A large family characterised by nocturnal sudden death.

BACKGROUND: We recently identified a novel mutation in large family characterised by premature nocturnal sudden death. In the present paper we provide an overview of the findings in this family. METHODS: From 1958 onwards, when the first patient presented, we collected clinical data on as many family members as possible. After identification in 1998 of the underlying genetic disorder (SCN5A, 1795insD), genotyping was performed diagnostically. RESULTS: Since 1905 unexplained sudden death occurred in 26 family members, 17 of whom died during the night. Besides sudden death, symptomatology was rather limited; only six patients reported syncopal attacks. In one of them, a 13-year-old boy, asystolic episodes up to nine seconds were documented. Until now, the mutation has been found in 114 family members (57 males, 57 females). Carriers of the mutant gene exhibited bradycardia-dependent QT-prolongation, intrinsic sinus node dysfunction, generalised conduction abnormalities, a paucity of ventricular ectopy, and the Brugada sign. Cardiomyopathy or other structural abnormalities were not found in any of the carriers. Electrophysiological studies showed that mutant channels were characterised by markedly reduced INa amplitude, a positive shift of voltage-dependence of activation and a substantial negative shift of voltage-dependence of inactivation of INa. From 1978 onwards, a pacemaker for anti-brady pacing was implanted for prevention of sudden death. In patients in whom a prophylactic pacemaker was implanted no unexplained sudden death occurred, whereas 5 sudden deaths occurred in the group of patients who did not receive a pacemaker. CONCLUSION: We have described a large family with a SCN5A-linked disorder (1795insD) with features of LQT3, Brugada syndrome and familial conduction system disease. Anti-brady pacing was successful in preventing sudden death. The mode of death is possibly bradycardic.

Serial nailfold capillary microscopy in primary Raynaud's phenomenon and scleroderma.

Eighty-four patients with long-standing Raynaud's phenomenon (RP) were evaluated by nailfold capillary microscopy (NCM) in a cross-sectional and longitudinal study. The patients were classified in five diagnostic groups: primary familial RP (n = 16), primary nonfamilial RP (n = 20), possible scleroderma (n = 27), scleroderma (n = 16), and the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome (n = 8). In the cross-sectional study, NCM showed gradually decreasing numbers of capillary loops and increasing numbers of widened and giant loops in the following order: primary RP, possible scleroderma, and scleroderma/CREST, suggesting that these diseases are part of a continuing spectrum of RP. In the longitudinal study there was a decrease in the total number of nailfold capillary loops in scleroderma/CREST but not in primary RP and possible scleroderma.

Pulmonary function in systemic lupus erythematosus is related to distinct clinical, serologic, and nailfold capillary patterns.

PURPOSE: The purpose of this study was to investigate whether systemic lupus erythematosus (SLE) patients with interstitial lung disease represent a particular subset of patients characterized by the presence of clinical, serologic, and nailfold capillary patterns overlapping scleroderma. PATIENTS AND METHODS: In 57 consecutive patients with SLE, a standardized detailed history was obtained and a physical examination performed, directed at signs and symptoms of connective tissue diseases, in particular scleroderma. Additionally, pulmonary function testing, chest radiography, radionuclide transit studies of the esophagus, nailfold capillary microscopy, and detailed serologic studies directed at the antigenic specificities of antinuclear antibodies were performed. Patients were divided into three groups based on the results of pulmonary function testing, i.e., normal lung function, restriction, or isolated impairment of diffusion. Clinical, serologic, and nailfold capillary microscopic findings were compared among these three groups. RESULTS: Twenty patients had normal lung function, 19 had restrictive lung function loss, and 9 had an isolated impairment of the diffusing capacity (T1,CO). Patients with obstructive lung disease (n = 9) were excluded from analysis. Sclerodermatous changes of the hands were associated with a restrictive lung function pattern. Interstitial changes on chest radiograph were associated with isolated impairment of T1,CO. Nailfold capillary abnormalities correlated with decreased T1,CO and Dm, the component of T1,CO representing the diffusing capacity of the alveolocapillary membrane. Antibodies to U1-RNA were associated with restrictive lung function and decreased T1,CO. CONCLUSION: We conclude that interstitial lung disease is present in a subset of SLE patients characterized by an increased prevalence of scleroderma traits and anti-(U1)RNA antibodies. Microvascular changes may contribute to the development of interstitial lung disease in SLE as well as in scleroderma.

