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2011年10月25日

2733 眼瞼痙攣 - 総説と最新の知識 第2部 治療編 (神経眼科、アジアセクションから再録)

眼瞼痙攣 - 総説と最新の知識 第2部 治療編

この論文は日本の医学雑誌である神経眼科の中の英文で記載されたアジアセクションに掲載された私たちの論文です。英語では読む人も少ないと思いますので、抄録部分だけですが私なりに日本語に翻訳し戻して付けておきます。末尾に引用文献も付いています。ご覧いただけますと幸甚です。
(Blepharospasm - A review and updates. Part II. The therapies.)
Emoto H, Suzuki Y, Kiyosawa M, Blepharospasm – A review and updates. Types and symptoms. Neuroophthalmology Japan, 28:257-263,2011

抄録
原発性本眼瞼痙攣(EB)は、まぶたの無意識の閉瞼を特徴とするありふれた局所性失調症の一形です。その治療は、その症状の軽減を目指します。その中心になる治療はボツリヌス毒素(BoNT) の注射です。

それは1985年以来原発性本眼瞼痙攣の治療に使用されました。また、科学的資料はその長期的な安全性および効能を示しています。いくつかの薬が原発性本眼瞼痙攣に有効であることが報告されました。しかし、それらの効能は限定的で、ほとんどの場合には一時的です。

薬剤性眼瞼痙攣は様々な向精神薬に関係しています。また、丁寧な観察下での徐々に行われる薬の減量は、徴候を改善する場合があります。

内科医は向精神薬による眼瞼痙攣を持った患者において、可能な限り向精神性の薬物治療を減らすことを考慮するべきです。 ボトックス(BoNT)注入に応答しない患者は外科治療を行うべき候補者です。

一般に、眼輪筋切除が最初に推奨されます。 前頭骨への釣り上げ手術は開瞼失行症の症例に役立つするかもしれません。クラッチ眼鏡は開瞼失行症に対する別のオプションです。

これらの手術は重篤な合併症のない患者にとっては有益です。しかし、手術後のボトックス(BoNT)注射は多くの場合に必要です。運動症状に対するこの他の治療法には脳深部刺激および反復する経頭蓋磁気刺激法が有ります。しかし、これらの方法れ臨床に用いられる様になるのには更に詳細な研究が必要です。

眼球刺激感とドライアイを含む知覚症状に対する治療には、点眼薬と涙小点プラグが有ります。

ーーーー此処からが本文ですーーーーーーー
Blepharospasm - A review and updates. Part II. The therapies.

Hirofumi Emoto MD1,2, Yukihisa Suzuki MD, PhD1,2, Motohiro Kiyosawa MD, PhD1

1 Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo, Japan
2 Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

Abstract
Essential blepharospasm (EB) is a form of common focal dystonia characterized by involuntary closure of eyelids. The therapy aims to alleviate the symptoms. The mainstay of treatment for the motor symptom is botulinum neurotoxin (BoNT) injection. It has been used for EB since 1985, and scientific data show its long-term safety and efficacy. Several drugs have been reported to be effective, but their efficacy is limited and temporary in most cases. Drug-induced blepharospasm is associated with various psychotropic agents, and the gradual reduction under close monitoring can improve the symptom in some cases. Physicians should consider reducing the psychotropic medication as far as possible in patients with blepharospasm on psychotropic agents. Patients who do not respond to BoNT injections are candidates for surgical treatment. Generally, orbicularis myectomy is recommended first. Frontalis suspension may help in cases of apraxia of eyelid opening. Lid crutches are another option to apraxia of eyelid opening. These surgeries are of benefit to the patients without severe complications, but postoperative BoNT injections are often necessary. Other therapies for the motor symptoms are deep brain stimulation and repetitive transcranial magnetic stimulation, but further studies are necessary for clinical use. Therapies for the sensory symptoms including ocular irritation and dry eye are eye drops and punctual plugs. FL-41 lens is effective for photophobia in EB.

Key Words: essential blepharospasm, drug-induced, apraxia of eyelid opening, photophobia, botulinum neurotoxin

Reprint request to: Hirofumi Emoto, Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, JAPAN

Introduction
Essential blepharospasm (EB) is a form of common focal dystonia characterized by involuntary closure of eyelids1-6. The etiology remains obscure, and the therapy aims to alleviate the symptoms. The mainstay of treatment for the motor symptom of EB is botulinum neurotoxin (BoNT) injection1-6. BoNT has been used for EB since 1985 and become the initial treatment of choice for EB1-6. There are few controlled trials, however, BoNT is considered highly effective with a success rate of approximately 90%3. Some patients respond to individual oral medications, but, the drugs have not been generally successful7. Patients who did not respond to BoNT injections are candidates for surgical treatment6, 8. In this article, we reviewed various treatments for EB.

