457
paramedian position SHORT
REPORTS
Stridor and focal laryngeal
dystonia Fibreoptic laryngoscopy in 6 patients with laryngeal stridor showed immobile vocal cords in a paramedian position but no other local cause. Thus a diagnosis of Gerhardt’s syndrome, usually ascribed to paralysis of vocal-cord abductor muscles, was made in 3 patients who had no other signs or symptoms of dystonia, and in 3 patients who had multifocal dystonia. Electromyography (EMG) showed evidence of overactivity of vocal-cord adductors, with
evidence of denervation in the abductor muscles. Botulinum toxin injection of the overactive thyroarytenoid muscles abolished stridor. These clinical and EMG findings indicate that Gerhardt’s syndrome is not caused by paralysis of vocal-cord abductors, but represents a focal laryngeal dystonia which may be treatable by botulinum toxin injections of vocal-cord adductor muscles rather than by arytenoidopexy or tracheostomy. no
Laryngeal stridor, caused by narrowing of the glottic aperture, is uncommon but may be distressing and even life threatening. It can be caused by immobility of the vocal cords in a paramedian position; in the absence of a local structural lesion and with a normal voice, such findings are usually ascribed to bilateral vocal-cord abductor paralysis. This condition, sometimes known as Gerhardt’s syndrome,l has been reported in degenerative diseases such as multiple system atrophy2-4 and amyotrophic lateral sclerosis,s and also as an isolated finding. We report 3 patients with segmental or multifocal dystonia and 3 with isolated respiratory symptoms, all of whom had typical clinical and laryngeal features of Gerhardt’s syndrome and were treated with botulinum toxin injections6 after electromyography (EMG) of the laryngeal muscles. Case histories of a patient from each group are given, and clinical features for all patients are summarised in the table. A 51-year-old man (patient 2) had a 5 year history of idiopathic segmental dystonia and a 2 year history of intermittent stridor, which might occur when awake or asleep, spontaneously or on slight exertion. On examination he had blepharospasm, spasmodic torticollis to the right, and right arm dystonia. During an episode of stridor, the vocal cords could be seen, apparently immobile, in a CLINICAL FEATURES
*Underwent arytenoidopexy without benefit BSP = blepharospasm, ST = spasmodic torticollis, WC = writers’ cramp
on
fibreoptic laryngoscopy. Nevertheless,
simultaneous percutaneous EMG of the thyroarytenoid muscles showed bursts of EMG activity for 2 s separated by short (011 s) periods of silence. Stridor disappeared after unilateral injection of botulinum toxin into the left thyroarytenoid muscle under EMG control. Subsequent fibreoptic laryngoscopy showed that the left vocal cord had moved to a lateral position at rest. We have followed the patient for 13 months and reinjected twice at 6-month intervals with the same benefit. A 63-year-old man (patient 4) presented with a 3 year history of inspiratory stridor without dysphonia which began suddenly when bird shooting one day, when he had a bird in his sights. Fibreoptic laryngoscopy showed vocal cords in a paramedian position and a diagnosis of Gerhardt’s syndrome was made. Arytenoidopexy to transpose the right vocal cord laterally’ had no lasting benefit. 2 years after surgery, fibreoptic laryngoscopy showed both vocal cords in a paramedian position; on phonation the right was less mobile than the left. EMG of the right thyroarytenoid muscle at rest showed bursts of activity for 1 s separated by periods of silence also for 1 s. Injection of botulinum toxin into the right thyroarytenoid muscle under EMG control led to a striking clinical improvement, with abolition of stridor and a 50% increase in peak expiratory flow rate. Fibreoptic laryngoscopy confirmed that the right vocal cord was now displaced laterally, so that the glottic aperture was greatly enlarged. A second injection on the same side 4 months later has had a sustained benefit for the past 8 months. Clinical details of all 6 patients are summarised in the table. EMG of the thyroarytenoid muscles showed evidence of three patterns of involuntary activity: prolonged bursts of 2 s or more followed by short (Ols) periods of silence; shorter bursts of activity for about 1 s separated by 1 s of silence; and brief bursts of activity for 0-2 s. In 1 patient from each group we were also able to record from the posterior cricoarytenoid muscle, a vocal-cord abductor: both had a normal rhythmic EMG pattern during quiet respiration, with no evidence of denervation or overactivity.
