RESEARCH LETTERS
Cases Knodell score Initial Final
Controls
p
4·8 (1·3) 8·4 (3·6)
5·3 (2·0) 5·3 (3·3)
0·016
Necroinflammatory score* Initial Final Progression % deterioration Yearly progression of activity
3·7 (1·4) 6·7 (2·8) 2·9 (2·4) 83·3 0·77 (0·63)
4·1 (1·6) 4·0 (2·5) ⫺0·1 (2·0) 25·0 ⫺0·14 (0·53)
0·5 0·007 0·007 0·02 0·001
Fibrosis score Initial Final Progression % deterioration Yearly progression of fibrosis: mean (SD)
1·1 (1·0) 1·7 (1·1) 0·7 (1·4) 41·6 0·09 (0·42)
1·2 (0·9) 1·3 (1·0) 0·1 (0·3) 8·3 0·02 (0·07)
0·8 0·4 0·2 0·15 0·4
*Sum of indices of portal necrosis, lobular degeneration, and inflammation. Data are mean (SD).
Comparison of serial liver biopsy samples in case and control HCV-infected women
Knodell score
when their absolute variation was equal to or greater than 2 and 1 points, respectively. The progression per year of the liver lesions was defined as the ratio of the score difference and the interval between the two biopsies. Comparisons between groups were made by use of 2, Fisher’s exact, and nonparametric tests (Wilcoxon). At the first biopsy, no patient had cirrhosis. The mean Knodell score was similar in cases and controls (table). At the second biopsy, the overall score was significantly higher in cases than in controls, with a significantly higher necroinflammatory score. The fibrosis score increased in five cases and in only one control and there were no significant differences between the groups. At the second biopsy, cirrhosis was present in one case and one control. The yearly rates of progression of activity and of fibrosis were higher in cases than in controls. There was no difference between the groups in aminotransferase activities at the time when the liver biopsies were done but measurements were not available for all cases in the months after delivery. This case-control study suggests that pregnancy may worsen HCV-related histopathological injury. The adverse effects of HCV are mainly immune mediated.3 During pregnancy, the synergistic action of oestradiol and progesterone increases the natural killer activity of mononuclear cells during the first 3
months; the activity then decreases and increases again after delivery.1 The more frequent histopathological liver deterioration in cases in this study may reflect the post-partum immune rebound, as occurs in HIV-positive patients given combination therapy.4 Immunosuppression is known to increase the severity of liver disease.2 Our observations are reinforced by a study of HCV transmission by breastfeeding, in which five of 65 HCV-infected mothers developed acute clinical and biological hepatitis 3 months after delivery.5 The long-term impact of this histopathological exacerbation is still unknown. Depending on the number of deliveries and on the ability of liver regeneration, it may be reversible (figure). HCV-related liver injury is moderate in most young female patients and there is no indication for antiviral treatments including interferon, which is contraindicated in pregnancy; thus, most of these patients are not treated before pregnancy. According to our results, should we treat them before or after pregnancy if it worsens liver histology? 1
2
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Hidaka Y, Amino N, Iwatani Y, et al. Changes in natural killer cell activity in normal pregnant and post-partum women: increases in the first and post-partum period and decrease in late pregnancy. J Reprod Immunol 1991; 20: 73–83. Pol S, Fontaine H, Carnot F, et al. Predictive factors for development of cirrhosis in parenterally acquired chronic hepatitis C: a comparison between immunocompetent and immunocompromised patients. J Hepatol 1998; 29: 12–19. Gonzales-Peralta RP, Davis GL, Lau JYN. Pathogenetic mechanisms of hepatocellular damage on chronic hepatitis C virus infection. J Hepatol 1994; 21: 255–59. Zylberberg, Pialoux G, Carnot F, Bréchot C, Pol S. Rapidly evolving hepatitis C virus-associated cirrhosis in HIV coinfected patients in relation to antiretroviral tritherapy. Clin Infect Dis 1998; 27: 1255–58. Kumar RM, Shahul S. Role of breast-feeding in transmission of hepatitis C virus to infants of HCV-infected mothers. J Hepatol 1988; 29: 191–97.
Unité d’Hépatologie and INSERM U-370, Hôpital Necker (H Fontaine MD, B Nalpas MD, C Bréchot MD, S Pol MD); and Service d’Anatomo-pathologie, Hôpital Laënnec (F Carnot MD), Paris, France Correspondence to: Dr Stanislas Pol, Unité d’Hépatologie, Hôpital Necker, 149, rue de Sèvres, 75015 Paris, France (e-mail:
[email protected])
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Continuous positive air pressure eliminates nocturnal stridor in multiple system atrophy
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Alex Iranzo, Joan Santamaria, Eduard Tolosa, on behalf of the Barcelona Multiple System Atrophy Study Group* We prospectively studied the sleep patterns and laryngeal function of 20 patients with multiple system atrophy and found sleep disturbances in all subjects and vocal cord abduction dysfunction in 14 (70%). In three patients with nocturnal stridor and complete vocal cord abductor dysfunction, continuous positive airways pressure eliminated laryngeal stridor, obstructive apnoea, and haemoglobin desaturation.
