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We report a rare association of familial cerebellar ataxia (without dementia) and cerebrovascular amyloid. Postmortem neuropathological examination of one member of the family showed amyloid angiopathy of the central nervous system with heavy infiltration of capillaries in the hippocampus and cerebellum. [ABSTRACT FROM AUTHOR]

Cycloleucine (CL), a synthetic amino acid is known to cause degeneration of motor nerve terminals. This paper describes the changes in neuromuscular transmission, the morphology of motor end-plates and the responses of muscle spindles after a single dose of CL was administered to weanling and adult mice. Animals were allowed to survive for between 12 h and 7 days. Twitch and tetanic responses of muscles stimulated through their nerves fell dramatically within 24 h in both young and adult mice and intracellular recordings revealed that a large proportion of end-plates in calf muscles became denervated, whilst at other end-plates intermittent failure of transmission and end-plate potentials (EPPs) with prolonged latency were demonstrated. End-plates with an abnormally high frequency of miniature end-plate potentials (mEPPs) were found in young mice at 12 h, and in the adult mice at 24 h. Morphological abnormalities in intramuscular nerves and nerve terminals included areas of electron lucent axoplasm, swollen degenerative mitochondria and loss of synaptic vesicles. Over the next 2-3 days further reductions occurred in the number of end-plates at which mEPPs or EPPs could be demonstrated. At 7 days a limited recovery of function occurred in distal muscles but proximal muscles, hitherto unaffected, now began to show abnormalities of transmission. Muscle spindles were found to be both functionally and structurally intact. It is suggested that this acute distal motor axonopathy is due to abnormalities in phospholipid composition of the axolemma of motor nerve terminals resulting from the failure of methyl-transfer pathways. These abnormalities in phospholipid composition might cause an increase in microviscosity of the axolemma and hence a decrease in efficiency of ion channels and pumps responsible for maintaining electrochemical gradients, essential for the structural and functional integrity of the neuromuscular junction.

Amyloid plaques, associated with argyrophilic dystrophic neurites, and cerebral amyloid angiopathy (CAA), but no neurofibrillary tangles, were found in the brains of three middle-aged marmoset monkeys that had been injected intracerebrally (ic) 6-7 yr earlier with brain tissue from a patient with early-onset Alzheimer's disease. Such changes were not found in the brains of three age-matched control marmosets. Immunochemically the amyloid plaques and CAA stained with antibody to beta (A4)-protein. The plaques and CAA displayed dichroic birefringence when stained with Congo red and viewed under polarized light. beta (A4)-amyloid plaques and CAA were also found in the brain of one of two marmosets injected ic 6 yr previously with brain tissue from a patient with prion disease with concomitant beta (A4)-amyloid plaques and CAA. An occasional beta (A4)-amyloid plaque was found in the brains of two of four marmosets injected ic > 4.5 yr previously with brain tissue from three elderly patients, two of whom had suspected (but untransmitted) CJD. No beta (A4)-amyloid plaques or CAA were found in six marmosets who were older than the injected animals, in four marmosets that had not developed spongiform encephalopathy (SE) having been injected several years previously with human brain tissue from three younger patients with suspected or atypical prion disease, or in 10 younger marmosets who had undergone various neurosurgical procedures. Seventeen marmosets injected in the same way with brain tissue from patients or animals with SE developed SE 17-49 mo after injection. These results suggest that beta (A4)-amyloidosis is a transmissible process comparable to the transmissibility of SE.

An 18-year-old male patient presented with clinical and radiological evidence of Leigh's syndrome (LS), having developed progressive myoclonic epilepsy and ataxia 11 years previously. Muscle biopsy showed cytochrome oxidase deficiency but no ragged red fibres. Autopsy confirmed the diagnosis of LS; there was additional degenerative change in the cerebellum and dentate and olivary nuclei, and an axonal peripheral neuropathy. Biochemical studies showed reduced activity of complexes I and IV of the respiratory chain in mitochondria from heart, liver and kidney. The mutation of mitochondrial DNA (mtDNA) at position 8344, commonly associated with the syndrome of myoclonic epilepsy and ragged red fibres, was detected in the patient's blood and was present in muscle, brain, liver, heart, and kidney in uniformly high amounts. It is clear that LS is genetically heterogeneous and represents one of the most severe phenotypes of a number of different mtDNA defects.

