A case report of psychoactive drugs aggravating and alleviating Meige syndrome

Shimiao ZHAO, Yingchun ZHANG, Luoyi XU, Lili WEI, Wei CHEN,*

·Case report·

A case report of psychoactive drugs aggravating and alleviating Meige syndrome

Shimiao ZHAO1,2, Yingchun ZHANG1, Luoyi XU1, Lili WEI1, Wei CHEN1,*

psychoactive drug; Meige syndrome; clonazepam; eszopiclone

1. Case history:

Miu was a sixty-one-year-old housewife. With her daughter’s accompany, she came to the department of mental health in our hospital on 22ndSeptember, 2014,because she had had discomfort in her eyes for two years and trouble sleeping for two months. Without any obvious cause, she began to have foreign body sensation in her eyes, photophobia, and blurred vision two years ago. Yet, she did not feel weak or dry. She was treated with artificial tears as she was diagnosed with xeroma when she went to the county hospital last year;however, her condition was not improved. After that,she was tested for the anti-nuclear antibody spectrum,the break up time of tear film, Schirmer test and so forth, and xeroma was excluded. In the meantime, she kept receiving treatment for xeroma, but the effect was not significant. One year ago, her eyes started to blink involuntarily. It happened occasionally at first,and then it became frequent gradually. Sometimes it was accompanied by twitches of cheek and mouth as well. This condition was relatively mild in morning, but the frequency increased in afternoon. Her MRI results showed no significant abnormalities when she went to the department of neurology in the local hospital;therefore, there was no exact diagnosis for her. She was given Tiapride Hydrochloride tablets 100mg per night for more than three months, but the blinking and twitching conditions were not improved obviously;moreover, she was sleepy often. Two months ago, she started having trouble falling asleep, and becoming intense and anxious after she stopped taking Tiapride Hydrochloride tablets. At this point, her highest blood pressure reached 138/110 mmHg, and her insomnia was not improved after two days of acupuncture treatment.The local department of mental health admitted her to the hospital as an anxiety disorder patient, and treated her with clonazepam intravenous infusion 0.5mg per day, paroxetine tablets 30mg per day, clonazepam tablets 0.5mg per night and haloperidol tablets 2mg per night. Her sleeping and anxiety conditions were improved after treatment; however, the blinking aggravated on the third or fourth day after she was admitted into the hospital. Her eyes were like a crack,and she could not open them for a long time. She left the hospital after more than 20 days. Shortly after she went home, her body started to shake, and she became restless and anxious. Later when she went to the local hospital’s mental health department, her treatment strategy was switched to taking escitalopram tablets(Lexapro) 10 mg per day and olanzapine tablets (Zyprexa)1.25-3.75 mg per night. Restlessness and anxiety were improved; while the blinking was not alleviated.During this period of time, she took olanzapine tablets only for a month due to her difficulty in tolerating the gastrointestinal side effects of escitalopram tablets.But still, the blinking and having trouble in opening eyes were not improved. In the recent two months, the patient’s normal life has been compromised by the fact that she needs to pull her eyelids up with hands while she walks. She was not able to ride bikes, cook or so on, and she is also timid, intense, worried easily, and negative. She wanted to inject botox to treat the eyelid spasm in our hospital’s botox specialist outpatient clinic.Bur considering her emotion might aggravate the eyelid spasm, she was advised to be admitted into the hospital after a consultation in mental health department.Past history: she received a hemorrhoid surgery and recovered well 20 years ago; a gastroscopy in 2013 showed that she had duodenal ulcer, and she had discomfort in her stomach often; a colonoscopy showed rectal erosion. She denied any history of trauma on her head and face. Personal history: the second child, poor health condition in childhood, outgoing and stubborn;junior middle school education; retired; Yingxingdamo needle allergy history. Obstetrical history: 15 (3-4/30)(menopause at 50 years old); one daughter; widowed 8 years ago; her husband died of liver cancer, and she denied any bereavement reaction. Family history: her father died of infarction, and her mother and younger brother are healthy. Examination: double eyelid spasm,involuntary eyes closed, paroxysmal double eyelid twitching, normal vision and visual field, no diplopia or strabismus, functional blindness, twitches of the cheek and mouth; the left side was more obvious, but there were no significant positive symptoms. Mental health examination: clear consciousness, normal orientation,coherent thinking, no delusions, secondary anxiety which was mainly the concern for double eyelid spasm.She denied any concern about the future. There was no significant abnormality of her act of will, while her social function was obviously impaired, but this was secondary to double eyelid spasm. Her insight was intact. After she was admitted into the hospital, the nurse noticed that the eyelid spasm was absent during her sleep.There was no significant abnormality of MRI and thyroid function results.

