An autopsy case of progressive multifocal leukoencephalopathy after rituximab therapy for malignant lymphoma

Progressive multifocal leukoencephalopathy (PML) is a rare fatal demyelinating disease of the central nervous system caused by reactivation of the JC virus (JCV), which is named after the initials of the patient from whom the virus was first isolated. JCV is highly prevalent worldwide, infects humans in early childhood, and the infection persists throughout the course of life in latent form. The present paper deals with the second autopsy case report of rituximab‐associated PML in Japan. A 63‐year‐old woman who had undergone chemotherapy for non‐Hodgkin lymphoma developed progressive dysarthria and cerebellar ataxia. Head magnetic resonance imaging (MRI) revealed small, scattered, hyperintense areas in the midbrain, pons and thalamus, and the patient was first diagnosed as having cerebral infarction. Follow‐up MRI showed tendency toward cerebellar atrophy and multiple system atrophy cerebellar type was suggested, which we concluded must have coincidentally occurred. It was challenging to perform biopsy due to the location of the foci and the patient's condition. Twelve months later she died of aspiration pneumonia caused by the bulbar lesion. At autopsy, the histological examination suggested the presence of demyelinating foci with numerous foamy macrophages. In the foci, oligodendrocytes with enlarged ground‐glass like nuclei were found in a scattered manner and astrocytes with bizarre nuclei were also detected. These findings verified the case as PML. The first diagnosis of cerebral infarction was later withdrawn, although appropriate disorders were not recalled even after testing with various antibodies. The rate of PML development tends to increase after treatment with molecular‐targeted therapies, which directly or indirectly attenuate the cellular‐mediated immune system. Various novel molecular‐targeted and immunosuppressive drugs have been released on the market; the cases of PML have consequently increased. Accordingly, pathologists should keep this disease in mind in the differential diagnosis when neural symptoms newly emerge in patients who are treated with these drugs.     

An autopsy case of drug‐induced diffuse cerebral axonopathic leukoencephalopathy: The pathogenesis in relation to reversible posterior leukoencephalopathy syndrome

An autopsy case of diffuse axonopathic leukoencephalopathy induced by drug treatment is reported. A 70‐year‐old woman with multiple myeloma developed encephalopathy several days after completing a course of intravenous human immunoglobulin (IVIg) and granulocyte‐colony stimulating factor (G‐CSF), and died within I month. T2‐weighted MRI demonstrated multifocal high‐signal areas in the bilateral cerebral white matter, especially in the right frontal lobe. Neuropathologically, multifocal hydropic axonal swelling with a poor glial reaction was recognized diffusely in the bilateral deep cerebral white matter, being especially marked in the frontal lobe. The cortex, subcortical U‐fibers, corpus callosum, and anterior commissure were spared. The cerebellar white matter also showed similar changes, albeit less marked, but the brainstem was spared. Microscopically, the myeloma involvement of the CNS was limited to the dura, and the cerebral arteries showed slight atherosclerosis, but neither thrombi nor angitis. This case, although ultimately fatal, neurologically and neuroradiologically resembled reversible posterior leukoencephalopathy syndrome (RPLS) induced by IVIg and/or G‐CSF, and the nature and selective distribution of the neuropathological changes suggested that the pathogenesis involved vasospasm of the bilateral internal carotid artery and the main trunks of the cerebral arteries, due to unknown cause, inducing ischemia in the deep white matter, which is supplied by long nutrient arteries.     

An autopsy case of hemimegalencephaly

This case report is a neuropathological study of a ten-month-old infant with unilateral megalencephaly . In this anomaly neuronal migration defect and disturbances of cortical organization resulting in micropolygyria were the most striking neuropathological feature.     

An autopsy case of progressive multifocal leukoencephalopathy: comparison of magnetic resonance imaging findings with the pathological findings

A 41-year-old man diagnosed with malignant lymphoma (MLy) in November 2007 developed paralysis that worsened rapidly in January 2008. Magnetic resonance imaging (MRI) showed multifocal T2 high-intensity lesions without edema or gadolinium enhancement in the white matter. The lesions were characterized by a central core with low signal intensity, surrounded by a rim of high signal intensity on diffusion-weighted images (DWIs). At first, we suspected brain metastasis of MLy and used anti-cancer drugs, but the patient's condition worsened. A brain biopsy was then taken to determine whether the patient had MLy metastasis or progressive multifocal leukoencephalopathy (PML) so that an appropriate course of treatment could be determined. The biopsy contained no characteristic nuclear inclusions of PML, but we were able to rule out MLy; therefore, the patient was treated with cytarabine in February 2008, but he died because of sepsis in March. Upon autopsy, many characteristic nuclear inclusions of PML were found in the periphery of the lesions, and in the central core, there was severe demyelinating and tissue softening without typical nuclear inclusions of oligodendroglias. This structure is similar to the structure observed on DWIs, in which a low signal intensity core is surrounded by a rim of high signal intensity. The presence of inclusion bodies in the rim would correspond to the high signal intensity area on DWIs. The peripheral area may have given high signal intensity on DWIs because of the active findings of many swelling oligodendroglias with typical nuclear inclusions. Conversely, the central lesions would give low signals on DWIs because of demyelination and softening. Hence, the region with high signal intensity adjacent to the central low signal area on DWIs would be an appropriate biopsy point for PML diagnosis. ).     