Therapies for the Motor Symptoms

Botulinum Neurotoxin Injection
BoNT injections are generally considered as the treatment of choice with its safety and efficacy1-6. The most common complications of BoNT injections are related to acute local effects: dry eye (7.5%), ptosis (2.8~12%), mild facial weakness (8.5%), and diplopia (1~13%)3. These adverse effects are local and temporary and there are few systemic adverse effects3. Distant effects are pruritis, dysphagia, nausea, and a flu-like syndrome1. BoNT injections into the pretarsal, rather than the preseptal portion of the orbicularis oculi can reduce the risk of ptosis and increase efficacy9, 10.

Long-Term Safety and Efficacy
Clinical use of BoNT for EB began in the early 1980s and it has been the treatment of choice since the early 1990s3.
Naumann et al. assessed the long-term safety of BoNT injections using meta-analysis of data from 36 randomized clinical trials4. The meta-analysis reported that any mild to moderate adverse events occurred in 25% in the BoNT-treated group (353/1425 patients) compared with 15% in the control group (133/884 patients), and no study reported any severe adverse events4. The adverse events were declined from 24 of 65 patients in the first year to 8 of 65 patients in the tenth year11.
Mejia et al analyzed longitudinal follow-up data on 45 patients who have received BoNT injections continuously for at least 12 years 12. In total, 20 adverse events occurred in 16 of 45 (35.6%) patients after their initial visit and 11 adverse events in 10 of 45 (22.2%) patients at their most recent injection visit12. Patients are currently responding better to BoNT, having statistically significant increases in global rating, peak duration of response (9 weeks to 13 weeks), and peak effect, compared with that after the initial visit12. They postulated this could be due to a significant increase in BoNT units over time (154 units to 221 units), partly explained by a cautious use of low doses of BoNT at the initial visit12. In spite of the increased dose, the frequency of adverse effects has decreased12.
Main concerns about long-term BoNT injections are emergence of blocking antibodies, and the neuronal and muscular changes due to chemodenervation4, 12.

Neutralizing Antibodies
The development of resistance to BoNT injections can be caused by the emergence of blocking antibodies13. In previous reports, 7.5~8.8% of EB patients developed blocking antibodies12, 14. These earlier studies used the original formulation of BoNT, and the higher rates of neutralizing antibody formation are possibly related to its higher protein load15.
Jankovic et al compared 130 patients treated with original BoNT (BOTOX; Allergan, Irvine, CA) for cervical dystonia, 42 of whom were exposed only to the original BoNT used before 1998 (25 ng protein/100 units) and 119 treated only with the current BoNT (5 ng protein/ 100 units) 16. Blocking antibodies were detected in 4 of 42 (9.5%) patients treated with original BoNT but in none of 119 patients treated exclusively with the current BoNT16. They concluded that the low risk of antibody formation with the current BoNT was related to lower protein load and that the use of the current preparation decreased the risk of antibody formation16.
Risk of the neutralizing antibody formation to BoNT depends on several factors: BoNT formulation (protein load), dose per treatment cycle, frequency of repeated treatment, an earlier age at onset, and total cumulative dose12, 15. Sub-analysis on patients with BoNT resistance identified three potential risk factors for the development of BoNT resistance: (1) frequent injections, (2) “booster” injections, and (3) high doses of BoNT per treatment12, 13, 17. In order to avoid developing BoNT resistance, physicians should avoid booster injections and are encouraged to extend the interval between treatments as long as possible, at least 1or 2 months between BoNT injections, and to use the smallest possible doses12, 17.

Chemodenervation
Histological studies support the safety and efficacy of repeated BoNT injections18. Histologic evaluation was conducted on 12 orbicularis oculi muscles of 11 patients with EB and Meige’s syndrome who had received an average of 11.3 injections over 3.5 years18. Within 11 weeks of the last injection, denervation was demonstrated by the spread of acetylcholinesterase staining on muscle, however, twelve weeks after the last injection, muscle fiber diameter was normal and acetylcholinesterase staining was confined to the neuromuscular junctions18. Denervation changes appear to correlate to the time interval since the last injection and repeated BoNT injections do not appear to cause irreversible muscle atrophy or other degenerative changes.