2. Diagnosis

Based on the patients’ medical history and clinical characteristics (61 years old female; developed double eyelid spasm, twitches of mouth and cheek;no abnormal MRI of her head or thyroid dysfunction;no facial trauma history), the diagnosis was Meige syndrome, and the aggravation of the conditions were related to the psychoactive drugs. Differential diagnosis:1) Xeroma: xeroma was ruled out by immunological tests and eye examinations, moreover, the patient did not experience any dry sensation of her eyes, which suggested that the prerequisite of xeroma was absent.2) Myasthenia gravis: the main symptoms were eyelid weakness and blepharoptosis, while the patients’symptoms were muscle spasm of eyelids and mouth,so we did not consider Myasthenia gravis. After three days of living in the hospital, the patient’s eyelid spasm aggravated suddenly. Her condition developed more quickly than what Meige’s syndrome’s regular pattern is. So we needed to consider the following factors: 1)Generalized anxiety disorder: the patient was intense and anxious, but it only limited to the concerns about her medical condition. She wasn’t anxious about the future or unspecific subjects. So we did not consider generalized anxiety disorder. 2) Adverse drug reactions:The spasm of eyelids aggravated after three days in hospital, so we considered that it was related to drugs used.

3. Treatment

The patient stopped taking olanzapine tablets and escitalopram tablets, and started to take eszopiclone tablets 3 mg/qn only after she was admitted. The eyelid spasm alleviated gradually, and it was improved significantly after a week. The patient stated: “Basically,I don’t blink uncontrollably, and I am like how I was when I was normal.” But the patient was still anxious mildly, and only had 4-5 hours of sleep a day. In order to improve her sleeping condition, her treatment was changed into taking clonazepam tablets 10 mg/qn,because adding eszopiclone tablets’ dose to the elders raise the risk. The patient felt blepharoptosis and having trouble opening eyes the next day. So she started to take eszopiclone tablets 3 mg/d again. Three days later, the conditions of eyelids were improved; five days later, they were alleviated obviously. The spasm was not serious in the morning any more. Closing eyes and twitches still occurred in the afternoon, but the degree and duration were clearly alleviated compared to those before. The anxiety was absent, and she checked out of the hospital on 5thOctober, 2014. When she paid a return visit a week later, the eyelid spasm was not obvious, and it did not affect her life. The botox outpatient clinic in the department of neurology did not recommend her to take the botox injection. Keeping taking eszopiclone tablets 3 mg/d for more than two months, she did not have obvious eyelid spasm, but she could not tolerate the nausea. After she stopped taking the eszopiclone tablets, her eyelid spasm relapsed. In the local mental health hospital, she was prescribed with “lorazepam tablets and flupentixol and melitracen tablets” which did not improve her condition. Her condition aggravated,and she could barely open her eyes again. On 27thJuly 2015, she went to our department of neurology to have the botox injection. She is not taking psychoactive drugs currently, such as “lorazepam tablets and flupentixol and melitracen tablets”. Her blinking symptom is absent,and she does not have any discomfort in her eyes. In addition, she does not have symptoms like anxiety and insomnia.

4. Discussion

Meige’s syndrome is a kind of focal dystonia disease,and it was first reported by French neurologist Meige in 1910. The main symptoms are double eyelid spasm and facial involuntary movements, and it is also called blepharospasm-oromandibular dystonia[1]. Marsdan[2]classified it into three types: (1) blepharospasm (BS):the symptoms are eyelid paroxysmal involuntary spasm or involuntary blinking. (2) blepharospasm with oromandilular dystonia (BS-OMD): the patients have eyelid spasm, and in the meantime, they also experience twitches of cheek and mouth, which appear as pouting,pulling back lips, opening mouth, sticking the tongue out and involuntary twitches of the mouth and face. The patient have strange expressions. (3) oromandibular dystonia (OMD): the symptom is limited to the twitches of mouth and cheek.

Meige’s syndrome usually starts to appear when people are 50 to 60, but there are teenage patients as well. It is more common in females. The ratio of the number of male and female patients is 1:3[3-4]. Double eyelid spasm is the most common symptom of this disease, and eyelid weakness and blepharoptosis are also quite common. A few patients’ first symptom is intense facial tension. It gradually develops to be unable to complete missions depending on vision.Patients with severe conditions could have functional blindness. The patient in this case had developed to be functionally blind with eyelid and lower facial muscle spasm. Therefore, the diagnosis was BS-OMD. The blinking condition disappearing after the botox injection supports the Meige’s syndrome diagnosis.

