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.

Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual.

BACKGROUND: In the setting of severe immunosuppression, the polyomavirus JC (JCV) can cause a lytic infection of oligodendrocytes. This demyelinating disease of the CNS white matter (WM) is called progressive multifocal leukoencephalopathy (PML). JCV has a very narrow host-cell range and productive infection of neurons has never been demonstrated. Patient, methods, and results: An HIV-1-infected patient presented with signs of pyramidal tract and cerebellar dysfunction. Brain MRI revealed T2 hyperintensities in the WM of both frontal lobes and cerebellar atrophy. His disease progressed despite therapy and he died 6 months later. In addition to classic PML findings in the frontal lobe WM, autopsy revealed scattered foci of tissue destruction in the internal granule cell layer (IGCL) of the cerebellum. In these foci, enlarged granule cell neurons identified by the neuronal markers MAP-2 and NeuN reacted with antibodies specific for the polyomavirus VP1 capsid protein. Electron microscopy showed 40 nm viral particles, consistent with polyomaviruses, in these granule cell neurons. In addition, JCV DNA was detected by PCR after laser capture microdissection of cells from the areas of focal cell loss. Finally, in situ hybridization studies demonstrated that many granule cell neurons were infected with JCV but did not contain viral proteins. Sequence analysis of the JCV regulatory region from cerebellar virions showed a tandem repeat pattern also found in PML lesions of the frontal lobe WM. CONCLUSION: JCV can productively infect granule cell neurons of the IGCL of the cerebellum. This suggests a role for JCV infection of neurons in cerebellar atrophy occurring in HIV-infected individuals.

Clinical course correlates poorly with muscle pathology in nemaline myopathy.

OBJECTIVE: To report pathologic findings in 124 Australian and North American cases of primary nemaline myopathy. METHODS: Results of 164 muscle biopsies from 124 Australian and North American patients with primary nemaline myopathy were reviewed, including biopsies from 19 patients with nemaline myopathy due to alpha-actin (ACTA1) mutations and three with mutations in alpha-tropomyosin(SLOW) (TPM3). For each biopsy rod number per fiber, percentage of fibers with rods, fiber-type distribution of rods, and presence or absence of intranuclear rods were documented. RESULTS: Rods were present in all skeletal muscles and diagnosis was possible at all ages. Most biopsies contained nemaline bodies in more than 50% of fibers, although rods were seen only on electron microscopy in 10 patients. Rod numbers and localization correlated poorly with clinical severity. Frequent findings included internal nuclei and increased fiber size variation, type 1 fiber predominance and atrophy, and altered expression of fiber type specific proteins. Marked sarcomeric disruption, increased glycogen deposition, and intranuclear rods were associated with more severe clinical phenotypes. Serial biopsies showed progressive fiber size variation and increasing numbers of rods with time. Pathologic findings varied widely in families with multiple affected members. CONCLUSIONS: Very numerous nemaline bodies, glycogen accumulation, and marked sarcomeric disruption were common in nemaline myopathy associated with mutations in skeletal alpha-actin. Nemaline myopathy due to mutations in alpha-tropomyosin(SLOW) was characterized by preferential rod formation in, and atrophy of, type 1 fibers. Light microscopic features of nemaline myopathy correlate poorly with disease course. Electron microscopy may correlate better with disease severity and genotype.

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.

JCV-specific cellular immune response correlates with a favorable clinical outcome in HIV-infected individuals with progressive multifocal leukoencephalopathy.

Most immunosuppressed individuals who develop progressive multifocal leukoencephalopathy (PML) have a rapid fatal outcome, whereas some become long-term survivors. We explored the impact of the cellular immune response against JC virus (JCV) on the clinical outcome of 7 HIV+ and 3 HIV- individuals with PML. Of the 4 HIV+/PML survivors, all had detectable cytotoxic T lymphocytes (CTL) specific for JCV T or VP 1 proteins compared to none of the 3 HIV+/PML progressors tested. Of the 3 HIV-/PML patients, 1 was recently diagnosed with PML and showed evidence of neurologic improvement without any treatment. This patient had CTL specific for the VP1 protein of JCV. The other 2 HIV-/PML survivors were stable 3-8 years after the diagnosis of PML. They did not have any detectable CTL against JCV. These findings suggest that JCV-specific immune response is associated with favorable outcome in HIV+ individuals with PML. The lack of detectable JCV-specific CTL in 2 HIV-/PML survivors might indicate a burnt-out disease without sufficient antigenic stimulation to maintain the cellular immune response. The detection of JCV-specific CTL in an HIV- patient recently diagnosed with PML, who was showing evidence of neurological improvement without any treatment, indicates that this finding may be used as a favorable prognostic marker of disease evolution in the clinical management of patients with PML. As the quest for an effective treatment of PML continues, JCV-specific cellular immune response deserves further attention because it appears to play a crucial role in the prevention of disease progression.

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.

Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.

