Changes in optic nerve head blood flow in children with cerebral malaria and acute papilloedema.

OBJECTIVE: To investigate capillary blood flow in the optic nerve head (ONH) of children with cerebral malaria. METHODS: Malawian children with cerebral malaria admitted to a paediatric research ward were examined by direct and indirect ophthalmoscopy. ONH blood flow was measured using laser Doppler flowmetry (LDF) in suitable patients. Mean blood volume and velocity were obtained from 30 to 60 s recordings from the temporal ONH and used to calculate blood flow. These were compared with admission variables, funduscopic findings and disease outcomes. RESULTS: 45 children with cerebral malaria had LDF recordings; 6 subsequently died and 5 survivors had neurological sequelae. 12 (27%) had papilloedema. The mean microvascular blood volume was higher in patients with papilloedema (3.28 v 2.54 arbitrary units, p = 0.002). The blood velocity correlated directly with haematocrit (r = 0.46, p = 0.001) and inversely with blood glucose (r = -0.49, p = 0.001). CONCLUSION: The increase in ONH microvascular blood volume in papilloedema measured by LDF is consistent with current theories of pathogenesis of papilloedema. LDF has potential as a tool to distinguish papilloedema from pseudopapilloedematous disc swellings. The relationship between blood velocity and haematocrit may relate to levels of sequestration in cerebral malaria.

Adult xanthogranulomatous disease of the orbit and ocular adnexa: new immunohistochemical findings and clinical review.

BACKGROUND/AIMS: Adult xanthogranulomatous disease involving the ocular tissues is rare and poorly understood. Adult onset xanthogranuloma (AOX), adult onset asthma and periocular xanthogranuloma (AAPOX), necrobiotic xanthogranuloma (NBX), and Erdheim-Chester disease (ECD) are the four syndromes within this disorder, which is diagnosed by characteristic histopathology. Experience with eight cases prompted a multi-institutional effort to study the histopathology, immunohistochemistry, clinical findings, and systemic associations in this disorder. METHODS: 22 cases, including histopathological slides, were compiled. Published reports were identified by an English language Medline search (1966-2005) and review of reference citations. Each case in this series and the literature was classified as one of four syndromes and then analysed for age onset, sex, skin xanthoma, orbital location, immune dysfunction, internal organ and bone lesions, treatment, and outcome. The histopathology in each of these cases was reviewed by two pathologists. Immunhistochemical stains (CD3, CD4, CD8, L26) were performed in 14 cases where unstained slides were available. RESULTS: 137 cases were compiled. There was no sex or age difference between syndromes. AOX, AAPOX, NBX affect the anterior orbit, ECD tends to be diffuse and intraconal. Skin lesions are found in all the syndromes. Immune dysfunction was noted in all cases of AAPOX and NBX; 11% of NBX and all ECD patients had internal organ disease. Treatment included surgery, corticosteroids, other chemotherapeutic agents, radiotherapy, and combinations of these. No AOX or AAPOX deaths occurred; 66% of ECD patients died. All 22 cases had xanthoma cells; most had Touton giant cells. Lymphocytes were present in all cases and occurred as aggregates (mostly in AAPOX) or diffuse populations mixed with fibroblasts (mostly in ECD). Immunohistochemistry revealed the majority of these to be CD8+. Necrosis was most marked in NBX. CONCLUSION: Adult xanthogranuloma of the orbit is rare, making prospective evaluation or meta-analysis impossible. The best treatment is unknown but seems to be with multiagent chemotherapy guided by histopathological, immunohistochemical, and systemic findings.

Partial deletions of the long and short arm of chromosome 3 point to two tumor suppressor genes in uveal melanoma.

Uveal melanoma is the most common form of primary eye cancer. Monosomy 3, which is an unusual finding in tumors but is present in approximately 50% of uveal melanomas, is significantly correlated with metastatic disease. To obtain positional information on putative tumor suppressor genes on this chromosome, we have investigated tumors from 333 patients by comparative genomic hybridization, microsatellite analysis, or conventional karyotype analysis. A partial deletion of the long arm was found in eight tumors, and the smallest region of deletion overlap (SRO) spans 3q24-q26. We found six tumors with a partial deletion of the short arm and were able to define a second SRO of about 2.5 Mb in 3p25. This SRO does not overlap with the VHL gene. Our finding suggests a role for two tumor suppressor genes in metastasizing uveal melanoma and may explain the loss of an entire chromosome 3 in these tumors.

