Transformation of Face Transplants: Volumetric and Morphologic Graft Changes Resemble Aging After Facial Allotransplantation.

Facial allotransplantation restores normal anatomy to severely disfigured faces. Although >30 such operations performed worldwide have yielded promising short-term results, data on long-term outcomes remain scarce. Three full-face transplant recipients were followed for 40 months. Severe changes in volume and composition of the facial allografts were noted. Data from computed tomography performed 6, 18 and 36 months after transplantation were processed to separate allograft from recipient tissues and further into bone, fat and nonfat soft tissues. Skin and muscle biopsies underwent diagnostic evaluation. All three facial allografts sustained significant volume loss (mean 19.55%) between 6 and 36 months after transplant. Bone and nonfat soft tissue volumes decreased significantly over time (17.22% between months 6 and 18 and 25.56% between months 6 and 36, respectively), whereas fat did not. Histological evaluations showed atrophy of muscle fibers. Volumetric and morphometric changes in facial allografts have not been reported previously. The transformation of facial allografts in this study resembled aging through volume loss but differed substantially from regular aging. These findings have implications for risk-benefit assessment, donor selection and measures counteracting muscle and bone atrophy. Superior long-term outcomes of facial allotransplantation will be crucial to advance toward future clinical routine.

Effects of early and late diabetic neuropathy on sciatic nerve block duration and neurotoxicity in Zucker diabetic fatty rats.

BACKGROUND: The neuropathy of type II diabetes mellitus (DM) is increasing in prevalence worldwide. We aimed to test the hypothesis that in a rodent model of type II DM, neuropathy would lead to increased neurotoxicity and block duration after lidocaine-induced sciatic nerve block when compared with control animals. METHODS: Experiments were carried out in Zucker diabetic fatty rats aged 10 weeks (early diabetic) or 18 weeks (late diabetic, with or without insulin 3 units per day), and age-matched healthy controls. Left sciatic nerve block was performed using 0.2 ml lidocaine 2%. Nerve conduction velocity (NCV) and F-wave latency were used to quantify nerve function before, and 1 week after nerve block, after which sciatic nerves were used for neurohistopathology. RESULTS: Early diabetic animals did not show increased signs of nerve dysfunction after nerve block. In late diabetic animals without insulin vs control animals, NCV was 34.8 (5.0) vs 41.1 (4.1) ms s(-1) (P<0.01), and F-wave latency was 7.7 (0.5) vs 7.0 (0.2) ms (P<0.01), respectively. Motor nerve block duration was prolonged in late diabetic animals, but neurotoxicity was not. Late diabetic animals receiving insulin showed intermediate results. CONCLUSIONS: In a rodent type II DM model, nerves have increased sensitivity for short-acting local anaesthetics without adjuvants in vivo, as evidenced by prolonged block duration. This sensitivity appears to increase with the progression of neuropathy. Our results do not support the hypothesis that neuropathy due to type II DM increases the risk of nerve injury after nerve block.

Pathology of tumors of the pineal region.

Tumors of the pineal region are rare and relatively few centers around the world have published substantial numbers of carefully studied cases. This review gives a historical account of our understanding of the normal pineal and the evolution of the classification of tumors and other mass lesions of the pineal region in human beings. Based on our experience over the past 30 years, a working classification is proposed and recent advances in the neuropathology of these lesions are discussed.

Apoptosis induced by HIV-1 infection of the central nervous system.

Apoptosis plays a role in AIDS pathogenesis in the immune system, but its role in HIV-1-induced neurological disease is unknown. In this study, we examine apoptosis induced by HIV-1 infection of the central nervous system (CNS) in an in vitro model and in brain tissue from AIDS patients. HIV-1 infection of primary brain cultures induced apoptosis in neurons and astrocytes in vitro as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and propidium iodide staining and by electron microscopy. Apoptosis was not significantly induced until 1-2 wk after the time of peak virus production, suggesting induction by soluble factors rather than by direct viral infection. Apoptosis of neurons and astrocytes was also detected in brain tissue from 10/11 AIDS patients, including 5/5 patients with HIV-1 dementia and 4/5 nondemented patients. In addition, endothelial cell apoptosis was frequently detected in the brain of AIDS patients and was confirmed by electron microscopy. Most of the apoptotic cells were not localized adjacent to HIV-1-infected cells, providing further evidence for induction by soluble factors. In six non-AIDS control patients with normal brain, apoptotic cells were absent or limited to rare astrocytes. However, TUNEL-positive neurons and astrocytes were frequently detected in seven patients with Alzheimer's disease or abundant senile plaques. These studies suggest that apoptosis is a mechanism of CNS injury in AIDS which is likely to be induced by soluble factors. The apoptosis of endothelial cells in the CNS raises the possibility that some of these factors may be blood-derived.