The brains of three marmosets (Callithrix jacchus) injected intracerebrally 6-7 years earlier with brain tissue from a patient with early onset Alzheimer's disease were found to contain moderate numbers of amyloid plaques with associated argyrophilic dystrophic neurites and cerebral amyloid angiopathy but no neurofibrillary tangles. The plaques and vascular amyloid stained positively with antibodies to beta (A4)-protein. The brains of three age-matched control marmosets from the same colony did not show these neuropathological features. The brain of one of two marmosets injected with brain tissue from a patient with prion disease with concomitant beta-amyloid plaques and cerebral amyloid angiopathy also showed beta-amyloid plaques and angiopathy but no spongiform encephalopathy. An occasional plaque was found in the brains of two of four marmosets injected with brain tissue from three elderly patients with age-related pathology, two of whom had an additional diagnosis of possible prion disease. Neither plaques nor cerebral amyloid angiopathy were found in six other marmosets who were older than the injected animals, in 12 further marmosets who were slightly younger but who had been injected several years previously with brain tissue which did not contain beta-amyloid, or in 10 younger marmosets who had been subjected to various neurosurgical procedures. These results suggest that cerebral beta-amyloidosis may be induced by the introduction of exogenous amyloid beta-protein.

Moderate numbers of amyloid plaques with associated argyrophilic dystrophic neurites and cerebral amyloid angiopathy (CAA) but no neurofibrillary tangles (NFTs) were found in the brains of 3 middle-aged common marmosets (Callithrix jacchus) inoculated intracerebrally (i.c.) 6-7 years earlier with brain tissue from a patient with early onset Alzheimer's disease. The plaques and vascular amyloid stained positively with antibodies to beta (A4)-protein. The brains of 3 age-matched control marmosets from the same colony did not show these neuropathological features. beta-amyloid plaques and CAA (but no spongiform encephalopathy) were also found in the brain of a marmoset inoculated with brain tissue from a patient with prion disease with concomitant beta-amyloid plaques and CAA. An occasional beta-amyloid plaque was found in the brains of two marmosets inoculated with brain tissue from elderly patients. No beta-amyloid plaques nor CAA were found in 6 other marmosets who were older than the inoculated marmosets, 10 further marmosets who were slightly younger but who had been inoculated several years previously with brain tissue which did not contain beta-amyloid, and 10 younger marmosets who had been subjected to various neurosurgical procedures. These results suggest that beta-amyloidosis is a transmissible process.

Two further cases of Creutzfeldt-Jakob disease (CJD) in association with cadaveric dura mater grafts are described. The clinical features of all such reported cases resemble more closely those of sporadic CJD, in contrast with kuru and the cases of CJD which have arisen after therapy with human pituitary-derived growth hormone. This observation may reflect the route of inoculation of the agent.

We report the clinical and neuropathological findings in a patient with a 216 base pair insertion in the prion protein (PrP) gene. She died aged 57 years after a 2.5-year illness characterized by falls, axial rigidity, myoclonic jerks and progressive dementia. There was no history of affected relatives. The pathological changes consisted of the deposition in cerebellum, basal ganglia and cortex of small plaques composed of variable amounts of amyloid and degenerative material which was associated with a marked macrophage reaction. The amyloid deposits in the cerebellum and basal ganglia gave a positive immunoperoxidase staining reaction for PrP. In some places plaques bore a resemblance to senile neuritic plaques and in the hippocampus there were abundant typical neuritic plaques giving positive staining reactions for beta-amyloid protein and tau protein, but not PrP. There were few neurons bearing neurofibrillary tangles. This is the first report of the neuropathological changes associated with this particular abnormality of the PrP gene and it seems to demonstrate a transition between the pathology of prion disease and that of Alzheimer's disease. The importance of PrP gene analysis to the understanding of neurodegenerative diseases is stressed.

