A postmortem case of an atypical form of dural graft associated Creutzfeldt-Jakob disease (CJD) is described. A 42 year old man developed progressive spastic paresis 163 months after a cadaveric dura mater graft. He presented with no myoclonus and very late occurrence of periodic synchronous discharges on EEG. The prion protein (PrP) gene was homozygous for methionine at the polymorphic codon 129. Neuropathological examination disclosed plaque-like PrP deposits with atypical distribution of synaptic PrP accumulations in the brain. This patient represents an atypical form of dural graft associated CJD characterised by unusual clinicopathological features.
- cadaveric dura mater graft
- Creutzfeldt-Jakob disease
- prion protein
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A considerable number of patients with Creutzfeldt-Jakob disease (CJD) have been reported to be associated with a cadaveric dura mater graft.1 The number of the dural graft associated cases was especially large in Japan; 67 such patients were reported in Japan during January 1985 to March 1999.2 In most of the dural graft associated cases, the clinical and neuropathological pictures were similar to those of sporadic (idiopathic) cases of CJD, although cerebellar signs were the most frequent early presentation in the dural cases.1 However, some patients with dural graft associated CJD have been reported to have atypical clinical features, with plaque formation in the brain.3-6 The plaque morphology in some patients has been reported to be identical with florid plaques,4-6 which have been described in the variant CJD (vCJD) recognised first in the United Kingdom.7 Here we describe a patient with an atypical form of dural graft associated CJD, showing unusual clinicopathological features.
A 42 year old man visited our hospital in February 1998 because of progressive right hemiparesis that had started 1 month before. In his medical history, he had had a pituitary adenoma with pituitary apoplexy and underwent an operation with a cadaveric dural graft in June 1984. The pituitary apoplexy was complicated by subarachnoid haemorrhage, which caused vasospasm resulting in infarction in the area of the left anterior cerebral artery. We have no further information about the dural graft. When he left the hospital, he had slight right hemiparesis; later he had no apparent paresis and no difficulty in activities of daily living. On neurological examination in February 1998, he was alert and oriented. The right upper and lower limbs were spastic. Although he had difficulty due to the right spastic hemiparesis, he could walk with help. There were no remarkable findings on cranial CT, MRI, or cerebral angiography, except for the old infarction in the area of the left anterior cerebral artery. Thereafter, dysarthria, dysphagia, and left spastic hemiparesis appeared. Then he became unable to walk and also showed urinary and bowel incontinence. On admission to our hospital in September 1998, he could answer to questions with only one or two words, but could respond to complicated commands. He could eat by himself and sit on a chair although he was unable to stand. He showed horizontal nystagmus, marked spasticity, and weakness in the bilateral upper and lower extremities with bilateral pyramidal signs. Ataxia was not evident. No involuntary movement was found. Laboratory tests were normal, except for low concentrations of serum sodium (125 mmol/l), which was compatible with the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and low concentrations of some pituitary hormones that were related to the postoperative state of the pituitary tumour. Analysis of CSF was normal, except for increased concentrations of neuron specific enolase (NSE) (26 ng/ml) and the presence of 14–3–3 protein. Brain CT and MRI showed only the old infarction of the left anterior cerebral artery territory as found in February 1999; except for that, there was no atrophy or abnormal intensity even on MRI diffusion images. EEG showed slow activity without periodic synchronous discharges. Prion protein (PrP) gene analysis8 of the DNA extracted from the blood disclosed no mutation in the open reading frame of the PrP gene. For the polymorphic codons, codon 129 was Met/Met, and codon 219 Glu/Glu. The diagnosis was possible CJD. After admission, he progressively deteriorated to the status of akinetic mutism after several weeks. He died of bronchopneumonia in February 1999, 13 months after the onset of the symptoms. The findings on CT and MRI were unchanged throughout his course. In repeated EEG studies, periodic synchronous discharges were first recorded 2 days before his death. At necropsy, a patch of the dural graft was found in the right frontal region. The brain weighed 1275 g. Macroscopically, the brain was slightly swollen and showed old cystic infarction scars in the territory of the left anterior cerebral artery with slight atrophy of the left cerebral hemisphere and right cerebellar hemisphere, and several, up to 10 mm sized, old infarction scars. Microscopically, there was mild to moderate spongiform change, neuronal loss, and astrocytosis in the cerebral cortex, especially in the paramedian cortical regions, subcortical grey matter, and brain stem (figure 1 A). !mmunohistochemistry for PrP showed extensive accumulation of PrP in the brain; the PrP immunoreactivities, which were mainly granular (the synaptic type), were particularly intense in the cerebellar cortex and nuclei, brainstem nuclei (especially the inferior olivary nuclei), and cerebral deep grey matter (figure 1 B). In the cerebral cortex, the PrP distribution was not uniform showing accentuation in the paramedian cortical regions including the cingulate gyrus and parahippocampal gyrus; the PrP immunoreactivities were relatively weak in the cerebral convexity regions, where the deposits were mainly in the 5th and 6th layers (figure 1 C). In the cerebral cortex, especially in the deep layers, plaque-like PrP deposits were found in addition to the granular PrP immunoreactivities of the synaptic type (figure 1 D). The plaque-like PrP deposits were unicentric and faintly eosinophilic with no or slight congophilia, suggesting that most of the plaque-like deposits would represent a preamyloid (non-fibrillary) form of PrP. Although some of the plaque-like PrP deposits were adjacent to spongiform changes, they were not surrounded by a distinct halo of spongiform change, and did not fulfil the criteria for florid plaques. In addition, there were PrP deposits surrounding neuronal cell bodies and processes in the cerebral cortex. A western blot analysis of protease resistant PrP with anti-PrP monoclonal antibody 3F4 disclosed a type 1 three band pattern showing no difference between this patient, dural graft associated patients without plaque-like PrP deposits, and patients with sporadic (idiopathic) CJD (data not shown).
