Severe autonomic nervous system imbalance in Lennox-Gastaut syndrome patients demonstrated by heart rate variability recordings.

OBJECTIVE: Patients diagnosed with Lennox Gastaut syndrome (LGS), an epileptic encephalopathy characterized by usually drug resistant generalized and focal seizures, are often considered as candidates for vagus nerve stimulation (VNS). Recent research shows that heart rate variability (HRV) differs in epilepsy patients and is related to VNS treatment response. This study investigated pre-ictal HRV in generalized onset seizures of patients with LGS in correlation with their VNS response. METHODS: In drug resistant epilepsy (DRE) patients diagnosed with LGS video-electroencephalography recording was performed during their pre-surgical evaluation. Six HRV parameters (time and-, frequency domain, non-linear parameters) were evaluated for every seizure in epochs of 10 min at baseline (60 to 50 min before seizure onset) and pre-ictally (10 min prior to seizure onset). The results were correlated to VNS response after one year of VNS therapy. RESULTS: Seven patients and 31 seizures were included, two patients were classified as VNS responders (≥ 50 % seizure reduction). No difference in pre-ictal HRV parameters between VNS responders and VNS non-responders could be found, but high frequency (HF) power, reflecting the parasympathetic tone increased significantly in the pre-ictal epoch in both VNS responders and VNS non-responders (p = 0.017, p = 0.004). SIGNIFICANCE: In this pilot data pre-ictal HRV did not differ in VNS responders compared to VNS non-responders, but showed a significant increase in HF power - a parasympathetic overdrive - in both VNS responders and VNS non-responders. This sudden autonomic imbalance might have an influence on the cardiovascular system in the ictal period. Generalized tonic-clonic seizures are regarded as the main risk factor for SUDEP and severe seizure-induced autonomic imbalance may play a role in the pathophysiological pathway.

Neurophysiological investigations of drug resistant epilepsy patients treated with vagus nerve stimulation to differentiate responders from non-responders.

BACKGROUND AND PURPOSE: In patients treated with vagus nerve stimulation (VNS) for drug resistant epilepsy (DRE), up to a third of patients will eventually not respond to the therapy. As VNS therapy requires surgery for device implantation, prediction of response prior to surgery is desirable. It is hypothesized that neurophysiological investigations related to the mechanisms of action of VNS may help to differentiate VNS responders from non-responders prior to the initiation of therapy. METHODS: In a prospective series of DRE patients, polysomnography, heart rate variability (HRV) and cognitive event related potentials were recorded. Polysomnography and HRV were repeated after 1 year of treatment with VNS. Polysomnography, HRV and cognitive event related potentials were compared between VNS responders (≥50% reduction in seizure frequency) and non-responders. RESULTS: Fifteen out of 30 patients became VNS responders after 1 year of VNS treatment. Prior to treatment with VNS, the amount of deep sleep (NREM 3), the HRV high frequency (HF) power and the P3b amplitude were significantly different in responders compared to non-responders (P = 0.007; P = 0.001; P = 0.03). CONCLUSION: Three neurophysiological parameters, NREM 3, HRV HF and P3b amplitude, were found to be significantly different in DRE patients who became responders to VNS treatment prior to initiation of their treatment with VNS. These non-invasive recordings may be used as characteristics for response in future studies and help avoid unsuccessful implantations. Mechanistically these findings may be related to changes in brain regions involved in the so-called vagal afferent network.

Cortisol release, heart rate, and heart rate variability in transport-naive horses during repeated road transport.

Domestic animals are often repeatedly exposed to the same anthropogenic stressors. Based on cortisol secretion and heart rate, it has been demonstrated that transport is stressful for horses, but so far, changes in this stress response with repeated road transport have not been reported. We determined salivary cortisol concentrations, fecal cortisol metabolites, cardiac beat-to-beat (RR) interval, and heart rate variability (HRV) in transport-naive horses (N = 8) transported 4 times over a standardized course of 200 km. Immunoreactive salivary cortisol concentrations always increased in response to transport (P < 0.001), but cortisol release decreased stepwise with each transport (P < 0.05). Concentrations of fecal cortisol metabolites increased from 55.1 +/- 4.6 ng/g before the first transport to 161 +/- 17 ng/g the morning after (P < 0.001). Subsequent transport did not cause further increases in fecal cortisol metabolites. In response to the first transport, mean RR interval decreased with loading of the horses and further with the onset of transport (1551 +/- 23, 1304 +/- 166, and 1101 +/- 123 msec 1 d before, immediately preceding, and after 60-90 min of transport, respectively; P < 0.05). Decreases in RR interval during subsequent transports became less pronounced (P < 0.001). Transport was associated with a short rise in the HRV variable standard deviation 2 (P < 0.001 except transport 1), indicating sympathetic activation. No consistent changes were found for other HRV variables. In conclusion, a transport-induced stress response in horses decreased with repeated transport, indicating that animals habituated to the situation, but an increased cortisol secretion remained detectable.