Neuropathology of immunosuppression.

Traditionally, the brain has been considered an "immunologically privileged" organ. Under normal conditions, the blood-brain barrier (BBB) is highly effective in preventing both cellular and humoral constituents of the blood from entering the brain parenchyma. In certain pathological conditions, such as viral infections and demyelinating disorders, the BBB may become altered, activated T cells and monocytes may gain access to the brain parenchyma, and microglia may assume the functions of antigen-presenting cells and macrophages. Naturally-occurring or clinically-induced immunosuppression may dramatically alter various cellular and/or humoral aspects of the immune system. Consequently, the brain may become susceptible to disorders that would otherwise be excluded or may develop more severe manifestations of diseases, such as certain infections. This review considers the neuropathologic aspects of various conditions that may be encountered in the setting of both acquired and inherited immunosuppression. The major categories include infectious, neoplastic, vascular, and metabolic disorders. The review also briefly addresses the neuropathology of complications of chemotherapeutic agents, radiotherapy, and organ transplantation inasmuch as they often occur in the clinical setting of acquired immunosuppression.

August 2000: Two cases with necrosis and hemorrhage in the putamen and white matter.

The August COM: Acute methanol poisoning is an uncommon, but well-recognized, cause of central nervous system injury. We present two autopsy cases showing the classic neuropathologic injuries in acute methanol poisoning: putamen and white matter necrosis and hemorrhage. In Case 1, putamen hemorrhages were striking; white matter pathology predominated in Case 2. The precise mechanism of methanol toxicity is unclear. Direct toxicity of metabolites, particularly formic acid, as well as ischemic injury and acidosis likely play a role. Methanol is readily available in many commercial products, and may be ingested accidentally or intentionally.

Hereditary ataxia with sensory neuronopathy: Biemond's ataxia.

We report the case of a man with late-onset hereditary ataxia and sensory loss. Three of his sisters were affected by a similar disorder; to date no other members of his family have developed symptoms. The clinical features of this family are similar to a rare form of autosomal dominant hereditary ataxia, recently classified as SCA4. Postmortem findings indicate that this syndrome is marked by degeneration of cerebellar Purkinje cells, dorsal root sensory ganglion neurons, and the ascending posterior columns. Similar clinical and pathologic findings were reported by Biemond in 1954.

Giant cell ependymoma of the filum terminale. A report of two cases.

We describe two histologically unusual cases of ependymoma of the filum terminale. Both tumors occurred in 14-year-old boys. An intradural encapsulated mass attached to the filum terminale was demonstrated radiologically in both cases and totally resected at surgery. In case 1 the neoplasm was uniformly composed of pleomorphic giant cells and was without perivascular pseudorosettes or myxopapillary changes. Case 2 was a myxopapillary ependymoma with multiple foci of pleomorphic giant cells. Neither tumor had prominent mitotic activity, necrosis, or endothelial proliferation. Both tumors were immunopositive for cytokeratin and glial fibrillary acidic protein. Ultrastructural features included basal laminae, interdigitating cell processes, microvilli, cilia, intercellular junctions, and cytoplasmic intermediate filaments. Cytogenetic analysis in case 1 showed a hypodiploid karyotype with monosomy of chromosomes 1, 10, 14, 16, 20, and 22. We interpret both tumors as most consistent with a variant of ependymoma. Because of the unique gigantocellular light microscopic appearance of the entire tumor in case 1, we propose classifying this tumor as a new morphologic subtype: giant cell ependymoma of the filum terminale. The combination of gigantocellular and myxopapillary features in case 2 supports a histogenetic relationship between giant cell ependymoma and myxopapillary ependymoma.

Xanthomatous hypophysitis.