The clinical and neuropathological features of 21 patients with prion disease were reviewed with special reference to the morphology and immunoreactivity of cerebral amyloid. Six cases had a mutation at codon 102 of the prion protein (PrP) gene and in these the characteristic pathology was the formation of multicentric amyloid plaques which were stained with PrP antibody, whereas spongiform changes were absent in one and minimal in two. In one case, with a 216 base-pair insertion in the PrP gene, there was no spongiform encephalopathy (SE) but cerebellar amyloid was a prominent feature of the pathology. One case with a PrP gene mutation at codon 200 had severe SE but no amyloid. Two iatrogenic and 11 sporadic cases had SE and some form of amyloid was identified in all but three. Amyloid angiopathy and senile neuritic plaques, which stained with antibody to beta-protein, were present in familial as well as in sporadic cases, including some who were rather young to be regarded as having Alzheimer's disease. Cerebellar amyloid and degeneration of granule and Purkinje cells were particularly common findings in sporadic as well as in genetically determined cases. This study serves to emphasize the association between prion disease and amyloid deposition in the brain. PrP is a component of some amyloid plaques in a high proportion of cases with inherited prion disease but may also be found in cases of sporadic SE without known mutations or base-pair insertions in the PrP gene.

The clinical and pathological findings of a male with the Brown-Vialetto-Van Laere syndrome are described. This rare and fatal affection of the nervous system involves mainly the brain stem with the prominent and early manifestation of sensorineural deafness. Increased awareness and documentation of this disorder has added information on the mode of inheritance.

Cycloleucine (CL), an inhibitor of methionine adenosyltransferase, has previously been used to produce an experimental model of subacute combined degeneration of the spinal cord. A re-investigation of its effects on the morphology of the nervous system and on brain concentrations of methionine and S-adenosylmethionine (SAM) was undertaken. Cycloleucine was administered as a single dose intraperitoneally (2 mg/g body weight) to young mice aged 21 d and adults aged 6 or 10 wks. The 21-day-old mice showed clinical evidence of toxicity within 24 h and thereafter developed progressive muscle weakness and ataxia. Animals did not survive longer than 1 wk. Light and electron microscopic examination of the central and peripheral nervous systems showed that intramyelinic vacuolation developed in the white matter of brain and cord within 12 h. The intramyelinic vacuolation in the white matter of brain and cord became more severe with longer survival, vacuoles coalescing and secondary axonal degeneration becoming evident. There was no myelin vacuolation in peripheral nerves. Axonal lesions occurred in the distal parts of motor nerves within 12-24 h resulting in degeneration of intramuscular nerve fibres and terminals. Later there was evidence of axonal degeneration in tibial and sciatic nerves. Many dorsal root ganglion cells became vacuolated or necrotic and numerous degenerated fibres were noted in the white matter of the spinal cord, particularly in the gracile funiculus. The optic nerves were not affected at any stage. In adult mice the pathology consisted of distal motor axonal degeneration which developed at 1-2 d. Little or no intramyelinic vacuolation in white matter was noted. Brain concentrations of SAM were reduced and levels of methionine became greatly elevated. The morphological effects of CL are considered to be the result of SAM deficiency impairing transmethylation processes known to be important in the formation and stabilization of myelin through the methylation of myelin basic protein. The immature developing central nervous system is much more vulnerable than the fully myelinated adult brain and spinal cord. The distal, predominantly motor axonopathy is a new observation and may be a reflection of the importance of transmethylation processes in the maintenance of axonal terminal membranes and the mechanisms of release of acetylcholine at the neuromuscular junction.

We report a reappraisal of patient NT who became severely amnesic after a right temporal lobectomy for intractable epilepsy (DINSDALE et al., Neuropsychologia 1, 287, 1964 [6]). Histological examination, albeit incomplete, indicated that there was no abnormality in the resected temporal lobe. At autopsy a sclerotic lesion of the unoperated left hippocampal formation was found. This case is therefore not an exception to the general rule that a severe and global amnesic state is only observed with bilateral lesions. Her performance on a wide range of memory tests is shown to be indistinguishable from patients with an amnesic syndrome due to Korsakoff's psychosis.

In the past 3 years there have been five further cases, in addition to one case reported in 1985, of Creutzfeldt-Jakob disease in recipients of human growth hormone in the United Kingdom. The clinical findings of two of these cases are described, demonstrating a typical presentation with a predominantly cerebellar syndrome at onset which is not commonly a presenting feature of sporadic Creutzfeldt-Jakob disease. In one case a 99mTc hexamethylpropylenamine single photon emission tomographic scan showed marked impairment of tracer uptake in the basal ganglia and cerebral cortex at a time when the clinical picture was predominantly cerebellar. This technique may be useful in early diagnosis. In the other case post mortem examination of the brain showed prominent amyloid deposition in the cerebellum, which has not been described previously in pituitary-hormone related Creutzfeldt-Jakob disease. The previously published cases of growth hormone-related Creutzfeldt-Jakob disease are reviewed and reasons for the particular clinical pattern seen are discussed.