Local recurrence in melanoma in situ: influence of sex, age, site of involvement and therapeutic modalities.

BACKGROUND: Melanoma in situ (MIS) occurs on various body sites, in various age groups, and is managed by a variety of treatment modalities. Despite early treatment, recurrences may be encountered. OBJECTIVES: To evaluate the influence of sex, age, body site and treatment modalities on recurrence rate in MIS. Methods Histologically confirmed cases of MIS from our dermatopathological database (n = 1351) from 1990 to 2000 were statistically analysed with respect to epidemiological characteristics, treatment modalities and outcome. Treatment modalities of the included MIS were evaluated by searching for data in the medical records and histopathological data sheets. RESULTS: There was a predominance of female patients (60.8%), and of involvement of the head and neck (53.4%). Total excision was performed in 95.9% of all patients; the remainder received cryotherapy, laser therapy or radiotherapy. In 265 patients, no data on definitive treatment were available. Alternatives to total excision were particularly performed in patients with advanced age and with lesions localized on the face. The mean +/- SD 5-year recurrence rate was 6.8 +/- 1.3% for surgically removed lesions, but was 31.3 +/- 8.5% for lesions treated by other modalities (log rank test: P < 0.0001). In a multivariate approach, mode of therapy and site of involvement, but not age, were significant prognostic variables (Cox proportional hazard model: P < 0.01). CONCLUSIONS: In MIS, treatment modalities other than surgical excision may be used in certain situations, but carry a significantly increased risk of local recurrence.

[Blueberry muffin baby: the pathogenesis of cutaneous extramedullary hematopoiesis]. / Blueberry-Muffin-Baby. Zur Pathogenese der kutanen extramedullären Hämatopoese.

Two neonates exhibited the clinical picture of the "blueberry muffin baby" at delivery. The integument manifested petechiae and purpuric magenta-colored macules, papules, and plaques, as well as blueberry-colored ecchymoses. These findings led to the diagnosis of a connatal cytomegalovirus infection and fetal erythroblastosis, respectively. The hemorrhagic-purpuric looking skin lesions reflected extramedullary hematopoiesis with ultrastructural study disclosing evidence of both erythro- and granulopoietic lineage. For the first time, we were able to demonstrate that complexes of red cells in various stages of maturation can occur in the skin, similarly to the erythroblastic islands of the bone marrow. In the pathogenesis of extramedullary hematopoiesis, mechanisms underlying the reconstitution of blood cells must be considered. These may reactivate hematopoiesis in organs where it previously occurred in embryonic and fetal life. Possible causative factors may be great compensatory demand, deficient replacement, or loss or dysfunction of corpuscular blood elements. This would explain the occurrence of this disease entity in conjunction with etiologically completely heterogeneous systemic diseases.

Double-blind, placebo-controlled, randomized, right-left study comparing calcipotriol monotherapy with a combined treatment of calcipotriol and diflucortolone valerate in chronic plaque psoriasis.

A double-blind, randomized clinical study was conducted to compare the efficacy and tolerability of twice-daily topical calcipotriol treatment with a combination treatment of calcipotriol once a day in the morning and diflucortolone valerate in the evening. Sixty-three patients with a clinical diagnosis of chronic plaque psoriasis and comparable psoriatic lesions on both sides of the body were included. After a washout phase of 1 week, psoriatic lesions were treated for 4 weeks with calcipotriol ointment twice daily on one side of the body and a combination of calcipotriol and diflucortolone valerate ointment on the other side. The treatment period was followed by a period of 4 weeks without any treatment. The psoriasis area and severity index (PASI) was used to compare the 2 groups. Furthermore, the overall therapeutic results were assessed independently by the investigators and by the patients. Both treatment regimens showed a significant, nearly identical, reduction in PASI. The mean PASI for calcipotriol alone was 5.7 at baseline, 1.9 after 4 weeks of treatment and 3.8 at the end of the follow-up period. For combination therapy, these values were 5.7, 1.8 and 3.8, respectively. There was a statistically significant advantage in favor of combined calcipotriol and diflucortolone valerate treatment at weeks 1 and 2 (p < 0.05); however, at the end of the treatment phase the difference between the 2 therapies was not significant. Subjective evaluation of efficacy by both the investigators and the patients revealed no difference between the 2 treatments. The frequency of side effects (e.g. irritation) was low in both groups. In conclusion, both therapies were effective for the treatment of chronic plaque-type psoriatic lesions. The combination of calcipotriol and a topical steroid appeared to produce a more rapid clinical response and was shown to be as effective as calcipotriol therapy alone.