Patients with Gerhardt’s syndrome are usually thought to have bilateral paralysis of the vocal-cord abductors because the vocal cords lie in a paramedian position and are apparently immobile. However, our EMG findings in 6 patients showed persistent overactivity of vocal-cord adductors with characteristic EMG features of dystonia,8 but a normal pattern in vocal-cord abductors in the 2 patients who underwent successful posterior cricoarytenoid EMG. We suggest that Gerhardt’s syndrome may therefore be caused by adductor overactivity rather than abductor paralysis, and that Gerhardt’s syndrome represents focal laryngeal dystonia. It can be distinguished clinically from spasmodic dysphonia, also thought to represent laryngeal dystonia,9,1O but in which symptoms appear on phonation. The presence of other obvious dystonic features in patients with segmental or multifocal dystonia might be a helpful diagnostic clue, but 3 of our patients had laryngeal dystonia without similar symptoms elsewhere. Treatment of Gerhardt’s syndrome has been disappointing. Attempts to enlarge the glottic aperture (as in patient 4) are not usually followed by lasting benefit and some patients have undergone tracheostomy because of the risk of sudden death. All 6 of our patients showed a striking response to botulinum toxin injections into the thyroarytenoid muscles under EMG control. Although such a technique is unlikely to be available outside specialist centres, and injections may need to be repeated every 4 to 8 months, we suggest that patients with typical Gerhardt’s syndrome should undergo EMG of the vocal-cord adductors. Similar investigations in patients with degenerative conditions such as multiple system atrophy and amyotrophic lateral sclerosis are under way, but we do not at present propose that such patients should be treated by botulinum toxin injections.
CHARACTERISTICS OF STUDY GROUPS
REFERENCES 1. Gcrhardt C. Studien und Beobachtungen uber Stimmbandlähmung. Virchows Arch 1863; 27: 68-99, 296-321. 2. Williams A, Hanson D, Calne DB. Vocal cord paralysis in the Shy-Drager syndrome. J Neurol Neurosurg Psychiatry 1979; 42: 151-53. 3. Lapresle J, Annabi A. Olivopontocerebellar atrophy with velopharyngolaryngeal paralysis: a contribution to the somatotopy of the nucleus ambiguus. J Neuropathol Exp Neurol 1979; 28: 401-06. 4. Bannister R, Gibson W, Michaels L, Oppenheimer DR. Laryngeal abductor paralysis in multiple system atrophy: a report on three necropsied cases, with observations on the laryngeal muscles and the nuclei ambigui. Brain 1981; 104: 351-68. 5. Alajouanine T, Bouchet M, Pialoux P, Lhermitte J. La sclerose laterale amyotrophique et la paralysie des dilatateurs de la glotte. Ann Otolaryngol (Paris) 1953; 70: 365-87. 6. Marion MH, Klap P, Perrin A, Elbaz E. Les dysphonies spasmodiques: méthodes d’investigations et de traitement. Rev Neurol (in press). 7. Woodman D. A modification of the extralaryngeal approach to arytenoidectomy for bilateral abductor paralysis. Arch Otolaryngol
1946; 43: 63-65. 8. Rothwell JC, Obeso JA. The anatomical and physiological basis of torsion dystonia. In: Marsden CD, Fahn S, eds. Movement disorders 2. London: Butterworths, 1987: 313-31. 9. Marsden CD, Sheehy MP. Spastic dysphonia, Meige disease and torsion dystonia. Neurology 1982; 32: 1202-03. 10. Blitzer A, Brin MF. Laryngeal dystonia: a series with botulinum toxin therapy. Ann Otol Rhinol Laryngol 1991; 100: 85-89.
