Re: 안구운동을 담당하는 3,4,5,6 cranial nerve palsy 회복 85% ..nature

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The 12 cranial nerves include the:

• olfactory nerve
• optic nerve
• oculomotor nerve 3
• trochlear nerve 4
• trigeminal nerve 5
• abducens nerve 6
• facial nerve
• vestibulocochlear nerve
•  
• glossopharyngeal nerve
• vagus nerve
• accessory nerve
• hypoglossal nerve

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Clinical features and natural history of acquired third, fourth, and sixth cranial nerve palsy

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• Clinical Study
• Published: 09 February 2007

Clinical features and natural history of acquired third, fourth, and sixth cranial nerve palsy

• U-C Park, 
• S-J Kim, 
• J-M Hwang & 
• Y S Yu 

Eye volume 22, pages691–696 (2008)Cite this article

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Abstract

Purpose

Clinical features of acquired third, fourth, and sixth cranial nerve palsy showed variation among previous studies. Eval‎uation of natural course with objective criteria will establish accurate recovery rates and important factors for recovery.

Methods

Retrospective chart review was performed on 206 patients who visited a neuro-ophthalmic department with acquired third, fourth, and sixth nerve palsy. Aetiology and results of ocular exam on each visit were reviewed, and multivariate logistic regression analysis was performed to identify independent factors affecting recovery.

Results

The sixth cranial nerve was affected most frequently (n=108, 52.4%) and vascular disease (n=64, 31.1%) was the most common aetiology. Recovery was eval‎uated with change of deviation angle for 108 patients, who were first examined within a month of onset and followed up for at least 6 months. Ninety-two (85.2%) patients showed overall (at least partial) recovery and 73 (67.6%) showed complete recovery. In univariate analysis, initial deviation angle was found to be only significant factor associated with complete recovery (P=0.007) and most patients who experienced successful management of treatable underlying disease showed recovery.

Conclusions

With objective criteria based on deviation angle, overall recovery rate from the third, fourth, and sixth nerve palsy was 85.2%. Patients who had smaller initial eyeball deviation or successful management of treatable underlying disease had a high chance of recovery.

요약

목적

후천성 제3, 제4, 제6 뇌신경 마비의 임상적 특징은 이전 연구들 간에 차이가 있었습니다. 객관적인 기준을 통한 자연적 경과에 대한 평가는 정확한 회복률과 회복에 중요한 요인을 확립할 것입니다.

방법

후향적 차트 검토는 후천성 제3, 제4, 제6 신경 마비로 신경안과를 방문한 206명의 환자를 대상으로 실시되었습니다. 각 방문 시의 병인 및 안구 검사 결과를 검토하고, 회복에 영향을 미치는 독립적인 요인을 파악하기 위해 다변량 로지스틱 회귀 분석을 실시했습니다.

결과

여섯 번째 뇌신경이 가장 자주 영향을 받았고(n=108, 52.4%),

혈관 질환(n=64, 31.1%)이 가장 흔한 병인이었습니다.

회복은 발병 후 1개월 이내에 처음 검사를 받고

최소 6개월 동안 추적 관찰한 108명의 환자의 편차 각도 변화로 평가했습니다.

92명(85.2%)의 환자가 전반적인(적어도 부분적인) 회복을 보였고, 73명(67.6%)이 완전한 회복을 보였습니다. 일변량 분석에서 초기 편차 각도는 완전한 회복과 관련된 유의한 요소로 밝혀졌으며(P=0.007), 치료 가능한 기저 질환의 성공적인 관리를 경험한 대부분의 환자가 회복을 보였습니다.

결론

편차 각도를 기준으로 한 객관적인 기준에 따르면,

제3, 제4, 제6 신경 마비 환자의 전체 회복률은 85.2%였습니다.

초기 안구 편차가 작거나 치료 가능한 기저 질환을 성공적으로 관리한 환자는 회복 가능성이 높았습니다.

Introduction

The third, fourth, and sixth cranial nerves participate in eyeball movement by extraocular muscle control. Acquired palsy of these nerves can result from various causes such as trauma, vascular disease, intracranial tumours, or aneurysm, and so on. The largest report from the Mayo Clinic, which included 4278 patients over 30 years, identified sixth nerve palsy and undetermined cause as having the highest preval‎ence.1 However, other studies showed variety in the aetiology and affected nerve distribution and wide range of recovery rates.1, 2, 3, 4, 5, 6 The recovery from cranial nerve palsy is thought to have to do with its aetiology, but there have been rare attempts to identify the factors affecting recovery.1, 4, 5, 6 We therefore performed this retrospective study to analyse the clinical features and natural history of acquired third, fourth, and sixth cranial nerve palsy and identify the factors affecting its recovery.