Morphological stages of pilomatricoma.

In 1983, Ackerman proposed that pilomatricoma represents an infundibular-matrix cyst in its early stages. To study the evolution of this cystic neoplasm, we examined 118 lesions from 116 patients with pilomatricoma histopathologically and categorized the lesions into four distinct and chronological stages: early, fully developed, early regressive, and late regressive. Early lesions (eight cases) were small cystic structures lined by squamoid and basaloid epithelium containing keratin filaments and faulty hair matrix material composed of shadow cells. Fully developed lesions (27 cases) were large neoplasms lined by basaloid epithelium at their periphery, and within, composed of irregularly shaped, densely packed zones of cornified masses containing shadow cells. Early regressive lesions (37 cases) had no apparent epithelial lining but did have basaloid cell foci at the periphery; within, they were composed of pink hair matrix material with shadow cells surrounded by granulation tissue with inflammatory infiltrate and multinucleated histiocytic giant cells. Late regressive lesions (42 cases) had no epithelial component and were composed of irregularly shaped, partially confluent masses of faulty hair material, and calcified (and sometimes metaplastically ossified) shadow cells embedded in a desmoplastic stroma, with little or no inflammatory infiltrate. In four cases, there was a relatively large dermal nodule composed of several interconnected lobules that consisted largely of basaloid cells with only a few areas of shadow cells. We interpreted these lesions as proliferating pilomatricomas. Based upon our histopathologic findings, we propose that pilomatricomas may be categorized into four distinct morphological stages and that these stages reflect the "life" of a pilomatricoma. Thus, the lesion begins as an infundibular matrix cyst and ends up as a calcified and ossified nodule with no visible epithelial component.

[Acquired generalized cutis laxa with paraproteinemia (IgG lambda). Immunofluorescence study, clinical and histologic findings with review of the literature]. / Erworbene generalisierte Cutis laxa mit Paraproteinämie (IgG-lambda). Immunfluoreszenzstudie, Klinischer und histologischer Befund mit Literaturübersicht.

A 49-year-old patient developed acquired generalized cutis laxa, manifest as involvement of the elastic fibres of the dermis and the internal organs, leading to pulmonary emphysema, bilateral inguinal hernia and two oesophageal diverticula. The patient's serum levels of IgG lambda paraprotein were elevated. Direct immunofluorescence examination revealed intensive linear deposits of IgG lambda light chains, an early component of complement C1q and discrete C3 deposits. The deposits were found along the preserved elastic fibres in the dermis, especially in the papillary dermis, at the dermoepidermal junction around the sweat and sebaceous glands and in the walls of small vessels. Dermal alterations of this kind have not been described previously.

[Skin symptoms in extracutaneous lymphomas, leukemias and plasmacytomas]. / Hautsymptome bei extrakutanen Lymphomen, Leukämien und Plasmozytom.

In neoplastic diseases of the haemopoietic and the lymphatic system, the skin may be infiltrated specifically by neoplastic cells or may display 'nonspecific' cutaneous reactions, frequently associated with a systemic malignancy. Acute febrile neutrophilic dermatosis associated with myeloproliferative disorders and scleromyxedema, lichen myxedematosus, diffuse plane xanthomas and necrobiotic xanthogranuloma associated with paraproteinemia may serve as examples. These conditions as well as several other, often atypical cutaneous manifestations should rise suspicion as to the potential presence of some underlying systemic neoplastic disorder.

Extramedullary hematopoiesis in pilomatricomas.

We report on seven adult patients with pilomatricomas showing histopathologic findings of extramedullary hematopoiesis. There was no Ovidence of hematological disorders or systemic diseases. Clinically, the lesions appeared to be firm, painless nodules situated on the upper extremities, head, and back. Histopathologically, they represented stereotypical examples of regressive pilomatricomas with relatively small basaloid areas and large masses of cornified eosinophilic material containing shadow cells with variable areas of calcification or ossification. Bone marrow cellular elements, including myeloid and erythroid precursors, and (in two cases) megakaryocytes were present. The finding of extramedullary hematopoiesis in seven (5.8%) of 120 cases of pilomatricomas may suggest that this phenomenon is not uncommon in these neoplasms. Interestingly, hematopoietic infiltrates were histopathologically detected to be contiguous with areas of osseous metaplasia in only two of the seven pilomatricomas in our study. It should further be stressed that extramedullary hematopoiesis in regressive lesions of pilomatricomas is a localized phenomenon and that these findings may not be linked with a systemic hematological disorder. The significance of extramedullary hematopoiesis in pilomatricomas, however, remains to be determined.