ADDRESSES: 4 rue Léon Delhomme, 75015 Paris (M -H Marion, MD), and Department of Otorhinolaryngology (P. Klap, MD, M
Cohen, MD) and Neurophysiology Laboratory (A. Perrin, MD), Fondation
Rothschild,
Correspondence to
75940
Paris
Cédex
19,
France.
Dr Marie-Hélène Marion.
Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes
Insulin-dependent diabetes is characterised by autoantibodies to several pancreatic-islet-cell antigens, including glutamate decarboxylase. We measured the proliferative responses to this antigen of peripheral-blood mononuclear cells from patients with newly diagnosed insulin-dependent diabetes, relatives of diabetic patients, and healthy controls. The likelihood of a positive response was substantially greater among the diabetic patients and relatives positive for islet-cell autoantibodies (ICA) than among subjects at low risk of diabetes (controls and Glutamate ICA-negative relatives). decarboxylase may have a pathogenetic role in insulin-dependent diabetes. is characterised diabetes Insulin-dependent chronic mononuclear-cell infiltration of a pathologically by the pancreatic islets.’ T lymphocytes make up most of the infiltrate and are thought to be important in the pathogenesis of the disorder.2 We have previously shown that autoantibodies to a 64 000 kDa protein, now known to be glutamate decarboxylaseare the earliest and most
ID D = insulin -dependent diabetes
marker of insulin-dependent diabetes.4,5 We have therefore tried to find out whether proliferation of peripheral-blood mononuclear cells (PBMC) in response to glutamate decarboxylase is associated with insulin-dependent diabetes.
predictive autoantibody
We studied cells from patients with newly diagnosed insulindependent diabetes, relatives of diabetic patients with or without islet-cell autoantibodies (ICA), and randomly selected healthy controls (see table) identified through our continuing studies on the natural history of insulin-dependent diabetes;6 all gave informed consent. ICA were assayed and HLA-DR was typed as previously6 Human glutamate decarboxylase 65 was produced in Escherichia coli by means of a T7 expression vector modified to contain aminoterminal histidines; this modification enables rapid purification by metal affinity chromatography (unpublished). PBMC were separated by ’Ficoll-Hypaque’ density-gradient centrifugation. 1 x 106 PBMC per well were cultured for 7 days in 24-well tissue culture trays in RPMI 1640 and 10% human AB-positive serum and one of the following (in triplicate wells): medium only; 10 )g/ml glutamate decarboxylase 65 (determined as the optimum concentration in preliminary studies); or 1 g/ml phytohaemagglutinin. After culture for 3 days in phytohaemagglutinin wells or 6 days in the other wells, 37 kBq tritiated thymidine was added to each well. The cultures were harvested after 18 h semiautomatically, their thymidine incorporation was assessed by liquid scintillation counting, and the mean value of each triplicate stimulation was calculated.9 Cellular proliferation was expressed as the stimulation index (SI=mean cpm incorporated in the presence of antigen divided by the mean cpm incorporated with medium alone). An SI of 2-7 or higher was taken as positive (ie, above the mean + 3 SD for controls). Fisher’s exact test was used to compare positive response frequencies among groups, and t tests (MannWhitney) to compare mean SI among the groups.