Pulmonary dirofilariasis: the great imitator of primary or metastatic lung tumor. A clinicopathologic analysis of seven cases and a review of the literature.

The clinical, radiologic, and pathologic features of seven patients with pulmonary dirofilariasis were studied. The findings were analyzed in conjunction with those of 76 cases previously reported from the United States. We found that, in most instances, the disease was acquired in states along the Atlantic and Gulf coasts and occurred predominantly in whites (94.7%) in their fifth or sixth decades of life, with a male to female ratio of 2:1. Symptoms, commonly chest pain, cough, or hemoptysis, were present in 37.6% of patients. Most patients (62.4%) were asymptomatic, and the disease was discovered incidentally on routine radiography or during the investigation of another problem. Peripheral eosinophilia was present in 20% of patients. The radiologic findings consisted of single (89.8%) or multiple (10.2%) pulmonary nodules that simulated primary or metastatic lung tumor. Dirofilariasis was not included in the clinical differential diagnosis in any of the patients. In one case, the diagnosis was accurately obtained by fine needle aspiration biopsy. All other patients required thoracotomy with excisional lung biopsy for diagnosis. Pathologically, the dirofilaria nodule consisted of a spherical subpleural infarct with a central thrombosed artery containing Dirofilaria immitis in various stages of disintegration.

Use of the polymerase chain reaction to detect B- and T-cell gene rearrangements in vitreous specimens from patients with intraocular lymphoma.

OBJECTIVE: To determine whether the polymerase chain reaction for B- and T-cell gene rearrangements could be applied to vitreous specimens to aid in the diagnosis of intraocular lymphoma. METHODS: Vitreous washing specimens from 4 patients were received in balanced saline solution and centrifuged, and a portion of the pellet was used to make routine cytospins. The remainder was used to make a crude extract of DNA that was amplified for immunoglobulin heavy chain and T-cell receptor gamma gene rearrangements and the 14;18 translocation by polymerase chain reaction. RESULTS: One patient had 2 specimens 2 years apart. In each, there was an identical band corresponding to the minor cluster region breakpoint of the bcl-2 oncogene, indicating the presence of a 14;18 translocation. One patient showed an immunoglobulin heavy chain gene rearrangement indicating a B-cell lymphoma. Two patients showed rearrangements of the T-cell receptor gamma gene, indicating the presence of a T-cell lymphoma. CONCLUSIONS AND CLINICAL RELEVANCE: Vitreous washing specimens can be used successfully to detect B- and T-cell gene rearrangements by polymerase chain reaction. This may be useful to confirm the diagnosis of intraocular large cell lymphoma in cases suggestive of the diagnosis. Prompt handling of the specimens is necessary to prevent degradation of the DNA.

Simple choristoma of the anterior segment containing brain tissue.

We report an unusual case of a simple choristoma of the anterior segment that contained only brain tissue. The clinical characteristics and findings of pathological examination of this unusual ocular malformation were reviewed. A newborn girl was seen with a fleshy, highly vascular cystic mass arising from the inferior limbus and extending across the cornea. On a computed tomographic scan, gross disruption of the anterior segment was present, with subluxation of the lens into the cyst. Excision of the abnormal tissue was followed by evisceration; polyglactin (Vicryl) ball implantation; patch graft of the globe; and, later, prosthetic fitting. Pathologic findings showed a choristomatous malformation, containing only mature brain tissue. To our knowledge, a choristoma in which the sole constituent is brain tissue has not previously been reported.

Lateral extensions of the Müller muscle.