A comparison was made of the effects of experimental intracerebral inoculation into marmosets of brain homogenates from a case of Creutzfeldt-Jakob disease (CJD) and from a member of the Wo. family with cerebral amyloid and spongiform encephalopathy--the Gerstmann-Sträussler-Scheinker (GSS) syndrome. All the inoculated marmosets developed spongiform encephalopathy (SE) after incubation times of 20-23 months in the CJD group and 25-32 months in the GSS group. Subsequent passage from 1 affected animal in each group resulted in SE developing after 17 months incubation. In every animal inoculated with CJD or GSS material and in the 2 passage experiments the most severely affected region of the brain was the thalamus which in all cases was almost totally occupied by vacuoles. Other grey matter masses were less severely and less consistently affected. Vacuolation was observed in the cerebellar granule cell layer as well as in the molecular layer and the brain stem was finely vacuolated in all cases. There were only minor and inconsistent differences between the disease transmitted from CJD compared with GSS and some differences between the original transmissions and the SE caused by passaged inocula. Severe astrocytic gliosis accompanied the spongiform changes but no amyloid was identified in any of the marmosets with experimentally transmitted disease. The pathogenesis of the spongiform change in the thalamus was studied in a series of marmosets by light and electron microscopy 3-22 months after the intracerebral inoculation of CJD or GSS homogenates and was compared with controls. Dilated irregularly-shaped cisternae and the large complex vacuoles typical of SE, present in abundance after 18 and 22 months incubation, were considered most probably to be derived from cisternae of neuronal smooth endoplasmic reticulum.

In the mutant mouse Sprawling, a deficiency of sensory ganglion cells is associated with a failure of the development of spindles and tendon organs particularly affecting muscles of the hindleg. Electrophysiological and morphological investigations were made on nerve, muscle and the neuromuscular junction of soleus and extensor digitorum longus (EDL). It was found that the absence of sensory innervation had no effect on the development of muscle bulk, on the fibre diameters or on histochemical profiles. The elimination of polyneuronal innervation proceeded at the normal rate and was complete by 3 wks of age. The strength of contractile responses and the number of motor units were normal in both muscles. End-plate areas were measured and the size distribution found to be normal in soleus. In EDL, however, there was a preponderance of small end-plates and a relative deficiency of large ones. This was associated with an abnormally low frequency of miniature end-plate potentials and of the mean quantal content of transmission. There was also a reduction in the complexity of the postsynaptic specialization at end-plates in the EDL. Localized axonal swellings packed with neurofilaments were observed in preterminal motor nerve fibres, which suggested an abnormality of axonal transport. There was no evidence of denervation of muscle fibres. The contractile characteristics of soleus and EDL were still distinguishable as slow and fast-twitch, respectively, despite the abnormalities found, and it seems likely that impulse traffic in the lower motoneuron is only marginally affected, if at all. An abnormality of axonal transport may be responsible for the inability of motoneurons to maintain large end-plates in fast-twitch muscles.

The peripheral nerves of the Trembler mouse are hypomyelinated. The effects of the neuropathy on muscle and motor end-plate morphology, and on neuromuscular transmission in slow-twitch (soleus) and fast-twitch (extensor digitorum longus) muscle are reported. After forming normally, motor end-plates developed ultraterminal sprouts by about 18 days of age in deep, slow-twitch muscles. The only ultrastructural abnormality in muscle at this age was disruption of Z-lines. Ultraterminal sprouting progressed, and by about 3 months the innervation zone consisted of a mass of branching axons associated in places with cholinesterase activity. The ultrastructure of end-plates became abnormal. Fascicular atrophy was present in older Tremblers and the ultrastructural morphology of muscle fibres became disorganized with accumulation of subsarcolemmal granular material. Abnormal muscle fibres were innervated by axonal sprouts. The superficial, predominantly fast-twitch, muscles showed milder changes at all ages even though the nerves supplying them were hypomyelinated. Studies of neuromuscular transmission showed that soleus retained its slow-twitch and extensor digitorum longus its fast-twitch characteristics, and miniature end-plate potentials were of normal frequency and amplitude. The latency of end-plate potentials and the refractory period of transmission were prolonged in both soleus and extensor digitorum longus. With repetitive stimulation at 50 Hz a cyclical pattern of responses and failures occurred which was probably caused by intermittent conduction block along the peripheral nerve. Although the pathological changes in Trembler muscle were like those of partial denervation, atrophic muscles contained an abundance of axons and there was no evidence of axonal degeneration. The changes in muscle are therefore a consequence of hypomyelination without axonal loss. Since slow-twitch muscles are normally subjected to prolonged stimulation, failure of Trembler axons to conduct sustained trains of stimuli in vivo may contribute to the development of pathological changes in slow-twitch muscle. Hypomyelimated axons may be capable of conducting short bursts of impulses, however, which is the pattern of stimulation in fast-twitch muscle in vivo, so that fast-twitch muscle fibres and end-plates remain relatively spared.