Apraxia of Eyelid Opening (AEO)
Difficulty in initiating the act of eyelid elevation is called apraxia of eyelid opening (AEO) and it is caused by failure of levator palpebrae contraction6. It is particularly common in EB, Parkinson’s disease and related disorders6. The specific causes of EB and AEO are unknown, but AEO is considered due to an abnormality in the supranuclear control of eyelid movement19, 20. These two conditions coexist in 10~33% of EB patients21, 22. The diagnosis of AEO remains largely based on careful clinical assessment and observation of delayed eye opening, with possible supplementation with electromyography of the pretarsal orbicularis oculi6.
BoNT injections were effective in 86% of EB patients without AEO, whereas the efficacy is decreased to 50% of those with AEO21. AEO is an important consideration when BoNT injections fail to improve blepharospasm even though the orbicularis oculi is weakened6.
BoNT injection into Riolan’s muscle, at the eyelid margin, may be effective as treatment for AEO6. Inoue et al treated six AEO patients with BoNT injections into the region of Riolan’s muscle at the medial and lateral portions of the upper and lower pretarsal orbicularis oculi23. Clinical benefit was observed in all 6 patients, 2 of whom had previously been treated with conventional pretarsal BoNT injections and had not improved23. The proposed mechanism is not that of muscle relaxation but rather modulation of the somatosensory cortex, similar to that of a ‘sensory trick’ in patients with dystonia23. As for another option, lid crutches may be of benefit for AEO20, 24, 25. They may also work by a sensory trick mechanism6.
Surgical approaches with shortening of the levator tendon or a frontalis suspension may be effective for some AEO patients6. De Groot et al performed frontalis suspension to treat 13 consecutive EB patients with AEO during a 4-year interval26. Good or excellent functional results were obtained in 10 of 13 patients and unsuccessful in 1 patient, and in 2 patients blepharospasm recurred after 9 months26.

Oral Medication
Patients who do not respond to BoNT injections may be considered for oral medication. Several drugs have been reported to ameliorate the motor symptoms of EB, but their efficacy is limited and temporary in most cases8, 27, 28. Drugs which have been used include antidepressants, anxiolytics, anticonvulsants, anti-Parkinsonian drugs, and muscle relaxants8.
Especially, trihexyphenidyl24, 27, 29 and clonazepam27, 30 were reported for the treatment of EB. Abrupt withdrawal of trihexyphenidyl can trigger severe exacerbation of the cranial dystonia associated with inspiratory stridor and acute respiratory difficulties31.

Cessation or Dose Reduction of Psychotropic Agents in Drug-Induced Blepharospasm
Drug-induced blepharospasm is most commonly associated with neuroleptics, as well as dopaminergic agents, antihistamines, calcium-channel blockers, and noradrenalin and serotonin reuptake inhibitors29, 32-35. Prolonged administration of benzodiazepine or thienodiazepine derivatives can also induce blepharospasm34. In some anxiolytics, the gradual reduction under close monitoring led to improve the motor symptom of blepharospasm [unpublished data]. The effect of psychotropic cessation was variable, however, it can benefit some patients. Physicians should consider reducing the psychotropic medication as far as possible in patients with blepharospasm on psychotropic agents.

Surgical Treatments
Patients who respond poorly to BoNT injections are candidates for surgical treatment6, 8. 1.3 ~ 14% of EB patients undergo surgical treatment36-38. Many surgical procedures including orbicularis myectomy, facial nerve avulsion, frontal sling/ suspension have been tried to ameliorate the motor symptoms8. The upper eyelid myectomy is often performed with postoperative BoNT injections28. The levator aponeurosis is tightened to help elevate the eyelids, and in cases of AEO a frontalis suspension may be required28. Facial nerve avulsion has a high recurrence rate and untoward side effects and is therefore at best useful in selected patients37. Dermatochalasis, ptosis and other eyelid deformities can be corrected at the time of surgery28. Therapy should be tailored to the patients’ manifestations and needs, and many patients benefit from combining all available treatments28.

Myectomy
Most authors recommend first only upper eyelid myectomy21, 37, 39, 40. The procedure was developed by Anderson before clinical use of BoNT injections. It is generally available and involves the complete removal of the orbicularis, corrugator superciliaris and procerus muscles37. 64~88% of patients noted an improvement8, 21, 38, 40. The complications are periorbital ecchymosis, hematoma, swelling and chronic lymphedema of the periorbital region, numbness of the forehead and exposure keratopathy37. Following the surgery, 46~66% of patients require additional BoNT injections40, 41. Postoperative BoNT injections are more effective and wear off less quickly, but injections may be more painful because of scarring37.

Frontal Suspension
Another surgical approach is frontalis suspension37. Frontalis suspension is a proven method for ptosis with poor levator function37. In patients with ptosis or AEO, attempted eye opening result in overaction of frontalis muscle. This led to the idea of frontalis suspension37. 73~91% of patients reported an improvement after surgery37, 38. About 4% of patients show no sufficient effect37. The effect of surgery generally remained stable over the years, with most patients needing postoperative BoNT injections37. In complication, there were postoperative corneal keratitis or erosion (7%) due to incomplete eyelid closure that can be successfully treated with ointments, and suture granulomas or extruded suture material (7%) that can be surgically removed37.

