Support of axonal regrowth by endogenous mechanisms following spinal cord injury in adult rats.

Because of its non-invasive nature and ease of regulation, a closely monitored cryogenic method of tissue injury was used to create a degree of spinal cord injury within which there would be an extended regrowth of axons. The parameters of cooling used in the present study resulted in an injury length of 1 cm through which 3 mm of measured axonal regrowth and 8 mm of observed regrowth occurred over a 56-day period in the ascending fibers of the dorsal column of the mature rat. This was associated with the development of a cellular matrix consisting of macrophages, macroglia and Schwann cells which gradually expands within the injured area initially dominated by macrophages. It is the authors' impression that the presence of a substantial microglial component within the macrophage population may be a significant factor in the success of the axonal regrowth. Under this influence and that of the invading axons, the astrocyte, which provides the immediate cell support to the growing axon, can be maintained in a functional state that is supportive and not obstructive to the axon, presumably through the recruitment of astrocyte precursors from an indigenous stem cell population. These tissue changes indicate that adult mammalian spinal cord tissue does have the capacity to develop on its own a matrix capable of supporting the regrowth of axons.

Cognitive deficits associated with a recently reported familial neurodegenerative disease: familial encephalopathy with neuroserpin inclusion bodies.

BACKGROUND: We recently discovered an autosomal dominant disease causing a progressive dementia. The disease is caused by a point mutation in the gene coding for the serine protease inhibitor (ie, serpin) neuroserpin. The mutation results in an unstable neuroserpin protein that readily aggregates into intraneuronal inclusions that we identify as Collins bodies. The bodies are distributed throughout the cerebral hemispheres but are significantly more numerous in the cortex and the substantia nigra. We have named the disease familial encephalopathy with neuroserpin inclusion bodies (FENIB). OBJECTIVES: To describe the cognitive and neurophysiological changes exhibited by individuals with FENIB and to correlate the phenotypic expression of the disease with the neuropathological findings. DESIGN: Multiple case studies using neuropsychological assessment, electroencephalography (EEG), magnetic resonance imaging (MRI), and single-photon emission computed tomographic (SPECT) studies of family members were performed. Using these measures, we also compared family members in whom the mutation is present with family members in whom the mutation was absent to control for nonspecific familial factors. SUBJECTS: Nine individuals (5 women, aged 31-64 years; 4 men, aged 43-67 years) from 2 generations of family members related to the first reliably identified individual with symptoms of this disease. Symptoms, by self-report and reports of other family members, ranged from asymptomatic to severe dementia. Six of the 9 individuals carried the disease mutation. RESULTS: All subjects with the mutation demonstrated some cognitive changes, with the greatest demonstrated by subjects older than 40 years. The changes included restricted attention, concentration, and response regulation functions, reduced controlled oral fluency (word-list generation), and restricted visuospatial organization. In general, recall memory was not as affected as other cognitive domains. The most severely affected subject demonstrated global dementia with prominent frontal lobe features. Findings on SPECT showed anomalies limited to frontal areas in the less affected subjects and more global, patchy areas of hypoperfusion in the more severely affected subjects. The 3 oldest and most affected subjects demonstrated slowing on EEG findings. The MRI findings were noncontributory except in the 2 most severe cases, which showed global cortical atrophy. CONCLUSIONS: Cognitive changes in mildly to moderately affected subjects were characterized by deficits in frontal and frontal-subcortical area-dependent processes. Continued progressive deterioration of cerebral functions with relative sparing of recall memory suggests a unique dementia associated with this disease.

Delayed onset of hemidystonia and hemiballismus following head injury: a clinicopathological correlation. Case report.

The authors report the case of a young man who suffered multiple injuries in a motor vehicle accident, the most significant of which arose in the brain, creating an unusual clinical syndrome. After experiencing an initial coma for several days, the patient was found to have a right-sided homonymous hemianopsia and a right hemiparesis, which was more marked at the shoulder and was accompanied by preservation of finger movement. Dystonic movements appeared 2 months later and progressed, along with increased spasticity on volition, to severe uncontrolled arm movements at 2 years postinjury. This motor disorder continued to worsen during the following 6 years prior to the patient's death. At autopsy, the left side of the brain was observed to have marked atrophy of the optic tract, a partial lesion of the posterior portion of the medial segment of the globus pallidus (GP), and a reduction in the size of the internal capsule at the level of the GP, suggesting impaired circulation to these areas at the time of injury. The isolated lesion of the internal segment of the GP was the presumed cause of the dystonia, acting through an alteration in thalamic inhibition. The atrophic subthalamic nucleus was the probable cause of the hemiballismus. The authors speculate that this and other delayed and progressive features of this case were the result of an active, but disordered, adaptive process that failed to compensate and, instead, caused even greater problems than the original injury.

Familial encephalopathy with neuroserpin inclusion bodies.