OBJECTIVES: To define the lateral extension of the Müller muscle and to elucidate its involvement in the development and surgical treatment of Graves (thyroid) eye disease. METHODS: Twelve lateral halves of orbits exenterated from patients with medial or posterior orbital neoplasms were fixed, embedded, and step sectioned at 250-microns intervals to produce histological sections. Gross anatomical dissections of human cadaver heads were also used to corroborate the histological findings. RESULTS: Histological analysis revealed that the Müller muscle extended laterally between the orbital and palpebral lobes of the lacrimal gland in all specimens. The smooth muscle fibers were found to interdigitate with lacrimal ducts passing from the orbital to palpebral lobe and to extend close to the ductal orifices at the conjunctival surface. Gross dissections confirmed that the Müller muscle accompanied the levator aponeurosis lateral extension, which is known to pass between the orbital and palpebral lobes of the lacrimal gland. CONCLUSIONS: Our anatomical findings suggest that the Müller muscle may contribute to the temporal flare frequently seen in eyelid retraction associated with thyroid eye disease. They may also explain the difficulty of treating lateral eyelid retraction in thyroid eye disease and indicate the need for new surgical approaches for severe lateral eyelid retraction.

Clinical-histopathological correlation of the abnormal retinal vessels in cerebral malaria.

BACKGROUND: Clinically abnormal retinal vessels unique to cerebral malaria have previously been shown to be associated with a poor outcome in African children. There have been no studies of the histopathological correlates of these vessels. DESIGN: This is a descriptive study of the clinical-histopathological correlates of the retinal vessels of 11 children who died with cerebral malaria. RESULTS: The retinal vessels in children with cerebral malaria contained many parasitized red blood cells; these cells tended to cluster at the periphery of vessels or, in the case of capillaries, to fill the vessel. Those with late-stage parasites had markedly reduced amounts of hemoglobin. The pattern of dehemoglobinization corresponds to the pattern of clinically abnormal vessels. CONCLUSIONS: The sequestration of late-stage parasitized red blood cells with reduced amounts of hemoglobin accounts for the unique white and pale orange retinal vessels seen in cerebral malaria. Clinical examination of these "marked" vessels offers a method to monitor a basic pathophysiological process of cerebral malaria in vivo. Arch Ophthalmol. 2000;118:924-928

Conjunctival and uveal melanoma in the dysplastic nevus syndrome.

The dysplastic nevus syndrome was conceptualized in the late 1970s, and the subsequent proposal of a genetic relationship with ocular melanoma has stimulated debate in the literature which remains unresolved. We present the case of a 60-year-old man with histologically proven sporadic dysplasic nevus syndrome and a prior history of nine cutaneous melanomas, who developed a large, exophytic melanoma of the cornea and limbal conjunctiva. Cytogenetic analysis of this melanoma revealed a clonal 1;14 translocation. We believe this is the first reported case to use cytogenetic techniques in the analysis of conjunctival melanoma, either associated with dysplastic nevus syndrome or in isolation. We review the clinical literature as well as the cytogenetic and molecular genetic data related to the possible association of cutaneous melanoma, conjunctival and uveal melanoma and the dysplastic nevus syndrome.

Monosomy 3 and isochromosome 8q in a uveal melanoma.

Chromosome analysis of a locally invasive uveal melanoma revealed monosomy 3 and i(8q). Sublines with multiple copies of the i(8q) were also present. Loss of heterozygosity for genes on chromosome 3 and duplication of genes on 8q may play an important role in progression of uveal melanoma.

Acquired homozygosity (isodisomy) of chromosome 3 in uveal melanoma.

Cytogenetic investigation of uveal melanoma (UM) has revealed that monosomy 3 is the most frequent karyotypic abnormality, present in approximately 60% of cases. We investigated a cohort of 41 cases of UM, 19 of which retained two apparently normal copies of chromosome 3. Investigation of loss of heterozygosity (LOH) status was undertaken in an attempt to detect subcytogenetic loss of genetic material in those cases with two copies of chromosome 3. DNA from peripheral blood lymphocytes and fresh frozen or paraffin-embedded tumor tissue from 19 patients was amplified by the polymerase chain reaction for polymorphic loci on chromosome 3, including dinucleotide repeats, a tetranucleotide repeat, and polymorphic restriction enzyme sites. Three tumors showed LOH at multiple informative loci on both short and long arms of chromosome 3. Two additional tumors showed localized LOH on 3q, which corresponded to large deletions seen by cytogenetic analysis. The remaining 16 tumors showed retention of heterozygosity at all informative loci. This study did not detect the presence of cryptic deletions but revealed instead complete chromosomal homozygosity or functional monosomy, which probably occurred by loss and then duplication of the remaining chromosome 3. The demonstration of acquired isodisomy (functional monosomy) in a subset of UM increases the percentage of cases with monosomy 3 and provides further evidence for a central role of chromosome 3 loss in the molecular pathogenesis of uveal melanoma.

