SIDS (53.1%, SD 12.8%) and control (53.6%, SD 14.0%) cases. The proportion of small fibers decreased with increasing age at an equivalent rate in both SIDS and control groups. Total numbers of myelinated fibers were similar in the right phrenic nerves of SIDS (3429, SD 440) and control (3457, SD 507) infants, but varied widely between cases and were not correlated with age. Maturation of the phrenic nerve, as judged by increasing size of myelinated fibers, is therefore similar in SIDS and control infants. This argues against a widespread developmental delay in SIDS. No changes in phrenic nerve fiber sizes were found to account for the finding of fewer type I fibers in SIDS diaphragms.

A 66-year-old woman presented with an alien limb syndrome without dementia. The course of her illness was unremitting and at autopsy 6 years later her diagnosis was confirmed as corticobasal degeneration without Alzheimer-type pathology. Although the presence of ballooned achromatic cortical neurons and cell loss from the substantia nigra distinguishes such patients, the site and density of achromatic neurons has not previously been quantified. We show that immunohistochemistry for the cell stress protein ubiquitin selectively stains these achromatic neurons, whereas they do not stain for abnormally phosphorylated tau protein. Phosphorylated neurofilament antibodies recognise both ballooned and non-ballooned neurons. In this case, high densities of ubiquitin-positive ballooned neurons were found in frontal cortical regions with the highest densities in layers V and VI of the anterior cingulate cortex. In addition, high densities of ubiquitin-positive ballooned neurons were found in the insular cortex, claustrum and amygdala. These results confirm past reports of frontal pathology, but show that there is also considerable pathology in insular and parahippocampal cortical regions and some subcortical regions. Our findings suggest that the distribution and staining characteristics of ballooned neurons in corticobasal degeneration may help to differentiate these cases pathologically, while the absence of dementia appears to be an important clinical criterion.

A 64-year-old woman developed septicemia and a generalized peripheral neuropathy while being ventilated postoperatively. No cause for the neuropathy could be found during life. At autopsy she was found to have infective endocarditis and multifocal inflammatory lesions in the central and peripheral nervous systems, consistent with damage due to septic emboli. Infective endocarditis may be a cause of a generalized polyradiculoneuropathy and could be responsible for a proportion of cases of “critical illness polyneuropathy”.

Objective To determine the neuroradiological abnormalities associated with subjects carrying the mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) tRNA ^Leu(UUR) A3243G point mutation Methods Mitochondrial genetic analysis was performed on 24 subjects from six kindreds with the MELAS tRNA ^Leu(UUR) A3243G point mutation. Cerebral CT and MRI were performed on 24 patients and 15 patients respectively. Previous neuroradiological investigations including cerebral CT from four deceased members of the families were also reviewed. Histological examination of postmortem specimens of two patients within the kindreds was performed. Results The commonest radiological finding was basal ganglia calcification. Other abnormalities included focal lesions and cerebellar and cerebral atrophy. Basal ganglia calcification was progressive, symmetric, and asymptomatic. Histologically, basal ganglia calcification in one patient was found to be in the pericapillary regions of the globus pallidus, with no neuronal involvement. Focal lesions most commonly involved the grey matter of the parietal and occipital lobes and cerebellum. Histopathological examination suggested that these were due to cellular rather than vascular dysfunction. Enlargement of the fourth ventricle was the first sign of cerebellar atrophy. Cerebral and cerebellar atrophy were only present with severe disease. Conclusions These radiological findings, when considered in the context of the clinical and pathological findings, seem to reflect two major disease processes: an intermittent abrupt loss of function associated with cell injury from which there is at least partial recovery and a slowly progressive degenerative process causing basal ganglia calcification, and cerebral and cerebellar atrophy. The clinical and radiological features resulting from these processes are distinctive and provide insight into the consequences of mitochondrial dysfunction on the brain.

Abstract: A 24-year-old man injected himself intravenously with metallic mercury in a suicide attempt, and died 5 months later after cutting his wrists. The brain was removed at postmortem and 7-μm paraffin sections were cut from representative blocks. Dense deposits of mercury were found on autometallography in large cortical motor neurons, but in no other cerebral neurons. Smaller mercury deposits were found in the brain stem (in the mesencephalic trigeminal nucleus, noradrenergic neurons, and in neurons for extraocular muscles), the cerebellum (in the dentate nucleus) and in lateral motor neurons in the C2/3 spinal cord. Mercury deposits were found in glial cells in all regions. The finding that elemental mercury enters human cortical motor neurons in preference to other cerebral neurons raises the possibility that this neurotoxin may play a part in the pathogenesis of some human motor neuron diseases.

To present a rare case of camptocormia due to myofibrillar myopathy.

Superficial siderosis of the central nervous system (CNS) is a rare condition that is thought to be caused by repeated subarachnoid haemorrhages. The major clinical features are progressive bilateral hearing loss, cerebellar ataxia and pyramidal dysfunction. Ante-mortem diagnosis is now possible due to MRI and post mortem reports of this condition are becoming rare. Despite the occurrence of typical clinical features the diagnosis is often missed during life if CT scanning alone is performed. We describe a case of superficial siderosis of the CNS with clinical and post mortem findings as a reminder of this unusual condition.

SUMMARY The clinical, electrophysiological and pathological features and prognosis of 34 patients with peripheral neuropathy caused by necrotizing vasculitis were evaluated. The causes included polyarteritis nodosa and its Churg-Strauss variant, rheumatoid arthritis, undifferentiated connective tissue disease. Wegeners granulomatosis, primary Sjögrens disease, and chronic lymphocytic leukaemia with cryoglobulinaemia; 2 patients had no evidence of systemic vasculitis. Mononeuritis multiplex was the most common clinical manifestation, followed by asymmetrical polyneuropathy and distal symmetrical polyneuropathy. Pain was a frequent symptom. Nerve conduction studies were abnormal in all cases, and in 3 patients there was conduction block or severe slowing of motor conduction. Necrotizing vasculitis was present in sural nerve biopsies of most cases, and severe active axonal degeneration was a dominant feature. Immunofluorescent staining of blood vessels for immunoglobulin, C3 and fibrinogen was positive in all cases in which it was performed, even when there was no cellular infiltration. All patients were treated with prednisone alone or in combination with other immunosuppressive agents, or with plasmapheresis. Long-term follow-up studies demonstrated that although the peripheral neuropathy usually improved and caused only mild to moderate functional disability, the long-term prognosis of the systemic disease was poor with a 5-yr survival of only 37%

This slide seminar is divided into two sections -brain tumours and diseases of skeletal muscle. In the first section, fifteen tumours arising in and around the brain will be viewed and discussed. The emphasis will be on the less common (but not exceeding rare) tumours that may be found in these regions. The use of immunohistochemical stains will be mentioned, but it will be demonstrated that most brain tumours can be diagnosed using routine stains. The second section will deal with the non-tumour pathology of skeletal muscle. A practical approach to the histological diagnosis of a muscle specimen will be presented and attention will be given to frequently encountered artifacts in muscle which may give rise to diagnostic difficulties. The emphasis will be on diagnosis using ctyosections of muscle and a small number of histochemical stains.