Digital blood flow in cooled and contralateral finger in patients with Raynaud's phenomenon. Comparative measurements between photoelectrical plethysmography and laser Doppler flowmetry.

The effects of cooling of a hand on lateral and contralateral digital skin blood flow were investigated in 18 patients with primary or secondary Raynaud's phenomenon. The aim of the study was to compare photoelectrical plethsmography (PhEP) and laser Doppler flowmetry (LDF). PhEP and LDF were used simultaneously for skin blood flow measurements of the third finger of both hands. One hand was cooled in water from 33 degrees to 3 degrees C in steps of 3 degrees C, each step lasting four minutes. It was followed by a recovery period of ten minutes in room air of 24 degrees C. During stepwise cooling from 33 degrees to 9 degrees C the relative PhEP and LDF values, measured on the cooled hand, decreased to 6.2% +/- 3.2% and 10% +/- 12% respectively. The correlation coefficients between LDF and PhEP varied between 0.79 and 0.99. In the contralateral hand the relative PhEP and LDF values decreased to 38% +/- 30.% and 64% +/- 7.9% respectively. The correlation coefficients between LDF and PhEP values were lower on the contralateral hand and ranged from 0.26 to 0.95. By calculating the LDF/PhEP ratios during cooling and recovery, more specific changes in red blood cell velocities during cooling were studied. Increasing LDF/PhEP ratios suggest increasing red blood cell velocities during cooling at 9 degrees C and a difference in the measuring methods. For testing the severity of Raynaud's phenomenon and the effect of treatment the results of both methods show consistent and quite comparable results when measured on the cooled hand. The effect of indirect cooling on the contralateral hand is, however, less consistent.

Rheological properties of blood in Raynaud's phenomenon.

Rheological tests were performed in four rigorously defined groups of patients with Raynaud's phenomenon: primary family-related (n = 21), primary family-unrelated (n = 30), 'possible scleroderma' (n = 26), and scleroderma (n = 19). Whole blood and plasma viscosity, and hematocrit were significantly higher in the 'possible scleroderma' group. We conclude that the contribution of central rheological abnormalities in the pathogenesis of Raynaud's phenomenon is limited.

Once daily felodipine in patients with primary Raynaud's phenomenon.

The symptomatic effects of felodipine (Plendil) have been assessed in 10 patients with primary Raynaud's phenomenon in a single blind study. After 2 weeks on placebo, the patients were treated for 6 weeks with felodipine, the dose being titrated stepwise every 2 weeks, starting with 5 mg, and increasing to 10 mg and 20 mg once daily if symptoms persisted. After the drug period the patients received placebo for 2 weeks. Objective measurement by cold exposure finger plethysmography did not show any benefit of felodipine in the higher temperature range, taking 33 degrees C as reference point. However, when using 24 degrees C as the reference point, the area under the plethysmography versus temperature curve (AUC) for 5 mg felodipine were significantly larger than the initial placebo area. The AUC during recovery from cold exposure for the maximal accepted dose of felodipine was significantly larger than for the initial placebo period. Subjective judgement by the patients showed a significant reduction in the number of Raynaud attacks and a trend to a shorter duration of attacks with the maximal dose of felodipine. Two patients became free from attacks of Raynaud's phenomenon. Felodipine 10 mg once daily was well tolerated. It was regarded as the optimal dose to treat patients with Raynaud's symptoms.

Clinical associations of antiribonucleoprotein antibodies in patients with systemic lupus erythematosus.

The authors undertook a cross-sectional study to investigate the clinical associations of antiribonucleoprotein (anti-RNP) antibodies in 49 patients with systemic lupus erythematosus (SLE) without other concomitant connective tissue disorders. The traditional counterimmunoelectrophoresis (CIE) and the immunoblotting (IB) technique were compared. Clinically, special attention was given to the identification of sclerodermalike features. All patients completed a detailed questionnaire, physical examination, and additional investigations including pulmonary function tests, chest roentgenogram, radionuclide transit studies of the esophagus, and nailfold capillary microscopy. Pulmonary function testing and radionuclide transit studies of the esophagus were very sensitive for the detection of (subclinical) pulmonary and esophageal involvement, respectively. Within the relatively homogeneous SLE population, a subset was recognized that was characterized clinically by the presence of sclerodermalike features such as Raynaud's phenomenon, sclerodactyly, interstitial changes on chest roentgenogram, and decreased numbers of nailfold capillary loops, and serologically by the presence of anti-RNP antibodies. IB was somewhat more sensitive than CIE for the detection of anti-RNP (anti-Sm/anti-nRNP) antibodies but did not identify other clinical associations. Thus, anti-RNP antibodies in SLE are associated with scleroderma-associated features. For clinical practice, CIE is the technique recommended for their detection.