4
2
20 00 Fe b
19 99 Ju ly
19 98 M ar ch
19 95 Ju ne
Ju ly
19 92
0
Histopathological course of an HCV-infected 29-year-old woman who had stable sporadic chronic hepatitis in the absence of any treatment Knodell score (range 0–22) was 5 (1,0,3,1) in July, 1992, and 4 (1,0,3,0) in June, 1995. In March, 1998, 3 months after the end of her first (uneventful) pregnancy, the score was 8 (1,1,3,3; there was biochemical and pathological exacerbation with an eight-fold increase in aminotransferase concentrations). Further biopsies (July, 1999, and February, 2000) confirmed spontaneous improvement (1,1,3,1).
THE LANCET • Vol 356 • October 14, 2000
Multiple system atrophy is a sporadic, progressive, neurodegenerative disorder characterised by parkinsonism, with cerebellar, pyramidal, and autonomic symptoms and signs in any combination.1 Sleep disturbances such as nocturnal stridor, may also occur.2,3 Nocturnal stridor results from vocal cord abductor dysfunction, a condition that is associated with sudden death during sleep and is treated by tracheostomy.4,5 Although tracheostomy relieves nocturnal stridor, frequent local complications and important psychosociological factors make tracheostomy undesirable. We prospectively studied the sleep patterns and laryngeal function of 20 patients (11 women and nine men with a mean
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For personal use only. Not to be reproduced without permission of The Lancet.
RESEARCH LETTERS
Episodes of apnoea per h CT85 (%) Total sleep time (min) Sleep efficiency (%) Sleep latency (min) WASO (min) Stage 1 (%) Stage 2 (%) Stages 3 and 4 (%) REM (%) Leg movements per h
Baseline
CPAP
21·3 (5·6) 22 (7·6) 238·3 (64·4) 54 (15·8) 44 (10·1) 158·3 (70·4) 7·6 (5·7) 29·8 (4·8) 43·9 (11·1) 18·5 (13·8) 50 (46·8)
2·4 (0·5)* 0† 247·6 (37) 53·6 (8·3) 76 (13) 125 (55·3) 15 (5) 44 (13·9) 35 (21·4) 5·4 (9·4) 51 (45·9)
Values are mean (SD). *p=0·03, †p=0·02 by paired t-test. CT85=percentage of oxygen saturation below 85% during sleep, sleep efficiency=total sleep time per total time in bed, WASO=wake time after sleep onset. REM=rapid eye movement sleep.
Polysomnographic studies at baseline and after 1 month of CPAP in three patients with multiple system atrophy and stridor
age of 64·1 [7·6] years) diagnosed with probable multiple system atrophy.1 We also assessed the effect of nasal continuous positive airways pressure (CPAP) in patients with nocturnal stridor and vocal cord dysfunction. We postulated that nasal CPAP could eliminate stridor and preserve upper airway patency by abducting the paralysed vocal cords, thereby increasing the glottic aperture. Laryngoscopy disclosed normal vocal cord movement in six awake patients (30%), bilateral partial abduction restriction in nine (45%), and complete vocal cord abduction restriction in five (25%), which was unilateral in three and bilateral in two. Sleep was assessed by clinical questionnaire and by all-night baseline standard polysomnography with continuous audiovisual recording, which allowed detection of stridor during sleep. All patients reported broken sleep, three (15%) had restless leg syndrome interfering with sleep onset, and 18 (90%) reported talking and vigorous movements associated with dreaming. In six cases (30%), sleep disturbances preceded the onset of the motor and dysautonomic symptoms by 7–20 years with a mean of 13·4 (SD 4·5) years. Baseline polysomnography was abnormal in all patients showing reduced total sleep time (264 [93] minutes), nocturnal stridor in five (25%) patients, obstructive sleep apnoea in eight (40%), periodic leg movements in 10 (50%) and rapid eye movement sleep behaviour disorder in 18 (90%). All five patients with nocturnal stridor had complete vocal cord abduction restriction, obstructive sleep apnoea, and repetitive haemoglobin desaturation. None of the patients showed diurnal stridor or dyspnoea. Mean nocturnal stridor duration was 2 (SD 0·5) years, and in all five patients it developed after the onset of the motor and dysautonomic symptoms. Stridor was audible immediately after the first stage of sleep was recorded, and occurred in all sleep stages and all body positions. All five patients with nocturnal stridor were offered CPAP treatment, and four accepted. Polysomonography with continuous audiovisual monitoring allowed us to identify the modification of stridor during CPAP titration. We adjusted CPAP pressure so that nocturnal stridor, obstructive apnoea and haemoglobin desaturation were abolished in all sleep stages and all body positions. In three patients CPAP eliminated nocturnal stridor, obstructive apnoea events, and haemoglobin desaturation. CPAP was generally well tolerated with optimum pressures of 8, 9, and 10 cm H2O. In another patient, CPAP was not tolerated because of mask discomfort although stridor was practically eliminated with a pressure of 10 cm H2O. In the three patients in whom CPAP was well tolerated, polysomnography at optimum CPAP was repeated after 4 weeks of continuous treatment and confirmed the elimination of stridor, obstructive apnoea, and haemoglobin desaturation (table). After 6 months of follow-up with CPAP therapy, patients and their relatives did not report recurrence of stridor, or any
