Introduction
Material and methods
Search strategy and inclusion of cases
Data extraction
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Clinical and epidemiological characteristics: age, age at onset of symptoms and delay of diagnosis, sex, country of origin, symptoms and sings, and presence of other associated diseases.
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Treatments received including muscle relaxants, antiepileptic drugs, corticosteroids, other immunosuppressants such as azathioprine, methotrexate, mycophenolate, tacrolimus, immunoglobulin therapy or a combination of these drugs. Duration of treatment and response were also recorded.
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Outcomes: time of follow-up, mortality and sequelae.
Data analysis
Results
All patients N = 64 | Patients where treatment was specified N = 47 | Patients treated with corticosteroids N = 30 | |
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Age of onset | 13.02 ± 9.08 | 14.19 ± 10.35 | 13.80 ± 10.32 |
Female sex | 47/64 (73%) | 35/47 (74%) | 23/30 (77%) |
Muscle manifestations | 100% | 100% | 100% |
Alopecia | 100% | 100% | 100% |
Alopecia universalis | 40/64 (63%) | 25/47 (53%) | 17/30 (57%) |
Diarrhea | 37/64 (58%) | 26/47 (55%) | 17/30 (57%) |
Weight loss, low weight or growth retardation | 33/64 (52%) | 23/47 (49%) | 14/30 (47%) |
Skeletal alterations | 22/64 (34%) | 16/47 (34%) | 10/30 (33%) |
Amenorrhea | 23/47 (49%) | 15/35 (43%) | 9/23 (39%) |
ANA + | 17/64 (27%) | 17/47 (36%) | 13/30 (43%) |
Other autoantibodies | 15/64 (23%) | 15/47 (32%) | 11/30 (37%) |
Deaths | 7 (11%) | 2 (4%) | 0 (0%) |
Anticonvulsant drugs
Drug | Number of times used | Monotherapy as initial treatment | As initial treatment in combination with other drugs | As second or further-line treatment option | Improvement | No improvement | Change of treatment | Comments |
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Dantrolene | 15 | 9 | 4 | 2 | 13 | 2 | 3 | Dantrolene improved muscular symptoms but no other manifestations. It was used as a first option in combination with corticosteroids in two cases [6, 46] and in another case with immunoglobulin therapy [47], although, subsequently, immunoglobulin therapy was replaced by corticosteroids. Although improvement was recorded in 13 patients, such improvement only lasted for a short time in one of them, which led to the change in treatment [32]. In another case, the treatment was changed to immunoglobulin therapy because dantrolene is not a radical treatment [3]. For one of the cases that did not respond adequately, a change of treatment was not recorded in the article [45]. |
Carbamacepine/Oxcarbacepine | 9 | 1 | 7 | 1 | 4 | 5 | 5 | In two cases carbamazepine was combined with corticosteroids [2, 41]. In five cases, the treatment was changed due to lack of effectiveness [9, 32, 40, 42, 70]. In one of them, it was necessary to use botulinum toxin to control masticatory spasms [32]. In another of these cases, authors stated that carbamazepine, phenobarbital, quinine sulfate, and chlorpromazine were tested during hospitalization and they were not effective for spasms [40]. In one case, carbamazepine was used with gabapentin without result [70]. |
Phenitoin | 7 | 0 | 4 | 3 | 3 | 4 | 1 | In the 3 SS patients in whom there was an improvement, phenitoin was the first option in combination with corticosteroids [5, 34, 35]. In another patient, it was combined with blaclofen and prednisone without response [33]. In one case, phenytoin was used as a second option and no satisfactory response was obtained. But after several treatment options, phenytoin was maintained combined with corticoids and mycophenolate [37]. In another case, phenytoin was used as second option treatment with carbamazepine, but it was not effective [32]. Averianov reported its use, but without effectiveness [36]. |