Our patient was characterised clinically by progressive spastic paresis (bilateral hemiparesis) which appeared 163 months after the neurosurgical operation with cadaveric dural grafting, and pathologically by atypical distribution of the PrP accumulations with PrP plaques. In the literature, there are two forms of dural graft associated CJD depending on the clinicopathological features. One is a common form showing clinicopathological features almost identical with classic presentations of sporadic (idiopathic) CJD1; dementia, ataxia, myoclonus, and other neurological abnormalities subacutely develop with periodic synchronous discharges on EEG in a relatively early phase of the clinical course, and show akinetic mutism in a few months; neuropathologically, granular PrP deposits of synaptic type are distributed mainly in the cerebral cortical and subcortical grey matter and cerebellar cortex without PrP plaques. The other is an atypical form characterised by unusual clinical and pathological features, different from the classic cases of CJD; so far, six patients with the atypical form of dural graft associated CJD have been reported including our patient (table 1).3-6 They are characterised clinically by relatively slow progression of neurological disorders such as ataxia and mental deterioration with a longer clinical course, no or late occurrence of myoclonus and periodic synchronous discharges on EEG, and no or slight progression of brain atrophy on CT/MRI. Pathologically they are characterised by the presence of PrP plaques, which have been in some cases been described as florid plaques, and atypical distribution of PrP deposits as found in our patient. For the genotype of PrP gene or western blot analysis of the protease resistant PrP with 3F4, no difference has been reported between the common form and atypical form of dural graft associated CJD, including our patient.6 Although our patient shares several features with the previously reported cases of the atypical form of dural graft associated CJD,3-6the following points are unique. Firstly, the main clinical presentation was progressive spastic paresis in our patient; by contrast, progressive ataxia is a common feature in the other reported cases (table 1).3-6 It is noteworthy that our patient previously had an area of old infarction in the left cerebral hemisphere and the dural graft in the right frontal region, and that, when the CJD developed, the patient initially showed right spastic hemiparesis and later progression to bilateral spastic hemiparesis. This suggests that the previous neurological deficit, but not the site of the dural graft, might have influenced the initial presentation of the subsequent CJD. In the five reported cases showing progressive ataxia,3-6 the sites of the dural grafts were variable including supratentorial (three cases) and infratentorial regions (two cases); it seems unlikely that the site of the dural graft would determine the phenotype of the subsequent CJD. Secondly, the plaque-like PrP deposits in the brain from our patient were mostly non-fibrillary plaques and morphologically different from florid plaques; by contrast, florid type PrP plaques4-6 and Kuru-type amyloid plaques3 have been described in the reported patients with the atypical from of dural graft associated CJD. We emphasise that dural graft associated CJD may present with various clinical manifestations and neuropathological findings that are different from the classic pictures of CJD. The pathogenesis of the atypical form of dural graft associated CJD may be related to difference(s) in unknown factors, including the prion “strain” of the infectious dural grafts, and the genetic backgrounds of the hosts other than the PrP genotype, such as genetic polymorphisms in apolipoprotein E or other related molecules. Further clinical and experimental studies are necessary to elucidate these.
This study was supported in part by a grant from the Research Committee of Slow Virus Infection (to MY) from the Ministry of Health and Welfare, Japan. We are grateful to Dr T Kitamoto for the western blot analysis.
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