소개

세 번째, 네 번째, 여섯 번째 뇌신경은

안구 근육을 제어하여

안구 운동을 담당합니다.

이 신경의 후천성 마비는

외상, 혈관 질환, 두개 내 종양, 동맥류 등

다양한 원인에 의해 발생할 수 있습니다.

메이요 클리닉의 가장 큰 보고서(30년 동안 4,278명의 환자를 대상으로 한)에 따르면,

6번 신경 마비와 원인을 알 수 없는 경우가

가장 높은 유병률을 보였습니다.1

그러나 다른 연구에서는 병인과 영향을 받는 신경 분포가 다양하고 회복률도 매우 다양하다는 사실이 밝혀졌습니다.1, 2, 3, 4, 5, 6 뇌신경 마비 회복은 병인과 관련이 있는 것으로 여겨지지만, 회복에 영향을 미치는 요인을 규명하려는 시도는 드물었습니다.1, 4, 5, 6

따라서

저희는 후천성 제3, 제4, 제6 뇌신경 마비의 임상적 특징과 자연사를 분석하고

회복에 영향을 미치는 요인을 규명하기 위해 이 후향적 연구를 수행했습니다.

Patients and methods

All outpatients who directly visited or were referred from local ophthalmic practitioners to the neuro-ophthalmic service or strabismus service at ophthalmology department of Seoul National University Hospital for diplopia, blepharoptosis, or ocular motor restriction, and diagnosed with acquired third, fourth, and sixth cranial nerve palsy from July 1998 to February 2005 were included. Institutional Review Board Ethics Committee approval was obtained for this study, and it was carried out in adherence to the tenets of the Declaration of Helsinki. The patients’ age of onset, sex, and previous medical history, especially the presence of vascular risk factors (diabetes, hypertension, ischaemic heart disease, vascular disease) were noted. The degree of ocular motor restriction in the worst motion direction, the deviation angle at each visit, the presence of other related ophthalmic or neurological signs, and the results of neuroradiological tests were also recorded. Deviation angle was measured with the simultaneous prism and cover test in the primary position at distance fixation.

As in the Mayo Clinic series, cases were categorized into six aetiological groups according to the authors’ best judgment: vascular, trauma, neoplasm, aneurysm, undetermined, or ‘other’.1, 2, 3, 4 Vascular cases were defined as having at least one vascular risk factor (diabetes, hypertension, ischaemic heart disease, or peripheral vascular disease) without trauma history or evidence of aneurysm or neoplasm in image studies. ‘Other’, or miscellaneous, causes included complications of neurosurgical procedures and other systemic syndromes or diseases related to the cranial nerve function. Congenital cases and other conditions that mimic cranial nerve palsy, such as orbital wall fracture, myasthenia gravis, and thyroid orbitopathy, were excluded. For the fourth cranial nerve palsy, history of head tilt dating back to infancy, definite facial asymmetry, amblyopia in the palsied eye, large vertical fusional amplitudes more than 10 prism dioptres (PD) were considered to be signs of congenital palsy and patients with any of these were excluded from the study.

The natural history of cranial nerve palsy was eval‎uated only in patients who received their first ocular exam within a month of palsy onset and followed for at least 6 months. We classified recovery at each follow-up visit as complete recovery, partial recovery, or persistence based on deviation angle and ocular motor restriction. Complete recovery was defined as the complete recovery of the angle of deviation, ocular motor restriction, and diplopia. Partial recovery was defined as a decrease in deviation angle by more than 10 PD from initial examination as measured in the primary position. For patients with an initial deviation angle of less than 10 PD, a decrease by more than 50% of the initial deviation angle was scored as partial recovery. Horizontal and vertical deviation angles in the primary position in fourth nerve palsy patients were much smaller than the general deviation angles of the third or sixth nerve palsy patients, even in the most severe cases. Therefore, in the fourth nerve palsy patient, a disappearance or decrease in the vertical deviation angle exaggerated with the head tilt test was used for the determination of recovery. Persistence was defined as the absence of total and partial recovery or cases that underwent extraocular muscle surgery. Baseline characteristics of the patients with complete recovery were compared to those without complete recovery by the t-test or χ2 test. Statistical analysis was performed with SPSS for Windows (version 12.0) and P-values less than 0.05 were considered significant.