When Meige’s syndrome’s initial symptoms are not typical, it should be differentiated from xeroma[5-6]. The eyes’ surfaces of patients with Xeroma are impaired by low tear secretion and bad stability of tear firms. It is easy to confuse xeroma with eyelids spasm, as xeroma’s symptoms are dry eyes, burning sensation, increasing scardamyxis and so forth. Supplementary inspection methods include the break up time of tear film, Schirmer test and corneal fluorescein staining. The clinical inspection emphasizes the self-reported symptoms. The patient in this case did not suffer from clear dry eyes during two years of curse of decease, and the increasing scardamyxis was due to the uncontrollable muscle twitches instead of dry eyes. Artificial tears can improve dry eyes and reduce scardamyxis, but the patient’s bilinking was not alleviated after being treated with artificial tear. Therefore, xeroma was not considered.This patient was misdiagnosed with xeroma at first, and was treated with ophthalmology methods after xeroma was ruled out with being diagnosed in time. So this led to the indiscreet use of psychoactive drugs.

Primary Meige’s syndrome’s nosogenesis is unclear;while secondary Meige’s syndrome could be related to the upper brain stem and abnormal basal ganglia dopamine receptor hypersensitivity, the hyperactive cholinergic nervous system (e.g., basal ganglia), low Gamma-aminobutyric Acid (GABA) function. But it is not simply about the function of dopamine, acetylcholine and GABA, it is also about the imbalance[7]. One third of the people with Meige’s syndrome have emotion disorder[8], and the symptoms are anxiety, depression and sleeping disorder. Moreover, the symptoms are aggravated when the patients are intense; so it is easy to misdiagnose. When the patients’ emotion conditions need to be treated, the medicine for improving emotion could affect the neurotransmitters described above,thereby affecting the symptoms of Meige’s syndrome.

Currently, the drugs for Meige’s syndrome include anticholinergics (e.g. Trihexyphenidyl), GABA’s receptor agonist (e.g. Benzodiazepine class of drugs), dopamine antagonist (e.g. Tiapride), antiepileptics (e.g. VPA)and so on. The majority is psychoactive drugs. Their effect is average, but they have many side effects[9].Botox injection is applied extensively in the clinical treatment, and it has positive effects. But it also loses its effect gradually, and leads antibody production and therapeutic resistance[10]. Stereotactic surgery is applied in neurosurgery, but it does not have ideal effects either[11]. Recent reports have mentioned that globus pallidus deep brain stimulation (GBS) is affective and has less side effects, but the research with large samples and follow-ups is still needed[12].

This patient used dopamine antagonist Tiapride,but it was of no effect. After she stopped taking Tiapride, she began to have significant anxiety. Her eyelid spasm was worsened after she started taking Clonazepam (i.e., GABA’s receptor agonist), Paroxetine(i.e., anti-acetylcholine) and Haloperidol (i.e.,dopamine antagonist). The later treatment also had the phenomena that using Olanzapine and Escitalopram together or using Lorazepam and Deanxit together aggravated symptoms. It is possible that these drugs affect acetylcholine, GABA and dopamine and lead to the imbalance of acetylcholine, dopamine and serotonin. Even though it is uncertain that which drug aggravates the symptoms, it suggests that joint uses might affect Meige’s syndrome’s symptoms. The later treatment which was using Nitrazepam or Olanzapine only also worsened eyelid spasm. The temporal relationship was clear, so Nitrazepam and Olanzapine were suspected to aggravate Meige’s syndrome. After she took Eszopiclone twice, her eyelid spasm symptom was basically gone. Her condition was better compared to when she was not taking any psychoactive drugs.After she stopped taking Eszopiclone, her eyelid spasm became worse. Therefore, Eszopiclone was suspected to be effective at treating this patient’s eyelid spasm.