Clinical and histopathologic spectrum of pilomatricomas in adults.

BACKGROUND: Pilomatricomas are benign cutaneous neoplasms with differentiation toward hair matrix. Although previously reported to occur mostly in children and young adults, Taaffe et al. recently observed a second onset peak in adults and the elderly. METHODS: To study the clinical and histopathologic features of pilomatricomas in adults we analyzed files and histologic sections of all cases of pilomatricomas seen at the Department of Dermatology, University of Graz, Graz, Austria, between January 1980 and December 1990. RESULTS: A total of 118 patients were identified, 58 of whom were > 45 years of age. The clinical features of patients > 45 years of age were generally similar to those of patients < 45 years of age. Differential diagnoses in both groups were also comparable except in some cases of the older study-group where differential diagnoses included basal cell carcinoma, keratoacanthoma, and metastasis. Recurrence of the lesions after simple excision was observed in one patient > 45 years of age. Histopathologically, lesions in both age groups showed similar features except in four lesions of the older patients where "atypical" features were present. The histopathologic differential diagnosis of the lesions with "atypical" features included pilomatrical carcinoma, basal cell carcinoma with matrical differentiation, and matricoma. CONCLUSIONS: Our study reveals the relatively frequent occurrence of pilomatricomas in adults and the elderly. Pilomatricoma should be considered along with other benign and malignant conditions in the clinical differential diagnosis of solitary, firm skin nodules presenting in adults and the elderly, especially on the head and neck.

Clinicopathologic and immunologic features associated with transformation of mycosis fungoides to large-cell lymphoma.

Mycosis fungoides (MF) can progress to a large-cell malignant lymphoma (LCL). This transformation is associated with a more aggressive biologic behavior and course. We reviewed cutaneous tumors of 36 MF patients and divided them into two groups, one showing histologic evidence of transformation into LCL, another characterized by infiltrates of small- to medium-sized cerebriform cells (nontransformed cases). Biopsies of patches or plaques from early MF stages were available from 34 patients. Twenty of the 36 cases (55.6%) showed transformation to a large-cell variant: nine tumor-stage (T) medium-sized and large-cell pleomorphic, five T immunoblastic, two T large-cell anaplastic, and four unclassified T LCL. Sixteen cases represented nontransformed tumor stage MF. In 23 cases, including both nontransformed (n = 6) and LCL (n = 17) groups, immunohistochemical investigations revealed aberrant patterns of antigen expression (partial loss of one or more T cell-associated antigens) and the presence of activation- and proliferation-associated antigens. Clusters of B-lymphocytes formed a distinctive component of the infiltrate in two nontransformed and nine LCL biopsies. Although survival rates after tumor onset did not significantly differ between the two groups (5-year survival rate 23% for nontransformed patients, 11.1% for LCL patients, p greater than 0.05), overall survival from first biopsy diagnostic of MF showed a statistically significant difference between patients with nontransformed tumor stage MF compared with LCL patients (10-year survival rate 46.6% and 11.2%, respectively, p less than 0.02). The recognition of transformation to LCL in MF should provide a better assessment of future therapeutic approaches.

[Clinical epidemiologic data of malignant melanoma based on 1,368 patients of the Graz University Dermatology Clinic (1970-1989)]. / Klinisch-epidemiologische Daten des malignen Melanoms anhand von 1368 Patienten der Grazer Universitäts-Hautklinik (1970-1989).

Epidemiological and histological data of 1368 patients with invasive malignant melanoma treated at the Department of Dermatology between 1970 and 1989 were analysed retrospectively. Frequency of melanoma increased from 103 cases between 1970 and 1974 to 593 between 1985 and 1989. The male/female ratio was 1/1.5 and did not change during the study period. Mean age of patients at the time of primary operation was 56.1 years and was approximately the same for males and females (males 55.8, females 56.3 years). The predominant site was the trunk in males (58.7 per cent) and the lower leg in females (41.6 per cent). There was a relative increase of melanomas of the back in males and the lower leg in females at the expense of melanomas of the face. The Breslow index was significantly higher in males than in females. In patients older than 69 years, the proportion of thick melanomas was above average. During the study period, the frequency of thick melanomas (greater than 1.5 mm) showed an encouraging decrease in both sexes. In 1989, 50 per cent of all melanomas were thinner than 1.01 mm. This can be interpreted as a successful outcome of efforts in preventive medicine.