An autopsy case of Prader-Labhart-Willi syndrome

An autopsy case of 23-years-old man with Prader-Labhart-Willi syndrome (P-L-W syndrome), who had died by acute renal failure due to burn injury, was reported. P-L-W syndrome was constituted by hypotonia, hypogonadism, hypomentia, obesity and other minor anomalies, however, CNS anomaly had not been reported. The patient sat at 3 years of age, walked at 4 years old, began to utter single words at 3-4 years, and he began to obese at 4 years of age. He fulfilled the condition of P-L-W syndrome mentioned above. On his age 15, laboratory findings on admission revealed remarkable diabetic pattern by oral glucose tolerance test and intelligence quotient was 28, and the other laboratory findings were within normal limit. During his clinical history, complications of diabetes mellitus, such as diabetic retinopathy and neuropathy, were aggrevated, and upstanding and gait were impossible at 20 years of age. On his age 23, he suffered from burn injury at left lower extremity and he fell in acute renal insufficiency. Five autopsy cases of P-L-W syndrome have been reported so far, however, CNS anomaly has not been observed. Following anomalies in our case was recognized, such as shortness of the frontal lobe, partial micropolygyria of the dentate nucleus, heterotopia of the inferior olivary nucleus, ectopia of Purkinje cell in the molecular layer, heterotopia of middle sized neuron in the deep white matter of the cerebellum and large number of residual nerve cells in the cerebral subcortical white matter.(ABSTRACT TRUNCATED AT 250 WORDS)     

An autopsy case of dementia and parkinsonism with severe degeneration exclusively in the substantia nigra

Summary We have recently encountered a patient with progressive dementia and parkinsonism beginning at the age of 68 years and developing for 2 years. Pathological examination revealed severe degeneration exclusively in the substantia nigra with absence of Lewy bodies and neurofibrillary changes. The features of this case are reported and discussed.     

An autopsy case of ornithine transcarbamylase deficiency

We present an autopsy case of ornithine transcarbamylase (OTC) deficiency with grumose degeneration in the dentate nucleus of the cerebellum. The patient had intractable neonatal convulsions and hyperammonemia from the 3rd day after birth. Diagnosis of OTC deficiency was made based on null activity of the enzyme and four-base deletions in exon 9 of the OTC gene. Death was due to sepsis as well as disseminated intravascular coagulation at 1 year and 2 months of age. Neuropathology showed multiple cystic changes and ulegyria in the bilateral frontal and parietal lobes. Multiple cysts were associated with the region, which was infiltrated with macrophages surrounded by astroglia showing palisading pattern. Ferrugination was marked in the thalamus and severe neuronal loss with astrogliotic change in the CA1-2 area of the hippocampus. Grumose degeneration was noted in the dentate nucleus of the cerebellum. This is the first report of grumose degeneration in OTC deficiency.     

An autopsy case of classical Pelizaeus-Merzbacher's disease

Summary A girl aged 8 years and 10 months at death had shown signs of a slowly progressive neurological disease with onset in early infancy. The main clinical features were nystagmus, spastic paraplegia, and mental deterioration. Pathological examination of the brain showed severe demyelination with perivascular preservation of myelin islands, presenting a tigroid pattern. The patient is the second case of classical Pelizaeus-Merzbacher's disease in Japan proven by autopsy.     

An autopsy case of transcortical motor aphasia

An autopsy case of transcortical motor aphasia is presented with a pathology located anterior and superior to the pars opercularis of the left inferior frontal gyrus. Case H. Y. A 60-year-old right-handed man. On Nov. 14, 1978, the patient had surgery to remove cerebral hematoma in the left frontal lobe. In the neuropsychological examination before the operation, he had shown the clinical features of transcortical motor aphasia characterized by good comprehension of language, preserved repetition, and spontaneous speech disorder. In this stage, it was supposed that the underlying disturbance of spontaneous speech was due to the disabilities of contextual constructions of sentences rather than the lack of speech initiation. Following the operation, however, spontaneous speech disappeared completely for several days. At the same time, the patient showed problems in comprehension, reading, writing and confrontation naming as well as symptoms of disorientation, pathological inertia and 'loss of initiation' in the psychomotor domain. During the following three months, however, the patient did show slight improvement, except for contextual sentence constructions and pathological inertia when taking the complex animal drawing test. In his terminal stages, the clinical symptoms could be summarized as transcortical motor aphasia and mild frontal lobe syndrome. On March 1, 1979, the patient died of Hamman-Rich syndrome. Postmortem examination: The brain weighed 1294 gm. The external observation of the brain disclosed the linear tissue defect, about 15 mm in length and 10 mm in width, along the radial sulcus of the pars triangularis of the left inferior frontal gyrus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Emery-Dreifuss muscular dystrophy. An autopsy case