The proportion of subjects whose cells gave a positive proliferative response to the recombinant glutamate decarboxylase antigen was significantly higher in the 836
relatives
relatives
Scatter plot of responses to glutamate decarboxylase. Mean (SEM) cpm for medium alone/medium plus glutamate decarboxylase/medium plus phytohaemagglutinin were: control 3978 (1112)/5287 (1718)/307 882 (23876); ICA-negative relatives 4100 (597)/6598 (1659)/192723 (21 772), ICA-positive relatives 4013 (631 )/36 955 (22 983)/306 420 (58995); and new diabetes (IDD) 9389 (2108)/43 627 (8816)/240 725 (34 915)
paramedian position SHORT
REPORTS
Stridor and focal laryngeal
dystonia Fibreoptic laryngoscopy in 6 patients with laryngeal stridor showed immobile vocal cords in a paramedian position but no other local cause. Thus a diagnosis of Gerhardt’s syndrome, usually ascribed to paralysis of vocal-cord abductor muscles, was made in 3 patients who had no other signs or symptoms of dystonia, and in 3 patients who had multifocal dystonia. Electromyography (EMG) showed evidence of overactivity of vocal-cord adductors, with
evidence of denervation in the abductor muscles. Botulinum toxin injection of the overactive thyroarytenoid muscles abolished stridor. These clinical and EMG findings indicate that Gerhardt’s syndrome is not caused by paralysis of vocal-cord abductors, but represents a focal laryngeal dystonia which may be treatable by botulinum toxin injections of vocal-cord adductor muscles rather than by arytenoidopexy or tracheostomy. no
Laryngeal stridor, caused by narrowing of the glottic aperture, is uncommon but may be distressing and even life threatening. It can be caused by immobility of the vocal cords in a paramedian position; in the absence of a local structural lesion and with a normal voice, such findings are usually ascribed to bilateral vocal-cord abductor paralysis. This condition, sometimes known as Gerhardt’s syndrome,l has been reported in degenerative diseases such as multiple system atrophy2-4 and amyotrophic lateral sclerosis,s and also as an isolated finding. We report 3 patients with segmental or multifocal dystonia and 3 with isolated respiratory symptoms, all of whom had typical clinical and laryngeal features of Gerhardt’s syndrome and were treated with botulinum toxin injections6 after electromyography (EMG) of the laryngeal muscles. Case histories of a patient from each group are given, and clinical features for all patients are summarised in the table. A 51-year-old man (patient 2) had a 5 year history of idiopathic segmental dystonia and a 2 year history of intermittent stridor, which might occur when awake or asleep, spontaneously or on slight exertion. On examination he had blepharospasm, spasmodic torticollis to the right, and right arm dystonia. During an episode of stridor, the vocal cords could be seen, apparently immobile, in a CLINICAL FEATURES
*Underwent arytenoidopexy without benefit BSP = blepharospasm, ST = spasmodic torticollis, WC = writers’ cramp
on
fibreoptic laryngoscopy. Nevertheless,
simultaneous percutaneous EMG of the thyroarytenoid muscles showed bursts of EMG activity for 2 s separated by short (011 s) periods of silence. Stridor disappeared after unilateral injection of botulinum toxin into the left thyroarytenoid muscle under EMG control. Subsequent fibreoptic laryngoscopy showed that the left vocal cord had moved to a lateral position at rest. We have followed the patient for 13 months and reinjected twice at 6-month intervals with the same benefit. A 63-year-old man (patient 4) presented with a 3 year history of inspiratory stridor without dysphonia which began suddenly when bird shooting one day, when he had a bird in his sights. Fibreoptic laryngoscopy showed vocal cords in a paramedian position and a diagnosis of Gerhardt’s syndrome was made. Arytenoidopexy to transpose the right vocal cord laterally’ had no lasting benefit. 2 years after surgery, fibreoptic laryngoscopy showed both vocal cords in a paramedian position; on phonation the right was less mobile than the left. EMG of the right thyroarytenoid muscle at rest showed bursts of activity for 1 s separated by periods of silence also for 1 s. Injection of botulinum toxin into the right thyroarytenoid muscle under EMG control led to a striking clinical improvement, with abolition of stridor and a 50% increase in peak expiratory flow rate. Fibreoptic laryngoscopy confirmed that the right vocal cord was now displaced laterally, so that the glottic aperture was greatly enlarged. A second injection on the same side 4 months later has had a sustained benefit for the past 8 months. Clinical details of all 6 patients are summarised in the table. EMG of the thyroarytenoid muscles showed evidence of three patterns of involuntary activity: prolonged bursts of 2 s or more followed by short (Ols) periods of silence; shorter bursts of activity for about 1 s separated by 1 s of silence; and brief bursts of activity for 0-2 s. In 1 patient from each group we were also able to record from the posterior cricoarytenoid muscle, a vocal-cord abductor: both had a normal rhythmic EMG pattern during quiet respiration, with no evidence of denervation or overactivity.