Baclofen | 3 | 1 | 2 | 0 | 0 | 3 | 3 | It has been used as a first option treatment only in one SS patient [50]. In another patient, multiple muscle relaxants and anticonvulsants were used without satisfactory results [42]. Baclofen was used in combination with phenytoin and prednisone in another patient [33]. In none of the cases the treatment had a good clinical response. |
Clotiapine and biperidene | 1 | 1 | 0 | 0 | 0 | 1 | 1 | It was not effective [51]. |
Clonazepam | 3 | 0 | 2 | 1 | 0 | 3 | 3 | Clonazepam was used in combination with carbamazepine without improvement [9] and the SS patient required changing treatment to dantrolene. Clonazepam was used in a patient adding it to dantrolene, but it was necessary to change treatment to phenytoin and carbamazepine [32]. In one patient clonazepam was used together with several other drugs such as dantrolene, carbamazepine or diazepam [42]. |
Tetrazepam | 1 | 0 | 1 | 0 | 1 | 0 | 0 | Tetrazepam in combination with carbamazepine improved spasms in a patient with SS [39]. |
Otilonium bromide | 1 | 0 | 1 | 0 | 1 | 0 | 0 | It was used in combination with carbamazepine with disappearance of spasms and diarrhea [38] |
Phenobarbital | 1 | 0 | 0 | 1 | 0 | 1 | 1 | Phenobarbital was used in a SS patient who was also receiving carbamazepine, quinine sulfate and chlorpromazine treatment. But it was not effective either [40]. |
Quinine sulfate | 1 | 0 | 0 | 1 | 0 | 1 | 1 | Quinine sulfate was used in a patient who was also receiving carbamazepine, phenobarbital and chlorpromazine treatment. But it was not effective either [40]. |
Chlorpromazine | 1 | 0 | 0 | 1 | 0 | 1 | 0 | Chlorpromazine was used in a patient who was also receiving carbamazepine, quinine sulfate and phenobarbital treatment. But it was not effective either [40]. |
Acetazolamide | 1 | 0 | 0 | 1 | 1 | 0 | 0 | Acetazolamide improved muscle symptoms in a patient [36]. It was used in this patient after thioridazine, haloperidol and phenytoin were unsuccessful. |
Neostigmine | 1 | 0 | 1 | 0 | 1 | 0 | 0 | Neostigmine was used in combination with traditional Chinese medicine in a patient with myasthenia. The authors stated that she remained stable after 8 months of follow-up [40]. |
Botulinum toxin | 3 | 0 | 1 | 2 | 3 | 0 | 1 | Botulinum toxin was used together with corticosteroids in a patient as a primary therapy. Treatment was changed by adding azathioprine [59]. In one case, botulinum toxin was added to the treatment to control masticatory spasms [47]. In another case, it was used after several previous treatments with dantrolene, diazepam, clonazepam, phenytoin and carbamazepine [32]. |
Amitriptilin | 1 | 0 | 1 | 0 | 1 | 0 | 0 | Amitriptilin was used in combination with corticosteroids as a maintenance therapy [61]. |
Thioridazine | 1 | 1 | 0 | 0 | 0 | 1 | 1 | [36] |
Haloperidol | 1 | 0 | 0 | 1 | 0 | 1 | 1 | [36] |
Diazepam | 2 | 1 | 0 | 1 | 1 | 1 | 1 | It was combined with several other treatments such as immunoglobulin therapy, cyclophosphamide and azatioprine [51]. Although this patient improved, it is difficult to attribute her improvement to diazepam. In another patient diazepam was used together with multiple muscle relaxants and anticonvulsants without satisfactory results [42]. |
Midazolam | 1 | 1 | 0 | 0 | 0 | 1 | 0 | The patient developed a neuroleptic malignant syndrome after the onset of iv midazolam and died [52]. |
Muscle relaxants
Benzodiazepines
Systemic corticosteroids
Drug | Number of times used | Monotherapy as initial treatment | In combination with other drugs as initial treatment | As second or other treatment option | Improvement | Not improvement | Change of treatment | Comments |