We reported the autopsy findings in a 50-year-old man with typical clinical features of Emery-Dreifuss muscular dystrophy. Special attention was directed to the spinal cord and ventral spinal roots to determine whether cause of the muscle wasting was denervation or myopathy. Neuropathological studies disclosed no abnormality of the spinal cord, and the ventral spinal roots were intact. The skeletal muscles showed dystrophic changes of varying degrees, and marked cardiomyopathy was evident. We consider that muscle wasting in this man was due to muscular dystrophy.     

An autopsy case of miliary brain metastases]

A 57-year-old man was admitted to our hospital with a diagnosis of psychiatric emergency. His symptoms were similar to encephalitis, metabolic encephalopathy or acute depressive psychosis because of poor focal neurological signs. Laboratory examinations, including routine hematological and biochemical investigations, serum vitamin B1 B12 levels, and cerebrospinal fluid obtained by lumbar puncture, were normal. Brain CT was also normal, therefore it was difficult to make a diagnosis. But, we could clinically diagnose him as having pulmonary adenocarcinoma with numerous metastatic nodules of the brain. Because miliary lesions in the cerebral hemispheres, brainstem and cerebellum were disclosed on brain MRI. Furthermore, chest CT revealed the lung tumor in the left S8 area. In addition, laboratory examination showed a rise of tumor marker and cytologic examination of sputum revealed class V. Fluid-attenuated inversion recovery and contrast-enhanced MR images demonstrated more prominently miliary metastases, in particular lesions in the cerebral cortex, than T1- and T2-weighted images. There was neither edema in the surrounding region of metastatic nodules nor mass effect on all MR images. Spinal MRI showed no metastatic lesions. The patient died of respiratory failure at the age of 58, about eight months after the disease onset. The brain weighed 1,575 g. Neuropathological findings revealed diffuse miliary brain metastases located in all parts of the brain, except for the medulla oblongata. Histological examination disclosed multiple metastases from a well-differentiated adenocarcinoma with a predominant tubular pattern. There was neither edema nor glial reaction in the surrounding area of metastatic lesions. Many pseudorosettes were recognized and carcinoma cells, extending through perivascular spaces into the subarachnoid space, were noticed.     

An autopsy case of atypical adrenoleukomyeloneuropathy in childhood

Adrenoleukomyeloneuropathy (ALMN) usually occurs in adulthood, it being extremely rare in childhood. We reported a quite atypical clinical case of ALMN as a variant of adrenoleukodystrophy (ALD). The onset was at 5 years 7 months and ataxia was the major symptom. His condition progressed rapidly to a vegetative state within 1 year. At the age of 11 years and 11 months he died of pneumonia and an autopsy was performed. We herein reported the neuropathological findings in this rare case. The autopsy revealed marked atrophy with diffuse demyelination and astrogliosis throughout the cerebrum, cerebellum and brainstem. Massive degeneration of the pyramidal tracts and loss of neurons were also seen in the spinal cord. The adrenal cortex showed marked atrophy with a striated cytoplasm in ballooned cells. These findings include pathological characteristics of both ALD and adrenomyeloneuropathy (AMN), suggesting ALMN. However, diffuse demyelination with gliosis in the cerebrum and cerebellum is quite atypical for ALMN. They might explain his atypical clinical course, especially the early onset of the disease with ataxia and rapid deterioration.     

An autopsy case of adult neuronal ceroid lipofuscinosis

This is a report of an autopsy case (45-year-old woman) of adult neuronal ceroid lipofuscinosis with a long-lasting course of 25 years. In the course of her illness, gait disturbance, bulbar palsy and dementia were observed. Pathologically severe neuronal loss and hemosiderin-like granules were found in the cortex, basal nuclei, thalamus and others. The residual cells of these tissues were swollen with lipofuscin-like pigments. The extremely swollen nerve cells were found in the anterior horn of the spinal cord. Electron microscopically, numerous curvilinear bodies, myelin figures and fingerprint profiles were seen in those cytoplasms. Ceroid and lipofuscin were proven by a histochemical examination.