Patients with Gerhardt’s syndrome are usually thought to have bilateral paralysis of the vocal-cord abductors because the vocal cords lie in a paramedian position and are apparently immobile. However, our EMG findings in 6 patients showed persistent overactivity of vocal-cord adductors with characteristic EMG features of dystonia,8 but a normal pattern in vocal-cord abductors in the 2 patients who underwent successful posterior cricoarytenoid EMG. We suggest that Gerhardt’s syndrome may therefore be caused by adductor overactivity rather than abductor paralysis, and that Gerhardt’s syndrome represents focal laryngeal dystonia. It can be distinguished clinically from spasmodic dysphonia, also thought to represent laryngeal dystonia,9,1O but in which symptoms appear on phonation. The presence of other obvious dystonic features in patients with segmental or multifocal dystonia might be a helpful diagnostic clue, but 3 of our patients had laryngeal dystonia without similar symptoms elsewhere. Treatment of Gerhardt’s syndrome has been disappointing. Attempts to enlarge the glottic aperture (as in patient 4) are not usually followed by lasting benefit and some patients have undergone tracheostomy because of the risk of sudden death. All 6 of our patients showed a striking response to botulinum toxin injections into the thyroarytenoid muscles under EMG control. Although such a technique is unlikely to be available outside specialist centres, and injections may need to be repeated every 4 to 8 months, we suggest that patients with typical Gerhardt’s syndrome should undergo EMG of the vocal-cord adductors. Similar investigations in patients with degenerative conditions such as multiple system atrophy and amyotrophic lateral sclerosis are under way, but we do not at present propose that such patients should be treated by botulinum toxin injections.
CHARACTERISTICS OF STUDY GROUPS
REFERENCES 1. Gcrhardt C. Studien und Beobachtungen uber Stimmbandlähmung. Virchows Arch 1863; 27: 68-99, 296-321. 2. Williams A, Hanson D, Calne DB. Vocal cord paralysis in the Shy-Drager syndrome. J Neurol Neurosurg Psychiatry 1979; 42: 151-53. 3. Lapresle J, Annabi A. Olivopontocerebellar atrophy with velopharyngolaryngeal paralysis: a contribution to the somatotopy of the nucleus ambiguus. J Neuropathol Exp Neurol 1979; 28: 401-06. 4. Bannister R, Gibson W, Michaels L, Oppenheimer DR. Laryngeal abductor paralysis in multiple system atrophy: a report on three necropsied cases, with observations on the laryngeal muscles and the nuclei ambigui. Brain 1981; 104: 351-68. 5. Alajouanine T, Bouchet M, Pialoux P, Lhermitte J. La sclerose laterale amyotrophique et la paralysie des dilatateurs de la glotte. Ann Otolaryngol (Paris) 1953; 70: 365-87. 6. Marion MH, Klap P, Perrin A, Elbaz E. Les dysphonies spasmodiques: méthodes d’investigations et de traitement. Rev Neurol (in press). 7. Woodman D. A modification of the extralaryngeal approach to arytenoidectomy for bilateral abductor paralysis. Arch Otolaryngol
1946; 43: 63-65. 8. Rothwell JC, Obeso JA. The anatomical and physiological basis of torsion dystonia. In: Marsden CD, Fahn S, eds. Movement disorders 2. London: Butterworths, 1987: 313-31. 9. Marsden CD, Sheehy MP. Spastic dysphonia, Meige disease and torsion dystonia. Neurology 1982; 32: 1202-03. 10. Blitzer A, Brin MF. Laryngeal dystonia: a series with botulinum toxin therapy. Ann Otol Rhinol Laryngol 1991; 100: 85-89.