Pulmonary diffusing capacity disturbances are related to nailfold capillary changes in patients with Raynaud's phenomenon with and without an underlying connective tissue disease.

PURPOSE: The aim of this study was to evaluate whether pulmonary microvascular damage is part of a more generalized involvement of the microvasculature in the spectrum of scleroderma (Scl)-like syndromes. PATIENTS AND METHODS: We studied four groups of patients, all with Raynaud's phenomenon (RP), distinguished by the extent and nature of their underlying connective tissue disease. Twenty-two patients had primary RP (pRP), another 22 patients had RP and an undifferentiated connective tissue disease (uCTD), 15 patients had Scl, and eight patients had the CREST syndrome (CREST). Pulmonary vascular damage in these groups was assessed by measuring the pulmonary diffusing capacity (T1,CO) and its components: the diffusing capacity of the alveolocapillary membrane (Dm) and the pulmonary capillary blood volume (Vc). Results were compared with morphologic abnormalities of the nailfold capillaries, as determined by nailfold capillary microscopy, and related to the presence of antinuclear antibodies. RESULTS: Vc was below normal in 38% and 43% of patients with pRP and uCTD, respectively (versus 52% in patients with Scl or CREST combined). In contrast, Dm was below normal in only 5% and 26% of patients with pRP and uCTD, respectively (versus 61% in patients with Scl or CREST combined). In patients with Scl and CREST, Dm was significantly decreased as compared with the former groups (p less than 0.01). Dm was also the pulmonary function parameter that correlated most strongly with both nailfold capillary abnormalities and the presence of antinuclear antibodies, whereas Vc did not. CONCLUSION: Early pulmonary involvement in Scl syndromes is functionally characterized by a lowered Dm, correlating with morphologic changes of the nailfold capillaries. Decreased Vc is probably a reflection of RP of the pulmonary vasculature.

Pulmonary function in patients presenting with Raynaud's phenomenon without an underlying connective tissue disease. A prospective, longitudinal study.

Forty-two patients presenting with Raynaud's phenomenon (RP) were prospectively evaluated for pulmonary function changes over a 6-year followup period. Fifteen patients had secondary RP at presentation, 27 patients had nonsecondary RP. In the latter group, decreased pulmonary diffusing capacity (Tlco) was observed in only 2 patients (7%) whereas 9 patients with secondary RP (60%) had decreased Tlco. In the group of patients with nonsecondary RP exhibiting one or more autoantibodies, Tlco values were lower than in the group without autoantibodies (p less than 0.01). In patients with nonsecondary RP the duration of disease was correlated with the level of Tlco (r = 0.55), probably explained by a higher prevalence of truly primary RP in patients with longstanding nonsecondary RP. During followup no significant changes in pulmonary function were observed in the group with nonsecondary RP. We conclude that pulmonary function testing in patients presenting with nonsecondary RP without autoantibodies does not appear of clinical value.

The effect of six months intensive physical training on the circulation in the legs of patients with intermittend claudication.

Out of 94 patients with intermittent claudication 65 completed a program of 6 months intensive physical training. Every 2 months the blood pressure indices at the thigh and at the ankle and the blood flow in the calf were measured at rest, after 5 min arterial occlusion and after exercise of the calf muscles until claudication. First the reproducibility of the blood pressure indices and the blood flow values was established. An increase of 15 in the pressure indices was considered to be substantial. An increase of 6.0 ml/100 ml/min in flow values was considered a substantial change. The blood pressure indices did not increase significantly during the training period, the blood flow values increased significantly. On the basis of the non-invasive tests no reliable statement can be made as to the expected result of the training.

Changes of walking distance in patients with intermittent claudication during six months intensive physical training.