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Systemic corticosteroids | 30 | 8 | 14 | 8 | 28 | 2 | 4 | In one case the treatment was changed to dantrolene for lack of efficacy [33]. In a case that had been previously treated with carbamazepine and otilonium bromide, systemic corticosteroids were prescribed for alopecia. However, treatment was interrupted a month later due to the appearance of adverse effects [13]. In one case, corticosteroids showed improvement of short duration and the treatment was changed [37]. In another case, a single pulse of corticosteroid diminished the frequency of muscle spasms during two weeks, but therapy was changed to cyclophosphamide and subsequently to azathioprine [51]. |
Corticosteroids have been combined with other immunosuppressants in 7 cases. In 5 patients as initial treatment [5, 37, 60, 67] and in two patients after other treatments [50, 62]. Corticosteroids were combined with immunoglobulin therapy in two patients, [60, 67] with mycophenolate mofetil in one patient [37], with cyclosporin in two patients reported by Rudnicka [5], with methotrexate in one patient [62] and with tacrolimus in another patient [50]. Other immunosuppressants have been used in combination to low doses of corticosterois, such as methotrexate [63], azathioprine [59]. Corticosteroids have also been used in combination with other drugs such as baclofen [33], phenytoin [5, 33‐35], dantrolene [6, 46], carbamazepine [2, 41] and botulinum toxin [59]. In one patient initially treated with corticosteroids in monotherapy, amitriptyline was added later [61]. | ||||||||
Immunoglobulin therapy | 9 | 1 | 3 | 5 | 4 | 5 | 6 | In one case, immunoglobulin therapy was used alone as a first option without improvement [64]. In two cases, immunoglobulin therapy was used in combination with corticosteroids [60, 67]. In one case, it was used as a first option in combination with dantrolene, but treatment was changed to pulsed treatment of methylprednisolone together with dantrolene [47]. In another case, immunoglobulin therapy was used as a second option after short-term improvement with corticoids and mycophenolate mofetil, with no response [37]. In another patient they were also used as second option treatment together with diazepam [51]. Endo used them as a second option with effect for 2 months and then changing to corticoids [50]. Arita used it as second option treatment after dantrolene with satisfactory response [3]. The treatment with immunoglobulin therapy was changed in six cases [37, 47, 50, 51, 64, 69] |
Cyclosporin | 2 | 0 | 2 | 0 | 2 | 0 | 0 | In one of the cases, both alopecia and spasms improved. In the other case, improvement of spasms was achieved, but it was less effective for alopecia [5] |
Mycophenolate mofetil | 1 | 0 | 1 | 0 | 1 | 0 | 1 | The initial treatment in this patient was with corticosteroids and mycophenolate mofetil. Later phenytoin was added. Treatment was changed due to short-term improvement. The treatment was changed to immunoglobulin without response, and subsequently, to plasmapheresis (5 cycles) with improvement in pain and cramps. Later this same case was treated with a combination of phenytoin, mycophenolate and corticosteroids [37], thus it can be deduced that mycophenolate and corticosteroids adminstarion was maintained throughout the course of the treatment. |
Azathioprine | 2 | 0 | 0 | 2 | 2 | 0 | 0 | |
Plasmapheresis | 1 | 0 | 0 | 1 | 1 | 0 | 0 | It was used after short-term improvement with both corticosteroids and mycophenolate mofetil as the first option, and failure of immunoglobulin therapy as a second option. After plasmapheresis (5 cycles) the patient improved in pain and cramps [37] |
Methotrexate | 2 | 0 | 0 | 2 | 2 | 0 | 0 | |
Tacrolimus | 1 | 0 | 0 | 1 | 1 | 0 | 0 | It was used together with corticosteroids after trying other treatments [50] |
Cyclophosphamide | 1 | 0 | 0 | 1 | 0 | 1 | 1 | It was used together with diazepam after trying other treatments, and was later changed to azathioprine [51] |