The effects of the venoms of the spiders Latrodectus mactans tredecimguttatus (black widow) and Latrodectus mactans hasselti (red back) on sensory nerve terminals in muscle spindles were studied in the mouse. A sublethal dose of venom was injected into tibialis anterior and extensor digitorum longus muscles of one leg. After survival from 30 minutes to 6 weeks muscles were examined in serial paraffin sections impregnated with silver or by electron microscopy. Sensory endings became swollen, some within 30 minutes, while over the next few hours there was progressive degeneration of annulospiral endings. By 24 hours every spindle identified by light or electron microscopy was devoid of sensory terminals. Degenerated nerve endings were taken up into the sarcoplasm of intrafusal muscle fibres. Regeneration of sensory axons began within 24 hours, new incomplete spirals were formed by 5 days and by 1 week annulospiral endings were almost all normal in appearance. Intrafusal motor terminals underwent similar acute degenerative and regenerative changes. These experiments show that intrafusal sensory and motor terminals are equally affected by Latrodectus venoms. Sensory nerve fibres possess a capacity for regeneration equal to that of motor fibres and reinnervate intrafusal muscle fibres close to their original sites of innervation.

We have used the noninvasive method of 31phosphorus nuclear magnetic resonance (31P NMR) in vivo to follow changes in phosphorous metabolite concentrations and the intracellular pH in the right and left hemispheres and in the cerebellum of gerbil brains after the occlusion of the right carotid artery. Spatial resolution over the brain was possible using surface coils. Ligation, which is know to cause ischaemia in this species in the ipsilateral hemisphere, resulted in the diminution of phosphocreatine and adenine nucleotides and a decrease in tissue pH. Less acidification occurred in the contralateral hemisphere and in the cerebellum. The high-energy metabolite concentrations, phosphocreatine and adenosine triphosphate (ATP), declined in unison in the ischaemic region, in marked contrast to the sequence of events in skeletal muscle, in which phosphocreatine buffers against an immediate fall in ATP concentration. In a separate series of gerbils, 31P NMR spectra were followed for exactly 1 h after carotid ligation. The animals were then sacrificed and brain grey matter specific gravity was rapidly measured to assess the development of oedema. There was a clear correlation between abnormality of spectra and the presence of oedema. It cannot, however, be confidently asserted that a normal spectrum is never seen in oedematous gerbil brains. 31P NMR spectra specific gravity and histological changes shown by light microscopy have been correlated and show that useful signals are received from a depth of at least 4 mm or more from the 10-mm diameter coil.

The mdx mutant mouse was first observed during a survey of genetic variations of pyruvate kinase in the mouse. Affected mice have high serum levels of this enzyme and although showing little disability they have widespread and severe muscle disease. Light and electron microscopy, muscle enzyme histochemistry and combined cholinesterase-silver impregnations were used for the study of affected and control animals aged 1 day to 1 year. An early ultrastructural abnormality present already at 1 day was scattered focal streaming of Z-lines. Later there was also segmental muscle fibre necrosis and regeneration. The proportion of muscle fibres showing either necrosis, regeneration or internal nuclei was assessed in several muscles, at ages ranging from 10 days to 1 year. Acute segmental necrosis and regeneration were most marked at 1 to 2 months, although they were present at all ages. The number of fibres with internal nuclei increased progressively until 3 months when 70-80% showed this abnormality. Nerve terminals were unaffected but there was a reduction in the number and depth of postsynaptic folds at motor end-plates in adult animals, confirmed by morphometric analysis. Quantitative study of L4 motor root and tibial nerve showed that fibre numbers, axonal calibres and myelin sheath thickness were normal at all ages. No qualitative abnormalities were found in the CNS or other organs. The findings strongly suggest that the mdx mutant has a primary muscle disease and that the nervous system is normal.