Preoperative endocrine and metabolic considerations.

Patients with endocrine dysfunction have an increased risk of intraoperative and postoperative morbidity. Identification of such patients prior to surgery, and preoperative management to achieve normal hormonal status may prevent or lessen episodes of morbidity. Diabetics undergoing elective surgical procedures can be managed by any number of approaches. Whatever the method used, close monitoring of blood glucose levels is imperative.

Correlation of retinal haemorrhages with brain haemorrhages in children dying of cerebral malaria in Malawi.

Retinal haemorrhages increase in number with severity of Plasmodium falciparum malaria and occur in 35-40% of children with cerebral malaria. We performed clinical retinal examinations and histopathological examinations of retina, and parietal and cerebellar sections of the brains, in 33 children in Malawi who died with cerebral malaria, severe malaria anaemia, or coma of other causes. Haemorrhages were counted in a standardized fashion: the Spearman correlation coefficient between the number of haemorrhages in retina and brain was 0.741 for parietal tissue and 0.703 for cerebellar (P < 0.01 for both). Severity of haemorrhage in the retina correlates well with that in the brain. Retinal examination in cerebral malaria is a useful tool in predicting some of the pathophysiological processes occurring in the brain.

Uveal malignant melanoma and optic nerve glioma in von Recklinghausen's neurofibromatosis.

A case of uveal malignant melanoma and contralateral optic nerve glioma is described in a 53-year-old Caucasian male with multiple uveal melanocytic hamartomas and neurofibromatosis. The eye was enucleated, and histologically the melanoma was found to consist of 70% epithelioid cells, with many bizarre, multinucleated forms. CT scan demonstrated a non-enhancing, fusiform enlargement of the contralateral optic nerve with enlargement of the optic canal and intracranial extension. This combination of tumours has not previously been reported in a patient with neurofibromatosis and serves to emphasise the common neuroectodermal origin of tumours in this autosomal dominant condition.

Monoclonal origin of localised orbital amyloidosis detected by molecular analysis.

AIMS: Primary localised orbital amyloidosis is a rare disease. The purpose of this study was to describe two cases of primary orbital amyloidosis and emphasise the value of molecular analysis of immunoglobulin gene rearrangement in identifying a monoclonal population of cells responsible for the amyloid production. METHODS: Charts and biopsy specimens of each case were reviewed. Conventional light microscopy, immunohistochemistry, and polymerase chain reaction (PCR) analysis for immunoglobulin gene rearrangement were performed in both cases. RESULTS: An unusual presentation of localised primary amyloidosis with bilateral and extensive enlargement of multiple extraocular muscles was seen in case 1. The presence of amyloid deposits was confirmed by biopsy in both cases. Evidence of a monoclonal population of plasma cells was shown by immunohistochemical analysis in case 2 only. The monoclonal origin of the cells responsible for the amyloid deposition was determined by PCR analysis demonstrating immunoglobulin heavy chain gene rearrangement in both cases. CONCLUSIONS: A monoclonal population of plasma cells responsible for the amyloid deposition was present in these two cases. PCR analysis is extremely helpful in determining monoclonality, a finding that may have important therapeutic and prognostic implications.

Atelencephalic aprosencephaly.

Absence of the telencephalon and diencephalon characterizes the syndrome of aprosencephaly, while in atelencephaly, only the telencephalon is absent. Atelencephalic aprosencephaly is characterized by the presence of at least a rudimentary diencephalon. Embryologically, aprosencephaly is thought to occur after the optic vesicles form but before the cerebral vesicles appear. The syndrome is quite rare, with only 10 cases previously reported. We describe two fetuses with atelencephalic aprosencephaly. A 25-week estimated gestational age fetus was born to first-cousin parents and had a prenatal ultrasonographic diagnosis of anencephaly. The second, a 19-week estimated gestational age fetus, was thought to have semilobar holoprosencephaly by prenatal ultrasound. At autopsy, neuropathologic examination in both cases showed virtual absence of the cerebral hemispheres with an incomplete diencephalon. Microscopic examination in one case revealed disorganized neuropil with a proliferative vasculopathy. The optic globes were completely formed and attached to hypoplastic optic nerves, but retinal dysplasia was apparent histologically in both cases, and bilateral colobomata were present in one case. The findings in these cases demonstrate a spectrum of congenital variations that lie between the syndromes of atelencephaly and aprosencephaly, underscoring the complexity of the congenital anomalies.