ADDRESSES: 4 rue Léon Delhomme, 75015 Paris (M -H Marion, MD), and Department of Otorhinolaryngology (P. Klap, MD, M
Cohen, MD) and Neurophysiology Laboratory (A. Perrin, MD), Fondation
Rothschild,
Correspondence to
75940
Paris
Cédex
19,
France.
Dr Marie-Hélène Marion.
Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes
Insulin-dependent diabetes is characterised by autoantibodies to several pancreatic-islet-cell antigens, including glutamate decarboxylase. We measured the proliferative responses to this antigen of peripheral-blood mononuclear cells from patients with newly diagnosed insulin-dependent diabetes, relatives of diabetic patients, and healthy controls. The likelihood of a positive response was substantially greater among the diabetic patients and relatives positive for islet-cell autoantibodies (ICA) than among subjects at low risk of diabetes (controls and Glutamate ICA-negative relatives). decarboxylase may have a pathogenetic role in insulin-dependent diabetes. is characterised diabetes Insulin-dependent chronic mononuclear-cell infiltration of a pathologically by the pancreatic islets.’ T lymphocytes make up most of the infiltrate and are thought to be important in the pathogenesis of the disorder.2 We have previously shown that autoantibodies to a 64 000 kDa protein, now known to be glutamate decarboxylaseare the earliest and most
ID D = insulin -dependent diabetes
marker of insulin-dependent diabetes.4,5 We have therefore tried to find out whether proliferation of peripheral-blood mononuclear cells (PBMC) in response to glutamate decarboxylase is associated with insulin-dependent diabetes.
predictive autoantibody
We studied cells from patients with newly diagnosed insulindependent diabetes, relatives of diabetic patients with or without islet-cell autoantibodies (ICA), and randomly selected healthy controls (see table) identified through our continuing studies on the natural history of insulin-dependent diabetes;6 all gave informed consent. ICA were assayed and HLA-DR was typed as previously6 Human glutamate decarboxylase 65 was produced in Escherichia coli by means of a T7 expression vector modified to contain aminoterminal histidines; this modification enables rapid purification by metal affinity chromatography (unpublished). PBMC were separated by ’Ficoll-Hypaque’ density-gradient centrifugation. 1 x 106 PBMC per well were cultured for 7 days in 24-well tissue culture trays in RPMI 1640 and 10% human AB-positive serum and one of the following (in triplicate wells): medium only; 10 )g/ml glutamate decarboxylase 65 (determined as the optimum concentration in preliminary studies); or 1 g/ml phytohaemagglutinin. After culture for 3 days in phytohaemagglutinin wells or 6 days in the other wells, 37 kBq tritiated thymidine was added to each well. The cultures were harvested after 18 h semiautomatically, their thymidine incorporation was assessed by liquid scintillation counting, and the mean value of each triplicate stimulation was calculated.9 Cellular proliferation was expressed as the stimulation index (SI=mean cpm incorporated in the presence of antigen divided by the mean cpm incorporated with medium alone). An SI of 2-7 or higher was taken as positive (ie, above the mean + 3 SD for controls). Fisher’s exact test was used to compare positive response frequencies among groups, and t tests (MannWhitney) to compare mean SI among the groups.
The proportion of subjects whose cells gave a positive proliferative response to the recombinant glutamate decarboxylase antigen was significantly higher in the 836
relatives
relatives
Scatter plot of responses to glutamate decarboxylase. Mean (SEM) cpm for medium alone/medium plus glutamate decarboxylase/medium plus phytohaemagglutinin were: control 3978 (1112)/5287 (1718)/307 882 (23876); ICA-negative relatives 4100 (597)/6598 (1659)/192723 (21 772), ICA-positive relatives 4013 (631 )/36 955 (22 983)/306 420 (58995); and new diabetes (IDD) 9389 (2108)/43 627 (8816)/240 725 (34 915)