Inflammatory lesions of the hypophysis include lymphocytic hypophysitis, pituitary abscess, and granulomatous inflammation, with or without specific infections (i.e., sarcoidosis, mycobacteria). These lesions are known to mimic pituitary neoplasms. We report the clinical and pathologic findings in three patients who underwent transsphenoidal resection for presumed pituitary adenoma. Two were women aged 30 years (one with a 5-month history of headache, the other with a 1-year history of menstrual irregularity) and one was a 12-year-old girl with headache, nausea, and diabetes insipidus. Preoperative endocrinologic studies showed increased prolactin in one patient and normal serum thyroid stimulating hormone and prolactin levels in another. By magnetic resonance imaging (MRI), the first case had a 1.2-cm mass with increased signal on T1 and isointensity on T2, ring enhancement after gadolinium, and lateral deviation of the pituitary stalk. The second patient had a 1.1-cm "cystic" mass seen during magnetic resonance imaging with adjacent bony changes seen during computed tomography. In the third, computed tomography showed a hypodense pituitary mass that enlarged during 1-month observation. At surgery, abnormal soft tissue surrounded liquefied material in the anterior pituitary in all cases. Histologic studies showed fragments of intact normal anterior pituitary with preserved vascular and reticulin network and regions of anterior pituitary infiltrated by foamy histiocytes. Other fragments resembled granulation tissue, and some consisted of acellular debris. Histiocytes were immunoreactive for the macrophage marker CD68 and negative for S-100 and CD1a. Ultrastructurally, the normal adenohypophysis was permeated by lipid-laden macrophages. There were no well-formed granulomas or giant cells, hemosiderin, acid-fast bacilli, or fungi. Serial sections and keratin immunostains failed to identify an epithelial cyst lining or keratin among the debris. We propose the term "xanthomatous hypophysitis" for this lesion.

Neuropathology of the spinal cord in the acquired immunodeficiency syndrome.

The neuropathologic findings in the spinal cord were reviewed in 138 consecutive autopsies of patients with the acquired immunodeficiency syndrome. In all cases both the brain and spinal cord were examined by conventional histologic techniques, and in 63 cases immunohistochemistry was used to detect human immunodeficiency virus (HIV), Toxoplasma gondii, cytomegalovirus, and JC papovavirus antigens. The most common observation was a normal spinal cord (60%). Vacuolar myelopathy (VM) was observed in 23 (17%) cases. Human immunodeficiency virus myelitis was evident in 8% of cases. Human immunodeficiency virus myelitis was associated with HIV encephalitis in 65% of the cases. Opportunistic infections of the spinal cord were uncommon, consisting of cryptococcosis (five cases), cytomegalovirus (four cases), toxoplasmosis (one case), and progressive multifocal leukoencephalopathy (one case), and almost always were seen with cerebral and/or systemic infection by these agents. Malignant lymphoma rarely involved the spinal cord (four cases); all were B-cell lymphomas and were associated with cerebral and/or systemic lymphoma. Other abnormalities rarely observed were Wallerian degeneration of the corticospinal tracts or posterior columns (6%) and focal microinfarcts. Most cases of VM (78%) were not associated with HIV myelitis, and in the five patients with both VM and HIV myelitis, HIV-infected cells were not found in the regions affected by VM. In contrast, 65% of cases with VM were associated with HIV encephalitis. The pathogenesis of VM remains unknown; it is probably not due to direct infection by HIV.

Intradural lipomas of the spinal cord. A clinicopathological correlation.

Nine original cases of intradural spinal cord lipomas have been examined from a clinical and pathological standpoint. These tumors occur more commonly in men in the second to fourth decade and are found most frequently in the thoracic spinal cord. Paraparesis, sensory changes, urinary incontinence, and pain are frequent presenting complaints. Myelography is the diagnostic study of choice. All lipomas in this series were located primarily within the cord; four of these also presented an extramedullary extension. Admixed nerve bundles were present in five cases with associated hypertrophic onion-bulb formation in three. Decompression with biopsy or subtotal resection is the operative procedure of choice.

Idiopathic pinealitis. Case report.

This 63-year-old man presented with complaints of "having a feeling of falling backward" over a 3-month period. Results of his general physical examination, laboratory studies, and neurological examination were unremarkable. A magnetic resonance image revealed a 1.8 x 1.4 x 1.2-cm enhancing mass in the posterior third ventricle just above the corpora quadrigemina. The pineal gland was found to be diffusely enlarged at operation and separable from the posterior thalamus and was totally resected. The patient had an uneventful postoperative course but continues to be somewhat confused. The lesion consisted of a remarkable chronic inflammatory cell infiltrate permeating the pineal lobules and was composed of T and B lymphocytes, macrophages, eosinophils, and mast cells. Immunoperoxidase studies did not demonstrate Langerhans cells, and a search for microorganisms was unrevealing. There was no evidence of neoplasia; results of immunostaining for germ cell markers and other tumor-associated antigens were negative.