Other Therapies for the Motor Symptoms
There are some case reports on Meige syndrome successfully treated with deep brain stimulation (DBS) 42, 43. DBS is an effective treatment for medically intractable dystonia, including primary generalized dystonia, myoclonic dystonia, and cervical dystonia42, 43.
In repetitive transcranial magnetic stimulation (rTMS) over the anterior cingulate cortex, there is a randomized, sham-controlled, observer-blinded prospective study in 12 EB patients44. rTMS improved clinical symptoms of EB (blink rate, number of spasms rated by a blinded physician and patient rating) immediately and 1 hour after stimulation without adverse events44.
DBS and rTMS could be used as a therapeutic tool in EB. Further studies will be necessary.

Therapies for the Sensory Symptoms

Therapy for Dry Eye and Photophobia
Physiologic studies on EB reported trigeminal sensitization45, 46 that can be associated with ocular irritation. Many patients complain of dry eye and it can coincide with EB because of abnormal blinking. However, slit lamp examination often shows less findings than the frequency of complaints6, Aggressive treatment of dry eye syndrome with eye drops and/or punctual plugs can often ameliorate eye pain or discomfort in EB. In photophobia, 71% of EB patients reported the greatest symptomatic relief of photophobia with the FL-41 lens that filters well <400 nm, and moderately between 400 and 550 nm47. In conclusion, the mainstay of treatment for the motor symptom of EB is BoNT injection. The scientific data show its long-term safety and efficacy. Several drugs have been reported to be effective, but their efficacy is limited and temporary in most cases. Drug-induced blepharospasm is associated with various psychotropic agents, and the gradual reduction under close monitoring can improve the symptom. Physicians should consider reducing the psychotropic medication as far as possible in patients with blepharospasm on psychotropic agents. Patients who do not respond to BoNT injections are candidates for surgical treatment. Generally, orbicularis myectomy is recommended first. Frontalis suspension may help in cases of AEO. Lid crutches are another option to AEO. These surgeries are of benefit to the patients without severe complications, but postoperative BoNT injections are often necessary. Therapies for the sensory symptoms including ocular irritation and dry eye are eye drops and punctual plugs. FL-41 lens is effective for photophobia in EB. References 1. Dutton JJ: Botulinum-A toxin in the treatment of craniocervical muscle spasms: short- and long-term, local and systemic effects. Surv Ophthalmol 41:51-65, 1996 2. Mauriello JA Jr, Dhillon S et al: Treatment selections of 239 patients with blepharospasm and Meige syndrome over 11 years. Br J Ophthalmol 80:1073-1076, 1996 3. Costa J, Espirito-Santo C et al: Botulinum toxin type A therapy for blepharospasm. Cochrane Database Syst Rev 25:CD004900, 2005 4. Naumann M, Albanese A et al: Safety and efficacy of botulinum toxin type A following long-term use. Eur J Neuro 13:35-40, 2006 5. Simpson DM, Naumann M et al: Practice Parameter: Botulinum neurotoxin for the treatment of movement disorders and spasticity: an evidence-based report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 70:1699-1706, 2008 6. Hallett M, Evinger C et al: Update on blepharospasm: Report from the BEBRF International Workshop. Neurology 71:1275-1282, 2008 7. Hallett M, Robert BD: Blepharospasm: Report of a workshop. Neurology 46:1213-1218, 1996. 8. 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Chapman KL, Bartley GB et al: Follow-up of patients with essential blepharospasm who underwent eyelid protractor myectomy at the Mayo Clinic from 1980 through 1995. Ophthalmol Plast Reconstr Surg 15:106-110, 1999 42. Capelle HH, Weigel R et al: Bilateral pallidal stimulation for blepharospasm-oromandibular dystonia (Meige syndrome). Neurology 60:2017-2018, 2003 43. Houser M, Waltz T: Meige syndrome and pallidal deep brain stimulation. Mov Disord 20:1203-1205, 2005 44. Kranz G, Shamim EA et al: Transcranial magnetic brain stimulation modulates blepharospasm. Neurology 75:1465-1471, 2010 45. Nguyen QT, Kleinfeld D: Positive feedback in a brainstem tactile sensorimotor loop. Neuron 45:447-457, 2005 46. Quartarone A, Sant’Angelo A et al: Enhanced long-term potentiation-like plasticity of the trigeminal blink reflex circuit in blepharospasm. J Neurosci 26:716-721, 2006 47. Herz NL, Yen MT: Modulation of sensory photophobia in essential blepharospasm with chromatic lenses. 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