A new autosomal recessive mutant rat (mutilated foot) with a neurological disorder is described. Affected animals become ataxic and the feet, generally of the hind limbs, are mutilated. Quantitative studies show a severe reduction in numbers of sensory ganglion cells and fibres, including unmyelinated fibres. The numbers of ventral root fibres, particularly those of small diameter, are also reduced. Markedly decreased numbers of spindles are found in the limb muscles. These quantitative abnormalities are present in animals of all ages and appear to be congenital. No nerve fibre degeneration is found in the spinal cord of young animals, but progressive degeneration of ascending tracts is seen with increasing age. Mossy fibre degeneration in the cerebellum confirms that the spinocerebellar tract is affected. The neurological disease in this mutant shows many similarities to that found in human hereditary sensory neuropathy.

The effect of X-irradiation on axonal sprouting of motor nerves induced by botulinum toxin was examined. Muscles of one leg in the mouse were X-irradiated (15 Gy) prior to the injection of a locally paralysing dose of botulinum toxin. It was found that axonal sprouting occurred as expected, but the sprouts remained unmyelinated and many degenerated. Fewer new end-plates were formed, muscles remained more severely atrophied and supersensitive to acetylcholine and recovery of neuromuscular transmission was greatly delayed when compared with the effects of botulinum toxin alone. The experiments show that X-irradiation did not prevent sprouting but, probably by impairing Schwann cell proliferation, altered axon-Schwann cell relationships and prevented the maturation of newly-formed axons and the differentiation of new end-plates.

The intermediolateral column neurons in the lateral horns of the grey matter of the thoracic spinal cord were counted in five patients who had died of motor neuron disease, two of the Shy-Drager syndrome and three of other neurological diseases not affecting the spinal cord or roots. The number of intermediolateral column cells in all the motor neuron disease cases was slightly reduced compared with the control cords, this difference being apparent both when the whole thoracic sympathetic outflow was assessed as well as its upper, middle and lower thirds. The difference, however, was not statistically significant. By contrast, in Shy-Drager cases there was a highly significant reduction in intermediolateral column cells compared with the normal cords.

Prolonged dosing of mice with amiodarone produced a myopathy characterized by autophagic vacuolation and phospholipid inclusions. A previous morphological study had shown that amiodarone did not affect the rate of nerve regeneration after sciatic nerve crush. In the present study, reinnervation was assessed by the reappearance of miniature endplate potentials that confirmed that axonal regeneration and motor reinnervation was not affected by amiodarone. However, there was a marked delay in the recovery of motor function in the amiodarone-treated mice. Denervation was found to induce an extensive necrosis of muscle fibers in the deeper parts of fast-twitch muscles. Histochemical studies showed that type 1 fibers were spared, necrosis affecting mainly type 2 fibers with relatively high oxidative enzyme activity (fast-twitch oxidative fibers). Biochemical studies showed a significant increase in the amount of amiodarone and its metabolite in denervated muscle of amiodarone-treated mice when compared with contralateral, normally innervated muscles.

A new inherited neurological disease in the mouse (the mutant twitcher) has been studied. Transmission is by an autosomal recessive gene (twi). Affected animals are apparently normal at birth but develop a generalized tremor at about 3 weeks of age followed by progressive weakness and wasting. The disease is fatal by 3 months. The principal pathological changes affect the myelin of both central and peripheral nervous systems. Degeneration of myelin sheaths and the presence of multinucleated macrophages with PAS-positive cytoplasm are characteristic findings. Peripheral nerves show remyelination following demyelination. Electron microscopically the macrophages contain a variety of inclusions in which there are crystalline and multi-angular structures and twisted tubules. The abnormalities closely resemble those found in globoid cell leucodystrophy (Krabbe's disease) in man.

