Stirling Carpenter

Neurologic Sequelae of Domoic Acid Intoxication Due to the Ingestion of Contaminated Mussels

In late 1987 there was an outbreak in Canada of gastrointestinal and neurologic symptoms after the consumption of mussels found to be contaminated with domoic acid, which is structurally related to the excitatory neurotransmitter glutamate. We studied the neurologic manifestations in 14 of the more severely affected patients and assessed the neuropathological findings in 4 others who died within four months of ingesting the mussels. In the acute phase of mussel-induced intoxication, the patients had headache, seizures, hemiparesis, ophthalmoplegia, and abnormalities of arousal ranging from agitation to coma. On neuropsychological testing several months later, 12 of the patients had severe anterograde-memory deficits, with relative preservation of other cognitive functions. Eleven patients had clinical and electromyographic evidence of pure motor or sensorimotor neuronopathy or axonopathy. Positron-emission tomography of four patients showed decreased glucose metabolism in the medial temporal lobes. Neuropathological studies in the four patients who died after mussel-induced intoxication demonstrated neuronal necrosis and loss, predominantly in the hippocampus and amygdala, in a pattern similar to that observed experimentally in animals after the administration of kainic acid, which is also structurally similar to glutamate and domoic acid. We conclude that intoxication with domoic acid causes a novel and distinct clinicopathologic syndrome characterized initially by widespread neurologic dysfunction and then by chronic residual memory deficits and motor neuronopathy or axonopathy.

Proximal axonal enlargement in motor neuron disease

THE PURPOSE OF TMS PAPER is to draw attention to a histological phenomenon which may be seen in certain cases of motor neuron disease, namely focal enlargement of axons of cells in the anterior horns of the spinal cord and in the somatic motor nuclei of the brainstem. Correlation between the clinical course of the disease and the presence of these axonal changes seems possible. The mechanism of their production is unknown, although some relevant data are available. The size and shape of the axonal enlargements may be such that they can be mistaken for chromatolytic neurons. This is perhaps the reason why they are seldom mentioned in pathological descriptions of the disease, although in 1957 Wohlfartl stated that argyrophilic axonal bodies were an invariable, though nonspecific, finding in motor neuron disease. He saw them in the ventral horns, the brainstem, and, to a lesser extent, the cerebral cortex. They were from 2 to 30 p in diameter. He felt that most of them represented terminal knobs of axons but that a few were separated from their parent axon. He envisaged 3 possibilities for their genesis: [l] that they were formed from collateral outgrowth from damaged axons of ventral horn cells, [2] that they were formed from axons having previous synaptic contact with now defunct ventral horn cells, or [3] that they were formed from dying back of terminal axons of corticospinal fibers entering the anterior horns. He noted that axonal enlargements were most numerous at the ventral side of the ventral horns but that they were seen fairly often close to neuronal perikarya. Hirano and associates2 have described swollen neuronal processes which were larger than neurons in a case of familial amyotrophic lateral sclerosis from the United States. Cytoplasmic inclusions, often multiple, were seen within the anterior horn cells. These inclusions sometimes appeared to distend the axons. The duration of the disease was nine months.

The syndrome of systemic carnitine deficiency Clinical, morphologic, biochemical, and pathophysiologic features

An 11 -year-old boy had had recurrent episodes of hepatic and cerebral dysfunction and underdeveloped musculature. Overt weakness developed at age 10. Lipid excess, especially in type I fibers, was found in muscle. Hypertrophied smooth endoplasmic reticulum and excessive microbodies were present in liver. Marked carnitine deficiency was shown in skeletal muscle, plasma, and liver. Ketogenesis was impaired on a high fat diet, but omega oxidation of fatty acids was enhanced. There was excessive glucose uptake and essentially no oxidation of labeled long-chain fatty acids by perfused forearm muscles in vivo. Oral replacement therapy restored plasma carnitine levels to normal, but not liver or muscle carnitine levels, and was accompanied by clinical improvement.

Inclusion body myositis: A distinct variety of idiopathic inflammatory myopathy

We report six cases of inclusion body myositis (IBM), a distinct but infrequently recognized inflammatory disease of skeletal muscle. Clinically, IBM differs from dermatomyositis and polymyositis. It lacks features of collagen-vascular disease, has a relatively benign and protracted course, frequently involves distal muscles, is found mainly in males, and does not improve with corticosteroid treatment. Electronmicroscopic demonstration of abnormal filaments in muscle cells is necessary for definite diagnosis, but IBM may be suspected by the finding on cryostat sections of numerous hematoxylinophilic granules in “lined” vacuoles in muscle cells. These correspond to whorls of cytomembranes. Although in dermatomyositis the capillary network is partly destroyed, in IBM it is usually augmented. A viral etiology of IBM has been suggested but remains unproven.