BACKGROUND: Inherited mutations cause approximately 35 percent of cases of dilated cardiomyopathy; however, few genes associated with this disease have been identified. Previously, we located a gene defect that was responsible for autosomal dominant dilated cardiomyopathy and conduction-system disease on chromosome 1p1-q21, where nuclear-envelope proteins lamin A and lamin C are encoded by the LMNA (lamin A/C) gene. Mutations in the head or tail domain of this gene cause Emery-Dreifuss muscular dystrophy, a childhood-onset disease characterized by joint contractures and in some cases by abnormalities of cardiac conduction during adulthood. METHODS: We evaluated 11 families with autosomal dominant dilated cardiomyopathy and conduction-system disease. Sequences of the lamin A/C exons were determined in probands from each family, and variants were confirmed by restriction-enzyme digestion. The genotypes of the family members were ascertained. RESULTS: Five novel missense mutations were identified: four in the alpha-helical-rod domain of the lamin A/C gene, and one in the lamin C tail domain. Each mutation caused heritable, progressive conduction-system disease (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and dilated cardiomyopathy. Heart failure and sudden death occurred frequently within these families. No family members with mutations had either joint contractures or skeletal myopathy. Serum creatine kinase levels were normal in family members with mutations of the lamin rod but mildly elevated in some family members with a defect in the tail domain of lamin C. CONCLUSIONS: Genetic defects in distinct domains of the nuclear-envelope proteins lamin A and lamin C selectively cause dilated cardiomyopathy with conduction-system disease or autosomal dominant Emery-Dreifuss muscular dystrophy. Missense mutations in the rod domain of the lamin A/C gene provide a genetic cause for dilated cardiomyopathy and indicate that this intermediate filament protein has an important role in cardiac conduction and contractility.

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.

Parasagittal solitary fibrous tumor of the meninges. Case report and review of the literature.

The clinical, radiologic and pathologic features of a case of parasagittal solitary fibrous tumor of the meninges are reported. The patient was a 44 year-old male who presented with a complex partial seizure and a history of headaches and confusion. Radiological studies showed a large extra-axial dural-based mass in the right parietal region, predominantly isointense with gray matter and hypointense with respect to white matter on T1-weighted images, and hypointense with respect to gray matter on T2-weighted images. At surgery, the mass was very vascular, quite firm and very adherent to the convexity. Histologically the tumor was composed of spindle-shaped cells growing in fascicles within a collagenous matrix. Solitary fibrous tumor of the meninges is a newly described entity, which should be kept in mind in the clinical and radiological differential diagnosis of extra-axial brain tumors.

Focal cortical dysplasia with glioproliferative changes causing seizures: report of 3 cases.

In contrast to neoplasia, lesions of focal cerebral dysplasia are thought to be completed developmental processes of abnormal neuronal migration. We present three children with seizures resulting from brain lesions which pathologically demonstrate regions of both clearcut focal cortical dysplasia and also hypercellularity and monomorphism typical of proliferative lesions such as low grade glial tumor. These cases suggest the existence of a distinct subgroup of patients with prominent glioproliferative changes in association with focal cortical dysplasia, challenging the conventional dichotomy between dysplastic and proliferative categories of brain lesions. Recognition of patients with dual pathology may be of practical as well as theoretical importance.

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.

Localization of HIV-1 co-receptors CCR5 and CXCR4 in the brain of children with AIDS.

The chemokine receptors CCR5 and CXCR4 are co-receptors together with CD4 for human immunodeficiency virus (HIV)-1 entry into target cells. Macrophage-tropic HIV-1 viruses use CCR5 as a co-receptor, whereas T-cell-line tropic viruses use CXCR4. HIV-1 infects the brain and causes a progressive encephalopathy in 20 to 30% of infected children and adults. Most of the HIV-1-infected cells in the brain are macrophages and microglia. We examined expression of CCR5 and CXCR4 in brain tissue from 20 pediatric acquired immune deficiency syndrome (AIDS) patients in relation to neuropathological consequences of HIV-1 infection. The overall frequency of CCR5-positive perivascular mononuclear cells and macrophages was increased in the brains of children with severe HIV-1 encephalitis (HIVE) compared with children with mild HIVE or non-AIDS controls, whereas the frequency of CXCR4-positive perivascular cells did not correlate with disease severity. CCR5- and CXCR4-positive macrophages and microglia were detected in inflammatory lesions in the brain of children with severe HIVE. In addition, CXCR4 was detected in a subpopulation of neurons in autopsy brain tissue and primary human brain cultures. Similar findings were demonstrated in the brain of adult AIDS patients and controls. These findings suggest that CCR5-positive mononuclear cells, macrophages, and microglia contribute to disease progression in the central nervous system of children and adults with AIDS by serving as targets for virus replication.

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.

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.

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.

Myotonia in colchicine myoneuropathy.

Colchicine may induce a myoneuropathy in patients with renal insufficiency. To date, myotonia has not been described in this disorder. We recently studied 4 patients treated with routine doses of colchicine who, in the setting of renal insufficiency, developed a severe myoneuropathy characterized by prominent myotonic discharges on electromyography. In addition, 1 of the 4 patients had profound clinical myotonia. In the 3 patients in whom biopsies were performed, marked myopathic change with intracytoplasmic vacuolization was identified. All 4 patients improved rapidly with discontinuation of the medication. The patient in whom electrophysiologic studies were repeated had a complete resolution of the myotonic discharges. Colchicine myoneuropathy can present with prominent clinical and electrophysiologic myotonia that resolves completely with discontinuation of the medication.

Lethal neonatal deficiency of carnitine palmitoyltransferase II associated with dysgenesis of the brain and kidneys.

We describe neonatal onset of a lethal multiorgan deficiency of carnitine palmitoyltransferase II (CPT II) associated with dysmorphic features, cardiomyopathy, and cystic dysplasia of the brain and kidneys. Concentrations of long-chain acylcarnitines were evaluated in blood and multiple tissues, diffuse lipid accumulation was present at autopsy, and a profound deficiency of CPT II activity was evident in heart, liver, muscle, and kidney tissue. This disorder constitutes another recognizable malformation syndrome with a metabolic basis. Deficiency of CPT II should be included in the differential diagnosis of patients with cystic renal dysplasia, dysmorphism, central nervous system malformations, and early death, along with glutaric acidemia type II, Zellweger syndrome, and other disorders in which peroxisomal beta-oxidation is impaired. The clinicopathologic similarities among these disorders raise the possibility that a common biochemical mechanism, namely the disruption of beta-oxidation of fatty acids, is responsible for the abnormal organogenesis.