Using antipsychotics drugs for a long period of time could cause eyelid spasm, which is secondary Meige’s syndrome. Its possible nosogenesis is the hypersensitivity of the basal ganglia dopamine receptor.Increasing the dose of antipsychotics can alleviate the symptoms. Despite eyelid spasm caused by atypical antipsychotics is rarer than by typical antipsychotics,it has been reported that the usage of olanzapine can worsen the eyelid spasm condition, most likely associated with the effects of the anti-DA and anticholinergic qualities of olanzapine on basal ganglia[13-14].It was reported that clonazepam activated GABA receptors could inhibit basal ganglia circuitry for Meige Syndrome treatment[15]. Nitrazepam and clonazepam have similar mechanisms, showing worsened eyelid spasm condition in the case patient. On the other hand,eszopiclone alleviates the eyelid spasm condition.Eszopiclone reacts with benzodiazepines(ω1 and ω2 receptors) at the specific binding sites of the GABA receptor complex. Nitrazepam reacts on even more subunits of the benezodiaqepines receptors, predicting that activation of the ω1 and ω2 receptor could possibly alleviate the eyelid spasm symptom, whereas activations of the other subunit could aggravate the symptoms. Patients with Meige syndrome that had no effects from the usage of clonazepam, benzhexol,baclofen, and intramuscular injection of botulinum toxin found zolpiden effective, reported from Miyazaki. The highly selective binding nature of zolpiden to GABAω1 receptor might play a role in the effectiveness.

In conclusion, this case study suggests that specific GABA receptor activators can help alleviate symptom of blepharospasm with oromandilular dystonia in Meige syndrome. One should be cautious when taking up mixed psychotic medications for improving the emotional symptoms engendered. Nitrazepam and olanzapine are likely to aggravate eye spasm;therefore, one should use them cautiously with careful observation.

Acknowledgement

We sincerely give our greatest gratitude to the reviewers of this case study.

Funding

The study is funded by the Zhejiang Medical Technology Project (project number: 2016KYB3).

Conflict of interest

The authors declared no conflict of interest related to this manuscript.

Informed consent

The participant signed the informed consent allowing us to publish this case study

Author contributions

The correspondence author of this article is the lead physician of the patient, who was responsible for the diagnoses and treatments of the patients as well as the verification and revision of this article. The first author is the treating physician of the patient, who took up the work of data collection, follow-ups, and article writing.Yingchun Zhang, Luoyi Xu, and Lili Wei were also the treating physician.

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Shimiao Zhao graduated from the Department of Clinical Medicine, Wenzhou Medical University in 2005. Now she is working on the Master program at Zhejiang University. Since 2005, she has started to work at the Department of Psychiatry and Psychosomatic in the Seventh People’s Hospital, Shao Xin. Her research interest includes psychosomatic disorder.

精神藥物加重及減輕美格綜合征一例

趙世苗 章迎春 許洛伊 魏麗麗 陳煒

精神藥物、美格綜合征、硝西泮、右佐匹克隆

The present case report described a 61-year-old female patient who was diagnosed as Meige syndrome with double eyelid spasm, anxiety and insomnia. After she was treated with psychoactive drugs, it was found that clonazepam tablets in the benzodiazepine class and dopamine antagonist olanzapine tablets aggravated double eyelid spasm; while eszopiclone tablets as a specificity γ-aminobutyric acid receptor binding drug alleviated this condition. The present case suggests that psychoactive drugs have both positive and negative effects on treating Meige syndrome. As for the patients who also have emotion disorder, their conditions should be observed carefully when choosing which psychoactive drug to use. The specificity γ-aminobutyric acid receptor binding drugs should be the prime choice, such as eszopiclone.

[Shanghai Arch Psychiatry. 2016; 28(4): 222-226.

http://dx.doi.org/10.11919/j.issn.1002-0829.216038]

1Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medical, and the Collaborative Innovation Center for Brain Science,Hangzhou, Zhejiang, China

2The Seventh People’s Hospital, Shaoxing, Zhejing, China

*correspondence: Dr. Chen Wei. Mailing address: No.3 East Qingchun Road, Hangzhou, Zhejiang, China. Postcode: 310016. E-Mail: srrcw@zju.edu.cn

概述：本病例報告描述了一女性患者，61歲，雙眼瞼痙攣，診斷美格綜合征(Meige syndrome)，伴焦慮失眠癥狀，使用精神藥物治療時發現，苯二氮卓類藥物硝西泮片、多巴胺拮抗劑奧氮平片加重眼瞼痙攣，特異性γ-氨基丁酸受體結合藥物右佐匹克隆片則減輕眼瞼痙攣。本病例提示精神藥物對美格綜合征的影響存在正面與負面的差異，對伴發情緒障礙的患者，在選用精神藥物治療時應仔細觀察評估病情，首選特異性γ-氨基丁酸受體結合的藥物，如右佐匹克隆。