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complaint or complication. Since the onset of CPAP treatment both patients and their spouses reported better sleep and improved daytime alertness. Our study confirms that patients with multiple system atrophy have poor and reduced sleep, and a high frequency of vocal cord abduction dysfunction, sleep-disordered breathing, rapid eye movement sleep behaviour disorder, and periodic leg movements during sleep.2–5 Restless leg syndrome, however, has not been previously reported in such patients. Overall, the high prevalence and variety of sleep alterations seen might reflect the topography of the degenerative lesions which involve the neuronal substrate for sleep organisation and maintenance, such as brainstem nuclei or basal ganglia. Nocturnal stridor was detected in all five patients with complete vocal cord abduction restriction, and was correlated with obstructive sleep apnoea and arterial haemoglobin desaturation, suggesting the presence of severe airway obstruction during sleep. Patients with partial abduction dysfunction of the vocal cords did not have nocturnal stridor or sleep apnoea. These observations indicate that patients without nocturnal stridor or sleep apnoea might have asymptomatic vocal cord abnormalities which may be detected by laryngoscopy. Patients with stridor have been treated almost solely by elective or emergency tracheostomy since this condition carries the risk of sudden death during sleep. However, tracheostomy is limited by long-term complications, and alternative surgical approaches such as vocal cord lateralisation might be associated with an increased risk of complications such as bronchial aspiration. Harcourt et al3 used CPAP successfully to treat two patients with moderate obstructive sleep apnoea without stridor. In our study, CPAP eliminated both nocturnal stridor and obstructive sleep apnoea in three patients with complete vocal cord abduction restriction. CPAP treatment was a rewarding experience for patients and their families, particularly due to the elimination of nocturnal stridor. Patient compliance with continued home use of CPAP was satisfactory during 6 months of follow-up. In patients with impaired vocal cord abduction while awake, loss of posterior cricoarytenoid muscle tone during sleep would accentuate the laryngeal obstruction leading to inspiratory stridor and recurrent obstructive apnoea associated with haemoglobin desaturation. We speculate that in our three patients with vocal cord abduction dysfunction, nasal CPAP acts as a pneumatic splint, passively abducting the paralysed vocal cords, keeping the larynx open, and subsequently eliminating nocturnal stridor and sleep apnoea. Although our study is limited by the small number of patients studied, our results indicate that nasal CPAP might provide a non-invasive form of treatment of patients with nocturnal stridor thereby avoiding permanent tracheostomy. *Details can be found at The Lancet website (www.thelancet.com) 1 2 3
4
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Gilman S, Low PA, Quinn NP, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 1999; 163: 94–98. Plazzi G, Corsini R, Porvini F, et al. REM sleep behavior disorder in multiple system atrophy. Neurology 1997; 48: 1094–97. Harcourt J, Spraggs P, Mathias C, Brookes G. Sleep-related breathing disorders in the Shy-Drager syndrome. Observations on investigation and management. Eur J Neurology 1996; 3: 186–90. Bannister R, Gibson W, Michaels L, Oppenheimer DR. Laryngeal abductor paralysis in multiple system atrophy. Brain 1981; 104: 351–68. Isozaki E, Naito A, Horiguchi S, Kawamura R, Hayashida T, Tanabe H. Early diagnosis and stage classifiation of vocal cord abductor paralysis in patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 1996; 60: 399–402.
Neurology Service (A Iranzo MD, J Santamaria MD, E Tolosa MD), Hospital Clinic i Provincial de Barcelona, Barcelona 08036, Spain Correspondence to: Dr Alex Iranzo (e-mail:
[email protected])
THE LANCET • Vol 356 • October 14, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