Spindle cell and pleomorphic lipoma: an immunohistochemical study and histogenetic analysis.

Twenty-two spindle cell lipomas and seven pleomorphic lipomas were investigated immunohistochemically in order to study the differentiation of the non-adipocytic elements. In all cases, neither spindle cells nor pleomorphic cells reacted with antibodies to a monocyte/macrophage antigen (MAC-387), fibronectin, laminin or type IV collagen. The absence of demonstrable basement membrane material argues against the possible prelipoblastic nature of these cells. With the antibody to S-100 protein, spindle cells were immunonegative, whereas pleomorphic cells sometimes revealed an intracytoplasmic weak to moderate staining reaction. In the light of what is known about the development of adipose tissue, our results would support the hypothesis of Bolen and Thorning (Am J Surg Pathol 1981; 5: 435-441) that spindle cell lipoma is composed of adipocytes and non-fat storing immature mesenchymal cells. It would appear that pleomorphic lipoma is similarly derived but that in some cases adipocytic differentiation is also abnormal. The characteristic clinical distribution of these two types of tumour may be of relevance in determining the cause of these unusual benign patterns of differentiation.

[Congenital pseudomelanoma]. / Kongenitales Pseudomelanom.

Benign congenital melanocytic nevi, removed shortly after birth, may histologically be misinterpreted as malignant melanomas. We present the criteria for the differential diagnosis. As a name for these unusual melanocytic tumors, which belong to the large group of pseudomalignancies of the skin, we suggest the term 'congenital pseudomelanoma'.

Surface microscopy. A new approach to the diagnosis of cutaneous pigmented tumors.

Clinical guidelines for the diagnosis of pigmented lesions of the skin are not always reliable. Surface microscopy (SM) represents an interesting approach to this problem. For this in vivo investigation, a stereomicroscope, a glass slide, and immersion oil are used. In the present study, the various criteria of SM that cannot be discerned by the naked eye are correlated with the histopathological structures in step-sectioned specimens. Characteristic SM features such as the pigment network, "black dots," or "irregular extensions" were found to correspond to particular histological findings. SM opens a new dimension of clinical morphology for the diagnosis and differential diagnosis of malignant melanomas, dysplastic nevi, or nonmelanocytic pigmented neoplasms, and facilitates a more reliable preoperative assessment of these lesions.

[A fluorescence-activated cell sorter--analysis of peripheral T lymphocyte subpopulations in psoriasis]. / FACS--Analyse peripherer T-Lymphozytensubpopulationen bei Psoriasis.

By means of the fluorescence activated cell sorter (FACS), we analyzed the T-lymphocyte subpopulations in peripheral blood samples from 82 patients showing various clinical manifestations of psoriasis. With regard to both the absolute values of T-helper and T-suppressor cells and those of the T-helper/T-suppressor cell ratios, there were no quantitative differences between the patients (i.e. either the entire collective of classified according to the various forms of psoriasis) and the control group. We discuss the pathophysiological relevance of peripheral and in situ analyses of T-lymphocyte subpopulations.

[Kaposiform angiodermatitis (pseudo-Kaposi's disease) on an amputation stump. A new entity]. / Kaposiforme Angiodermatitis (Pseudo-M. Kaposi) am Amputationsstumpf. Eine neue Entität.

Kaposiform cutaneous lesions were observed on the amputation stump of a 65-year-old male whose leg had been amputated above the knee. Histological examination revealed pronounced stasis dermatitis. This finding, together with phlebectasias and fine arborized cutaneous varices on the stump end, suggested that the pathogenesis may involve venous congestion. This may be caused by suction in the prosthesis socket and compression of the stump at the socket edge.

[Direct light microscopy of pigment tumors of the skin]. / Zur Auflichtmikroskopie von Pigmenttumoren der Haut.

Clinical guidelines for the diagnosis of pigmented skin lesions are not always reliable. Incident light microscopy provides an interesting approach to solving this problem. For this investigation a stereomicroscope, a glass slide and immersion oil are used. The various in vivo criteria of this method, which go beyond the changes discernible by the naked eye, are correlated with the histopathological structures. Incident light microscopy opens up a new dimension of clinical morphology for the diagnosis and differential diagnosis of malignant melanoma, dysplastic nevi or non-melanocytic pigmented neoplasms and facilitates a more precise preoperative assessment of these lesions.