Immunocytochemical study of ballooned neurons in cortical degeneration with neuronal achromasia.

We studied the immunocytochemical characteristics of the ballooned neurons (BN) in three patients with cortical degeneration with neuronal achromasia (CDNA) using antibodies to phosphorylated neurofilaments (PNF), tau, Alz-50, ubiquitin, beta (A4) amyloid, and glial fibrillary acidic protein. All BN exhibited intense perikaryal staining for PNF protein. Most BN and some normal-appearing neurons also stained for ubiquitin and Alz-50. The BN did not immunostain for tau protein, and none of the cases had tau-reactive neocortical neurofibrillary tangles or Pick bodies. One case had occasional senile plaques that stained for beta amyloid; no case had amyloid angiopathy. Our findings suggest that the pathophysiologic basis of the cortical degeneration in CDNA involves an alteration of neuronal cytoskeletal metabolism affecting neurofilament and possibly microtubular proteins in conjunction with activation of the ubiquitin proteolytic system.

Neuropathology of liver transplantation.

We reviewed retrospectively the clinical records, autopsy protocols and central nervous system tissue sections of 50 patients who underwent orthotopic liver transplantation for end-stage liver disease between 12/83 and 8/93. The postoperative survival period ranged from hours (6), weeks (17), months (17), to years (10). All patients received immunosuppressive drugs from the immediate postoperative period to the time of their death (cyclosporine, steroids; occasionally azathioprine, OKT3, FK506). Nineteen patients had neurological manifestations (hepatic encephalopathy) prior to surgery. Post-transplant neurologic signs and symptoms included: hepatic encephalopathy/altered mental status (11), focal or generalized seizures (9) and stroke (2). In the majority of cases (37) the cause of death was septicemia and/or bleeding diathesis. The neuropathologic findings present in 36 patients could be classified into 3 distinct categories: metabolic disorders: hepatic/anoxic encephalopathy, central pontine myelinolysis (15); cerebrovascular disease: subarachnoid and/or intracerebral hemorrhage, bland or hemorrhagic infarction (23); and infection: bacterial meningitis/cerebritis, multifocal fungal microabscesses, presumptive viral meningitis/encephalomyelitis (10). In conclusion, 72% of 50 patients who came to autopsy after liver transplantation were found to have neuropathologic abnormalities; these abnormalities were predominantly infections and vascular diseases.

Immunohistochemistry of synapsin I and synaptophysin in human nervous system and neuroendocrine tumors. Applications in diagnostic neuro-oncology.

Synapsin I is a phosphoprotein localized to the cytoplasmic surface of synaptic vesicles and is one of the best characterized neuron-specific proteins. Synaptophysin is an integral membrane glycoprotein, also located on presynaptic vesicles, which has been shown to be a useful immunohistochemical marker for neuroendocrine/neuronal differentiation in tumor diagnosis. The sensitivity and specificity of immunohistochemical staining for these two proteins in formalin-fixed, paraffin-embedded tissues was studied in a series of 67 neuroectodermal, neuroendocrine, and non-neural tumors. Intense immunoreactivity for both synapsin I and synaptophysin was observed in tumors containing well-differentiated neurons (gangliocytoma, ganglioglioma, neurocytoma). In these tumors, immunostaining was primarily concentrated along the outer surface of the cell membrane of the neuronal cells. Primitive neuroectodermal tumors (PNETs) (cerebral PNET, medulloblastoma, neuroblastoma) and most neuroendocrine tumors generally showed less intense and more variable immunoreactivity for these proteins. In most cases, immunostaining for synapsin I was sharper and often more intense than for synaptophysin. Some PNETs and neuroendocrine tumors that were immunoreactive for synapsin I did not stain for synaptophysin. We conclude that synapsin I is a reliable, sensitive immunohistochemical marker for neuronal/neuroendocrine differentiation in human neoplasms and may offer some advantages over synaptophysin when applied to formalin-fixed, paraffin-embedded tissues, particularly in the evaluation of primitive neuroectodermal tumors and neuroendocrine tumors.