Exaggerated somatomedin-C response to human growth hormone infusion in patients with type II diabetes mellitus.

The suggestion of a role for the abnormally regulated growth hormone (GH) in the pathogenesis of diabetes mellitus (DM), implicates also the somatomedins, as mediators of some of GH actions. The present study was aimed at assessing the somatomedin response to exogenous GH administration in diabetes type II (NIDDM) subjects as well as its possible relationship with the degree of control of diabetes. Twenty-two subjects (seven controls and 15 NIDDM patients), matched for sex and age, underwent human GH infusion (0.1 U/kg b.w.) over a one-hour period (time 0 to 1 hour). Total somatomedins (SMs) were measured by human placental membrane radioreceptor assay (in which all SMs crossreact) and Somatomedin-C (SM-C) was determined by a specific RIA. Values were obtained from plasma samples at times 0, 1, 4, 6, and 24 hours. Glycosylated hemoglobin (HbA1a-c) measurements were done from blood samples obtained at time 0. The increase in SMs following GH infusion in NIDDM group was not significantly different from that of the controls. In contrast, the SM-C increase at time 6 and 24 hours were significantly higher than in controls (p less than 0.05 and p less than 0.01, respectively). No significant difference was found between SMs or SM-C response to GH infusion in patients with HbA1a-c greater than 10% vs. less than 10%. These results indicate an exaggerated and prolonged increase in SM-C synthesis following exogenous GH infusion in NIDDM subjects, apparently unrelated to the degree of control of diabetes.

Hyperprolactinemia from radiation-induced hypothalamic hypopituitarism.

In 1975 Samaan et al described the effects of radiation damage of the hypothalamus in 15 patients with head and neck cancer. Shalet et al in 1977 described endocrine morbidity in adults who as children had been irradiated for brain tumors. This report describes instances of hyperprolactinemia and associated hypothalamic, pituitary, and thyroid dysfunction following irradiation of a young adult female for brain neoplasia.

Ductal carcinoma-in-situ of the breast: fine-needle aspiration cytology of 12 cases.

Aspiration specimens from 12 patients with histologically documented ductal carcinoma-in-situ (DCIS) of the breast (seven patients) or DCIS with minute foci of stromal invasion (five) were evaluated. Five patients presented with palpable masses, 1.5-4.0 cm, and four patients presented with localized thickening, associated with nipple erosion and discharge in two of them. One patient had nipple inversion, and one patient had bilateral nipple discharge. In one patient, no apparent abnormality of the breast was present. Mammography was either suspicious for or strongly suggestive of carcinoma in 10 patients and negative in two. Aspirates from all patients were composed of fragments of atypical ductal epithelium and numerous single epithelial cells. In nine cases, the smears were hypercellular and similar to aspirates of typical invasive ductal carcinoma. Calcifications were present in six cases. In four of these, associated tumor necrosis was evident. Cytologic features separating DCIS patients from those showing minimal stromal invasion or common types of invasive ductal carcinoma (IDC) were not identified. We conclude that fine-needle aspiration cytology of DCIS is identical to that of IDC. If preoperative radiotherapy or chemotherapy is considered in the management of invasive breast carcinoma, cutting-needle biopsy for confirmation of tumor invasion is necessary.

Changing indications for penetrating keratoplasty in Vancouver, 1978-87.

Indications for penetrating keratoplasty (PK) were assessed by clinicopathological review of 659 corneal buttons submitted from 1978 to 1987 to the Ophthalmic Pathology Service in Vancouver. Leading indications for PK were bullous keratopathy (22.2%), keratoconus (17.1%), scarring with or without chronic inflammation (13.5%), graft failure (12.1%), scarring or active keratitis secondary to virus (9.0%) and Fuchs' dystrophy (8.3%). The principal factors responsible for graft failure were also judged by clinicopathological correlation. The authors compare their findings with those in other series.