Peripheral nerves and lumbar nerve roots of Sprawling, a neurological mutant mouse, were examined with light and electron microscopy. The peripheral nerves and the dorsal roots were thin and grey and were composed predominantly of small myelinated and unmyelinated axons. No evidence of axonal or myelin degeneration was found. Quantitative studies showed a marked reduction in the total number of myelinated axons with preponderance of those of 2-5 micron in diameter or less, most marked in the dorsal roots in which there was also an increase in the proportion of axons which were unmyelinated. In the ventral roots there was a deficiency in the contribution formed by myelinated axons of small calibre, probably indicating a deficiency of gamma fibres. Examination of the myelinated axons in nerves and roots showed a normal relationship between fibre size and internodal lengths and number of myelin lamellae. The findings suggest that the genetic defect in Sprawling is responsible for a failure of myelination of sensory axons. The deficiency of large sensory axons and of small motor axons can be correlated with the deficiency of muscle spindles.

Morphological changes in peripheral nerve caused by the venoms of the scorpions Leiurus quinquestriatus and Centruroides sculpturatus were compared with those caused by Phoneutria nigriventer spider venom. Both scorpion venoms are known to delay the inactivation of sodium currents, Centruroides venom also altering the voltage dependence of sodium gating. Venom was injected by means of a glass micropipette into the sciatic nerves of anaesthetized mice. After survival times ranging from 15 min to 24 h the nerves were examined by light and electron microscopy. The two scorpion venoms caused alterations virtually identical to those produced by Phoneutria venom, which included swelling of the nodal axoplasm and accumulation of fluid in the periaxonal space of myelinated fibres. These alterations were most marked after 1 to 2 h and had largely disappeared by 24 h. Pre-treatment of the nerves with tetrodotoxin, which specifically blocks sodium channels, completely prevented both the nodal axoplasmic swelling and the periaxonal oedema. It seems likely that these effects result from an action common to the three venoms and that this is probably a delay in the inactivation of sodium current at the node of Ranvier.

The choline acetyltransferase activity of submandibular glands that had previously received a retrograde injection of botulinum toxin via their ducts was found to be markedly lower than in the untreated contralateral glands. In the parotid glands exposed to the same treatment the activity of this enzyme was less affected.

The L4-6 sensory root ganglia of young and adult Sprawling (Swl) and normal mice were studied. Cell counts showed a great reduction in the total number of ganglion cells in Swl. Cell degeneration was observed in young Swl animals but not in normal littermates. Most of the remaining ganglion cells showed morphological abnormalities very similar to those seen in chromatolytic neurons-enlarged nucleolus, eccentric nucleus with an infolded nuclear membrane, loss of juxtanuclear Nissl bodies and an increase in neurofilaments, Golgi membranes, autophagic vacuoles, and dense bodies. In contrast to the classical changes of chromatolysis the abnormalities in Swl neurons persisted throughout the lifespan of the animals. Reconstructions from serial sections showed that ganglion cells in Swl were highly irregular in shape.

A case is reported of Creutzfeldt-Jakob disease associated with amyloid infiltration of cerebral vessels. The duration of progressive dementia was only 4 months. Neuritic plaques were not a feature of the pathology. This report emphasises the association of spongiform encephalopathy with the presence of amyloid in the brain.

Nine cases of infantile spinal muscular atrophy were studied post-mortem. Their ages at death ranged from 5 months to 10 years. In all cases severe loss of anterior horn cells in the spinal cord and neurogenic muscular atrophy were characteristic of this disease. In 6 cases there was also loss of myelin in the posterior columns particularly affecting the lumbar contribution. Sensory ganglia, especially from the lumbar region, contained nodules of Nageotte, indicating sensory neuron degeneration. These sensory abnormalities were more severe in the longer surviving cases. It seems possible that sensory neuron degeneration occurs more commonly in Werdnig-Hoffmann disease than has previously been supposed but that it is less severe and develops more slowly than motor neuron degeneration.