Patients with intermittent claudication were treated with six months intensive physical training. They were instructed to walk with a speed of 6 km/h until they got complaints and then to rest for some time. This sequence was repeated until men below 65 years had walked 2 km. Men above the age of 65 years and women had to walk 1.5 km. This training session was performed 3 times a day. Every two months the claudication distances in a corridor and on a treadmill were measured. Out of 95 patients 65 completed the training. In 38 patients (59%) there was no substantial change in walking distance. Fourteen patients (22%) doubled their walking distance, seven (11%) could walk more than 1000 m, but their complaints remained. Six (9%) could walk more than 1000 m without claudication pain. Most patients gained their result during the last 2 months of the program. After the training 48% of the patients were satisfied with their walking distance.

Development of connective tissue disease in patients presenting with Raynaud's phenomenon: a six year follow up with emphasis on the predictive value of antinuclear antibodies as detected by immunoblotting.

Eighty five patients referred because of Raynaud's phenomenon (RP) were followed up for six years. Every two years they were screened for signs and symptoms of connective tissue disease (CTD) according to a protocol, and serum was stored. Initially, 30 patients had primary RP, 16 had one symptom of CTD ('possible CTD'), 18 had two or more symptoms ('probable CTD'), and 21 had definite CTD (14 of whom had scleroderma). Most of the symptoms were related to scleroderma. There was an insidious progression to scleroderma or CRST syndrome (calcinosis, Raynaud's phenomenon, sclerodactyly, telangiectasia): 11 of 46 patients with primary RP or possible CTD developed probable scleroderma (two or more symptoms but not fulfilling all criteria), and seven of 13 patients with probable scleroderma developed definite scleroderma or CRST. The presence of distinct antinuclear antibodies (ANAs) as detected by immunoblotting in patients with primary RP and possible CTD at the start of the study was associated with the evolution of symptoms of CTD (chi 2 = 5.7, p less than 0.01). In patients initially with primary RP or possible CTD the antibody specificities of ANAs as determined by immunoblotting had prognostic value for the development of certain disease entities: anticentromere (CR-19) for CRST (sensitivity 60%, specificity 98%) and antitopoisomerase I (Scl-70 or Scl-86) for scleroderma or probable scleroderma (sensitivity 38%, specificity 100%).

Nifedipine in Raynaud's phenomenon: relationship between immediate, short term and longterm effects.

Sixteen patients with Raynaud's phenomenon (8 with primary Raynaud's, 8 with systemic sclerosis including 3 patients with CREST) were treated for 4 weeks in a double blind crossover study with nifedipine, 20 mg twice daily. Treatment resulted in improvement of symptoms (p less than 0.05), a lower frequency of attacks (p less than 0.05) and a tendency to a shorter duration of the attacks. Photoelectric plethysmography during nifedipine treatment showed greater amplitudes on cooling (p less than 0.05) and a better and faster recovery on rewarming (p less than 0.05) than during placebo. The immediate effect of nifedipine, 10 mg sublingually, on the amplitude of the plethysmogram, finger temperature, heart rate and blood pressure did not correlate with the effect of maintenance treatment. Dose titration based on therapeutic effect and side effects resulted in a dose of 20 mg daily for 5 patients, 40 mg for 7, and 80 mg daily for 3 patients. Longterm treatment (16-20 weeks) resulted in sustained efficacy, both by subjective and objective standards (plethysmography).

Diagnostic significance of nailfold capillary patterns in patients with Raynaud's phenomenon. An analysis of patterns discriminating patients with and without connective tissue disease.

Nailfold capillary patterns were systematically evaluated in 51 controls and 107 patients with Raynaud's phenomenon (RP) by 2 observers. Fifty patients had primary RP, 18 RP with minor signs of connective tissue disease, and 39 secondary RP (scleroderma, CREST syndrome or mixed connective tissue disease [MCTD]). Nailfolds of all 10 fingers were photographed and blindly evaluated. Qualitative and quantitative scoring of patterns was reproducible. The 4th finger showed the fewest nonevaluable photomicrographs and best distinguished primary from secondary RP. Capillary morphology in primary RP did not differ from controls. A decrease in capillary loops best distinguished primary from secondary RP. Addition of the scores for bushy patterns, extravasates, or giant loops led to better discrimination. No item allowed distinction between different connective tissue diseases. The number of enlarged loops was inversely related to the total number of capillary loops (r = 0.55; p less than 0.01).