We report on a new familial neurodegenerative disease with associated dementia that has presented clinically in the fifth decade, in both genders, and in each of several generations of a large family from New York State-a pattern of inheritance consistent with an autosomal dominant mode of transmission. A key pathological finding is the presence of neuronal inclusion bodies distributed throughout the gray matter of the cerebral cortex and in certain subcortical nuclei. These inclusions are distinct from any described previously and henceforth are identified as Collins bodies. The Collins bodies can be isolated by simple biochemical procedures and have a surprisingly simple composition; neuroserpin (a serine protease inhibitor) is their predominant component. An affinity-purified antibody against neuroserpin specifically labels the Collins bodies, confirming their chemical composition. Therefore, we propose a new disease entity-familial encephalopathy with neuroserpin inclusion bodies (FENIB). The conclusion that FENIB is a previously unrecognized neurodegenerative disease is supported by finding Collins bodies in a small kindred from Oregon with familial dementia who are unrelated to the New York family. The autosomal dominant inheritance strongly suggests that FENIB is caused by mutations in the neuroserpin gene, resulting in intracellular accumulation of the mutant protein.

Familial dementia caused by polymerization of mutant neuroserpin.

Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders; however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease. Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the superfamily of serine proteinase inhibitors (serpins). Here we describe a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically as an autosomal dominantly inherited dementia, histologically by unique neuronal inclusion bodies and biochemically by polymers of the neuron-specific serpin, neuroserpin. We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families. The significance of one mutation, S49P, is evident from its homology to a previously described serpin mutations, whereas that of the other, S52R, is predicted by modelling of the serpin template. Our findings provide a molecular mechanism for a familial dementia and imply that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps for other more common neurodegenerative diseases.

Intrinsic cervical spinal cord deformation on MRI: "the distorted 'H' sign".

Extrinsic and intrinsic pathologic processes involving the spinal cord can affect its gross morphologic appearance. Contour-related abnormalities of the spinal cord can be determined by both noninvasive and invasive imaging techniques. Detailing internal dysmorphism of the spinal cord is more difficult to determine because the internal architecture of the cord is not usually visualized. Now magnetic resonance (MR) imaging can readily demonstrate the central "H" configuration of the normal spinal gray matter on axial T2* gradient-recall echo pulse sequences; thus, it should also be capable of demonstrating distortions of it. We initially reviewed 55 abnormal cervical spine 1.5-T MR imaging studies. Of 37 large lesions, 31 deformed the "H" whereas 18 small lesions did not. To compare potential differences in visualization of the "H" by MR scanners of different field strengths (1.5-0.5 T), a total of 125 additional patients were reviewed at different State University of New York (SUNY) sites. Visualization of the "H" varied from 51.4% at 1.5 T to 18.4% at 0.5 T. As resolution of the spinal cord increases on MR imaging, it becomes possible to more accurately map the altered cord "interior," which may have a detectable clinical (neurologic) counterpart.

The prevalence of Dirofilaria immitis in dogs in Sydney.

Four hundred and four dogs from 9 pounds in Sydney were examined for circulating microfilariae and antigens of Dirofilaria immitis. One hundred of these were also examined post mortem for adult heartworms. The prevalence of infection in the 404 dogs as shown by serology was 11.4%, and 5.9% had circulating microfilariae of D immitis. Adult heartworms were present in 15 of 100 dogs. Dipetalonema reconditum microfilariae were present in 3.7% of dogs. Dirofilariosis is still a common and important parasite of dogs in the Sydney region and chemoprophylaxis is recommended.

Identification of human T cell leukemia/lymphoma virus type I antibodies, DNA, and protein in patients with polymyositis.

OBJECTIVE: To investigate a possible association between human T cell leukemia/lymphoma virus type I (HTLV-I) and polymyositis (PM). METHODS: Sera and muscle biopsy samples from 9 Jamaican PM patients were compared with specimens from American HTLV-I-positive PM patients and normal controls. Sera were evaluated for HTLV antibodies by enzyme-linked immunosorbent assay and Western blot. The biopsy samples were analyzed for HTLV-I/II DNA by polymerase chain reaction and were also immunohistochemically stained for HTLV gp46 envelope protein. RESULTS: Seven of the 8 Jamaican PM patients from whom sera were available were HTLV-I seropositive. The muscle biopsies of all 9 Jamaican patients demonstrated severe lymphocytic infiltration, cellular degeneration, myofiber atrophy, and fibrosis. Each muscle biopsy specimen contained HTLV-I DNA. Two of 6 samples demonstrated intense staining for HTLV-I gp46 in many of the invading mononuclear cells and weak staining for HTLV-I gp46 in many of the invading mononuclear cells and weak staining in the adjacent myocytes. Two other specimens were weakly positive for gp46 in rare mononuclear cells. All control specimens were negative for the presence of HTLV-I DNA and protein. CONCLUSION: HTLV-I is associated with an inflammatory muscle disease characterized by direct invasion of the affected muscle by HTLV-I-infected mononuclear cells.

Cryogenic spinal cord injury induces astrocytic gene expression of insulin-like growth factor I and insulin-like growth factor binding protein 2 during myelin regeneration.