Progressive myoclonus epilepsies: specific causes and diagnosis.

RECENT advances in the diagnosis and classifcxation of epileptic seizures and epileptic syndromes, together with improvemenss in anticonvulsant therapy, have enabled the great majority of patients ...

Strikingly Different Clinicopathological Phenotypes Determined by Progranulin-Mutation Dosage

We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and 2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.

Dystrophin-deficient mdx muscle fibers are preferentially vulnerable to necrosis induced by experimental lengthening contractions.

Lengthening contractions were induced in the right anterior tibialis muscles (ATM) of anaesthetized normal and mdx (dystrophic) mice by supramaximal, nonfatiguing stimulation of the sciatic nerve for 180 min. In the left ATM of the same animals identical stimulation caused shortening contractions because of a prestimulation Achilles tenotomy. The prevalence of recently necrotic fibers was determined in all stimulated ATM by demonstrating the presence of IgG in the necrotic fibers using immunoperoxidase staining of cryostat sections. The results were compared to unstimulated normal and mdx ATM. A significantly higher rate of necrosis was demonstrated after lengthening contractions in the mdx ATM than normal ATM. Unstimulated normal and mdx ATM have either no or extremely infrequent necrotic fibers. We suggest that the enhanced vulnerability of mdx muscle fibers to lengthening contractions is related to the deficiency of dystrophin, which renders the sarcolemma more susceptible to suffer focal breaks. A similar situation may occur in Duchenne muscular dystrophy.

Experimental ischemic myopathy

Abstract The acute and chronic morphological changes in ischemic rat solei and gastrocnemii produced by abdominal aortic ligation were studied with histochemical and electron microscopic techniques. By light microscopy, the fully developed lesions 4 days after aortic ligation consisted of grouped or scattered necrotic fibers undergoing phagocytosis as well as regenerating fibers. By electron microscopy, the earliest lesions seen 2 hr after aortic ligation, consisted of trilaminar plates in the intracristal space of mitochondria and muscle cell necrosis as evidenced by interruption of the plasma membrane and dissolution of the Z-discs. From 18 hr onward post ligation, prominent Z-disc streaming was also present. Regenerating fibers were numerous by 4 days post-ligation. Six and 12 weeks after aortic ligation prominent “type grouping” was the only significant alteration by histochemistry. An increase of the endomysial connective tissue was conspicuously absent. The ischemic lesions were much more severe in amount and degree in the solei than in the gastrocnemii. Sciatic nerve section, Achilles tenotomy and skeletal fixation of the ankles and knees prevented ischemic lesions as viewed with light microscope. A comparison of the experimental ischemic lesions to the lesions of early or late Duchenne dystrophy revealed significant dissimilarities, while muscle biopsies in childhood dermatomyositis share many ultrastructural features of experimental ischemic myopathy.

The childhood type of dermatomyositis

The childhood type of dermatomyositis, which occurs in children and young adults, shows a specific constellation of pathologic changes in muscle. Capillary necrosis leads to capillary loss, generally starting on the periphery of muscle fascicles. Electron microscopy discloses undulating tubules in endothelial cells, lymphocytes, pericytes, and pseudosatellite cells. The muscle fiber damage is coextensive with capillary damage and probably results from progressive ischemia. The muscle cells, before atrophying, show mitochondrial elongation, Z disk streaming, focal myofibrillary loss, and occasionally selective thick filament loss. Muscle cell necrosis is rare and limited to infarctlike lesions. Inflammatory infiltrates, if present, occur only in connective tissue septa. The cause of the capillary damage has not been determined.

Neurofibrillary axonal swellings and amyotrophic lateral sclerosis

A series of 22 cases of amyotrophic lateral sclerosis (ALS) and 22 controls have been assessed for the presence of neurofilamentous accumulations in axons and perikarya. Large axonal swellings were seen in the spinal cord of 12 controls and of 13 ALS cases. When they were present in ALS cases they tended to be much more numerous than in controls, and when they were not present in ALS cases there tended to be severe neuronal loss in the cord. Axonal swelling on lower motor neurons appears to be a significant feature of the pathology of ALS. Its implications in terms of etiology are unknown.