Neuropathology of the acquired immunodeficiency syndrome.

This review attempts to assess critically the literature on the neuropathology of acquired immunodeficiency syndrome in light of our experience with 172 patients with acquired immunodeficiency syndrome who underwent extensive postmortem examinations of the central and peripheral nervous systems. The neuropathologic manifestations of the disease can be divided into three categories: (1) primary or putative/indirect effects of the human immunodeficiency virus, (2) opportunistic infections, and (3) neoplasms. We discuss the known etiologic agents and postulated pathogenetic mechanisms responsible for the broad range of neurologic diseases observed in patients with acquired immunodeficiency syndrome.

Neuro-glial hamartoma of the suprasellar cistern.

A unique case of a suprasellar hamartoma in a 29-year-old woman is presented. The lesion was discovered in the context of a work-up for amenorrhea that had lasted 1 year and was resistant to clomiphene and medroxyprogesterone acetate treatment. Magnetic resonance imaging (MRI) revealed a 1.2-cm anterior suprasellar lesion with no apparent connection to the hypothalamus or hypophysis. She underwent surgical resection of the mass. Pathologic examination revealed randomly arranged mature neurons, glial tissue, and myelinated fibers. There was no evidence of gonadotropin-releasing hormone producing neurons on immunohistochemical studies. Postoperative MRI showed complete resection of the lesion, and 1 year later mensus resumed off medication.

[Pathologic study of the eye and central nervous system in 25 cases of AIDS]. / Etude pathologique de l'ceil et du système nerveux central dans 25 cas de SIDA.

We have reviewed the clinical and pathologic findings of 25 patients with the acquired immunodeficiency syndrome (AIDS) who had a complete post-mortem examination including a study of the nervous system and of one or both eyes. Cytomegalovirus (CMV) retinitis was the most frequent type of ocular infection observed fundoscopically (9 of 18 cases examined clinically). There were only 3 cases of CMV encephalitis amongst the 8 cases of CMV retinitis documented pathologically. Cerebral toxoplasmosis was found in 12 of the 25 cases and in only one of these could Toxoplasma gondii cysts be demonstrated in the optic nerve. Cotton wool spots were the most frequent lesion observed fundoscopically (10 of 18 cases examined clinically). In the 3 cases where they were observed microscopically they corresponded to cytoid bodies which represented axonal swellings within the nerve fiber layer. The pathogenesis of this lesion in patients with AIDS is not understood. Intraocular lymphoma was present in only one case.

Lovastatin/gemfibrozil myopathy: a clinical, histochemical, and ultrastructural study.

Lovastatin has been used with increasing frequency over the past few years to reduce serum cholesterol. The onset of muscle weakness, one of the most serious side effects of long-term treatment with the drug, constitutes a contraindication to the continuation of therapy and commonly occurs in patients who are also receiving gemfibrozil or cyclosporine. We report the clinical and pathologic findings in a patient treated for hypercholesterolemia with lovastatin and gemfibrozil who developed a rapidly progressive necrotizing myopathy. A 57-year-old woman with hyperlipidemia, treated with lovastatin and gemfibrozil, was admitted to the hospital for evaluation of muscular weakness in her legs and neck. Neurologic examination revealed severe proximal muscle weakness involving both upper and lower extremities as well as proximal muscle tenderness and areflexia in the lower limbs. A biopsy of the quadriceps muscle showed multiple foci of mononuclear cell infiltration with myophagocytosis and slight variation in the size and shape of muscle fibers. Electron microscopy of the affected fibers showed accumulations of subsarcolemmal autophagic lysosomes. The patient's condition dramatically improved after discontinuation of lovastatin-gemfibrozil therapy.

Clear cell pleomorphic xanthoastrocytoma: case report.

Pleomorphic xanthoastrocytoma (PXA) is a well-described astrocytic neoplasm with distinctive clinical and pathological features. Although most patients with PXAs are cured by surgical excision, other patients experience malignant progression and tumor recurrence. We describe a 47-year-old woman with a left temporal lobe PXA that had classic histopathological characteristics as well as extensive clear cell and focal papillary changes, and some anaplastic findings. The patient has now suffered two recurrences after complete resection. The case illustrates a rare, previously undescribed histological variant of PXA, with a prominent clear cell and focal papillary morphology. The study of histologically similar cases is needed to determine whether this variant is always associated with a greater likelihood of recurrence.