To study injury-induced astrocytic responses associated with regrowth of axons and regeneration of myelin, the method of Collins and colleagues was used to make focal cryogenic lesions in spinal cords of adult rats (Collins et al.: J Neuropathol Exp Neurol 45: 742-757, 1986). The duration of cryogenic injury (CI), the size of the cryode, and its temperature were chosen to destroy all myelin sheaths and axons without producing cavities or hemorrhages. Messenger RNA and peptide distributions of insulin-like growth factor I (IGF-I), IGF-I receptor (IGFR-I), IGF binding protein 2 (IGFBP-2), glial fibrillary acidic protein (GFAP), and myelin basic protein (MBP) were studied 3-56 days after CI by in situ hybridization and immunocytochemistry. At 3 days, vimentin-positive, GFAP-negative astrocyte-like cells in the lesion expressed IGF-I mRNA and peptide and 7 days after CI, both were expressed by typical GFAP-positive, hypertrophic astrocytes, many of which also were vimentin-positive. Levels of IGF-I, IGFBP-2, and GFAP mRNA and peptide were higher in lesion astrocytes after 14 days. They attained maximum levels at 21-28 days before declining to near control levels at 56 days. Decreasing relative levels of oligodendroglial MBP mRNA were found in and around lesions 7-14 days after CI; subsequently, rising levels accompanied remyelination. At 28 and 56 days after CI, some transferrin-positive, oligodendroglia-like cells also were immunostained by anti-IGFR-I. Our findings suggest that early astrocytic production of IGF-I and IGFBP-2 may be involved in the myelin regeneration which occurs in this model of spinal cord injury.

Pathology of infection with Paramphistomum ichikawai in sheep.

Lambs were given 40,000 or 50,000 metacercariae of Paramphistomum ichikawai by injection into the rumen and necropsied at 21, 42 and 84 days after infection. Pathological changes were observed grossly and confirmed histologically in the small intestine and rumen. The numbers of flukes and their location in the gastrointestinal tract were recorded and the populations of eosinophils, mast cells and globule leucocytes estimated. Changes varied, according to the numbers of flukes present, from a localised enteritis and villous atrophy in the duodenum in light infections to severe destruction of the mucosa extending into most of the jejunum in heavy infections. As the infection progressed changes were characterised by extensive thickening and fibroplasia in the mucosa and submucosa. Severe damage to the mucosa of the rumen was also observed in heavy infections. Heavy infections were associated with increased infiltration with eosinophils. Mast cells were generally depleted and globule leucocytes only appeared after the flukes had left the small intestine. Migration of the flukes from the small intestine was delayed in heavy infections exacerbating the effect of the infection. It is suggested that the presence of 20,000 to 25,000 flukes would result in clinical disease; smaller numbers would cause significant subclinical disease.

Demyelinating and gliotic cerebellar lesions in Langerhans cell histiocytosis.

PURPOSE: To describe the involvement of the cerebellum by a gliotic and demyelinating process in Langerhans cell histiocytosis. METHODS: A retrospective analysis of all (N = 30) cases of Langerhans cell histiocytosis followed at our institution since 1975 yielded four patients with CT and/or MR evidence of cerebellar abnormalities. RESULTS: Four patients manifested strikingly similar findings of symmetric nonenhancing hypodensities in the dentate nuclei region of the cerebellum, which were hypointense on short-repetition-time/short-echo-time MR and hyperintense on long-repetition-time/long-echo-time MR. Biopsy in one patient yielded areas of demyelination, cell loss, and gliosis without histiocytic infiltration. CONCLUSION: Langerhans cell histiocytosis involves the cerebellum in a specific and poorly understood manner. Lesions on imaging may precede clinical findings by years. Lesions may occur in patients who have never experienced radiation therapy and may act as a marker for eventual central nervous system deterioration.

Antemortem diagnosis of Baló concentric sclerosis: correlative MR imaging and pathologic features.

PURPOSE: To report a case of a rare demyelinating disease called Baló concentric sclerosis. MATERIALS AND METHODS: A 32-year-old woman had left hemiparesis that progressed to hemiplegia, hemihypesthesia, and left hemianopsia. Laboratory evaluation was notable only for a mildly elevated erythrocyte sedimentation rate and an elevated level of myelin basic protein in cerebrospinal fluid. RESULTS: The antemortem diagnosis was made on the basis of magnetic resonance (MR) imaging of the brain, which showed numerous areas of concentric demyelination alternating with "spared" white matter. With the exception of a temporary improvement with high-dosage intravenous steroid therapy, the clinical course was monophasic and relentless, leading to death approximately 1 year after the onset of symptoms. Pathologic examination helped confirm the diagnosis. CONCLUSION: Because MR imaging shows alternating ringlike lesions involving the deep and superficial white matter, which correspond to pathologic findings, it may play a central role in antemortem diagnosis of this rare disease, leaving more invasive diagnostic procedures for evaluation of equivocal cases.