Pathologic changes in the autonomic nervous system were studied postmortem in five cases of insulin-dependent diabetes of early onset. All had had clinical evidence of peripheral sensorimotor neuropathy and developed disturbances of autonomic function that included postural hypotension, diarrhoea, bladder dysfunction, impotence (in the men), and signs of cardiac denervation. In coeliac and other sympathetic ganglia there were many distended ('giant') or vacuolated neurons as well as enlarged club-shaped neural processes. The vagus nerve and sympathetic trunks showed severe loss of myelinated fibres. Smooth muscle in many viscera showed a hitherto undescribed focal hyaline degeneration. There were inflammatory changes in the autonomic ganglia in all cases and in or around bundles of unmyelinated nerve fibres in many. These findings suggest that there may be several different pathogenetic mechanisms involved in the development of autonomic neuropathy in diabetes.

A female patient developed persistent facial pain beginning at age 19 years. Intermittent motor and sensory disturbances referable to one hemisphere began nine years later and by the age of 41 she had developed signs of increased intracranial pressure. Exploratory craniotomy revealed replacement of the leptomeninges by thick, fibrous tissue. The histological appearance was that of a chronic, benign and minimally infiltrative process with a mild, non-specific inflammatory component, underlying cortical ischaemic changes, and white matter oedema. The lesion resembled nodular fasciitis, a soft tissue process. No cause of the reactive fibrosis of the meninges in this case is known.

The clinical and neuropathologic findings of five cases of Pick disease were studied. All had severe anterior temporal atrophy and abnormal neurons with highly argyrophilic cytoplasm of Pick bodies. The amygdala was abnormal in every case and had severe involvement of all nuclear subdivisions. Behaviorally, the patients exhibited elements of Kluver-Bucy syndrome early in the disease. Language abnormalities were also prominent. Memory and spatial orientation were frequently spared until late. Computed tomography (CT) demonstrated marked lobar atrophy in one of two patients examined. The early appearance of Kluver-Bucy syndrome and the late occurrence of amnesia and spatial disorientation allow clinical identification of this variant of Pick disease.

The percentage of neurons undergoing necrosis during foetal and early post-natal development in normal and Sprawling (Swl) mutant mice was determined. Two major peaks in the occurrence of necrosis were found at the 13th and the 19th foetal days in both groups of mice but at all stages the incidence was greater in Swl. Electron microscopically the first degenerative changes seemed to involve the perikaryon while many of the cells undergoing necrosis in Swl already showed the characteristic abnormalities previously described in that mutant.

The foetal and early post-natal development of dorsal root ganglion cells in normal and Sprawling (Swl) mutant mice was studied by light and electron microscopy. As early as the 11th foetal day the nucleus of some neurons showed an indentation of its membrane and by the 13th day this abnormality was marked and present in many ganglion cells of foetuses which were, therefore, identified as presumptive Swl'. A peripherally situated nucleus and the aggregation of filaments and organelles in the central perikaryon were also early abnormalities, similar to those of the sensory neurons of the adult Swl mouse. In the normal ganglion cells, nuclei were rounded and central by the 16th foetal day and nuclear indentations were never seen, thus making a clear distinction possible between normal and Swl foetuses.

1. A sublethal quantity of black widow spider venom was injected into the calf muscles of mice. After 30 min to 6 weeks soleus muscles were examined by light and electron microscopy and by electrophysiological techniques. 2. Within 30 min motor nerve terminals were swollen and depleted for synaptic vesicles and by 6 h were disrupted and engulfed by Schwann cells. By 24 h every end-plate examined was denervated. Some preterminal myelinated axons also showed degenerative changes. 3. Re-innervation was first seen at 2 days. By 3 days axon terminals were present at most end-plates and by 8 days their morphology was nearly normal. The normal pattern of innervation of the muscle was re-established in that axons re-innervated their original end-plates and very few ultraterminal axonal sprouts were found. 4. Physiological study showed complete failure of transmission and absence of miniature end-plate potentials (m.e.p.p.s) and end-plate potentials (e.p.p.s) until day 3, when muscles responded weakly to indirect stimulation and m.e.p.p.s were recorded at 30% and e.p.p.s at 40% of fibres. The mean quantal content of e.p.p.s was low and there was rapid fatigue on repetitive stimulation. Extrajunctional sensitivity to acetylcholine developed within 1 day, was maximal at 3 days and declined to normal at 12-14 days. 5. The proportion of fibres at which m.e.p.p.s and e.p.p.s were recorded returned to normal by day 6 and mean quantal content was normal by day 9. 6. These findings show that the re-innervation of original end-plates is of importance in facilitating the rapid return of transmission to normal levels and limiting the extent of axonal growth.