환자 및 방법

1998년 7월부터 2005년 2월까지 서울대학교병원 안과에서 직접 방문하거나 지역 안과 의사의 소개를 통해 안과 신경과 또는 사시 서비스에 방문한 모든 외래 환자를 대상으로, 복시, 안검하수 또는 안구 운동 제한으로 진단받고 후천성 제3, 제4, 제6뇌신경 마비로 진단받은 환자를 포함했습니다. 이 연구는 기관 검토 위원회 윤리위원회의 승인을 받았으며, 헬싱키 선언의 원칙을 준수하여 수행되었습니다. 환자의 발병 연령, 성별, 이전 병력, 특히 혈관 위험 요인(당뇨병, 고혈압, 허혈성 심장 질환, 혈관 질환)의 유무를 기록했습니다. 최악의 움직임 방향에서 안구 운동 제한 정도, 방문 시마다의 편차 각도, 기타 관련 안과적 또는 신경학적 징후의 유무, 신경 방사선학적 검사 결과도 기록되었습니다. 편차 각도는 원거리 고정 상태에서 동시 프리즘 및 커버 테스트를 통해 측정되었습니다.

메이요 클리닉 시리즈에서와 마찬가지로, 저자의 최선의 판단에 따라 혈관, 외상, 종양, 동맥류, 미확인 또는 '기타'의 여섯 가지 원인 그룹으로 분류되었습니다.1, 2, 3 4 혈관 질환은 외상 병력이나 영상 검사에서 동맥류 또는 신생물의 증거가 없는 상태에서 최소 한 가지의 혈관 위험 인자(당뇨병, 고혈압, 허혈성 심장 질환 또는 말초 혈관 질환)를 가진 것으로 정의됩니다. '기타' 또는 기타 원인은 신경외과적 시술의 합병증과 두개골 신경 기능과 관련된 기타 전신 증후군 또는 질병을 포함합니다. 선천성 사례와 안와벽 골절, 중증 근무력증, 갑상선 안와병증과 같은 두개골 신경 마비를 모방하는 기타 상태는 제외되었습니다. 제4뇌신경 마비의 경우, 유아기부터 머리를 기울이는 습관이 있고, 얼굴이 뚜렷하게 비대칭이며, 마비된 쪽 눈의 약시가 있고, 수직 융합 진폭이 10 프리즘 디옵터(PD) 이상인 경우를 선천성 마비의 징후로 간주하여 이러한 증상이 있는 환자는 연구에서 제외했습니다.

뇌신경 마비의 자연적 경과는 마비 발병 후 한 달 이내에 안과 검사를 처음 받은 환자들 중에서 최소 6개월 동안 추적 관찰을 받은 사람들만 대상으로 평가되었습니다. 추적 관찰 방문 시 회복 정도를 편차 각도와 안구 운동 제한 정도에 따라 완전 회복, 부분 회복, 지속으로 분류했습니다. 완전한 회복은 편위각, 안구 운동 제한, 복시의 완전한 회복으로 정의됩니다. 부분 회복은 초기 검사에서 측정한 편위각이 주 위치에서 10 PD 이상 감소한 것으로 정의됩니다. 초기 편위각이 10 PD 미만인 환자의 경우, 초기 편위각의 50% 이상 감소가 부분 회복으로 점수화됩니다. 제4신경마비 환자의 주요 위치에서의 수평 및 수직 편차 각도는 가장 심한 경우를 포함하여 제3신경마비 또는 제6신경마비 환자의 일반적인 편차 각도보다 훨씬 작았습니다. 따라서 제4신경마비 환자의 경우, 머리 기울임 검사로 과장된 수직 편차 각도의 소실 또는 감소가 회복 여부를 판단하는 기준으로 사용되었습니다. 지속성은 전체 또는 부분 회복이 없거나 안구 근육 수술을 받은 경우로 정의되었습니다. 완치된 환자들의 기준 특성은 t-검정 또는 χ2 검정을 통해 완치되지 않은 환자들과 비교되었습니다. 통계 분석은 Windows용 SPSS(버전 12.0)를 사용하여 수행되었으며, p-값이 0.05 미만인 경우 유의한 것으로 간주되었습니다.

Results

A total of 206 patients were included in the study and all of them were Koreans. The distributions of affected nerve, gender, laterality, aetiology, and average onset ages of each group are summarized in Table 1. For entire 206 patients, average onset age was 48.1 years (range, 1–83 years), and the vascular group had the highest onset age (63.9 years). The sixth nerve was most commonly affected (n=108, 52.4%) and the vascular disease was the most common aetiology (n=64, 31.1%).

Table 1 Distribution of the third, fourth, and sixth cranial nerve palsy patients by age, gender, laterality, and aetiology

Full size table

The distribution of aetiologies within nerve groups showed similar distributions, except that there was no case of fourth nerve palsy caused by neoplasm or aneurysm, and that cases with ‘other’ aetiologies were more common in the sixth nerve palsy (20 of 108, 18.5%) than in the third or fourth nerve palsy. Neoplasm as the cause of cranial nerve palsy included multiple neuromas in neurofibromatosis type 2, brain stem glioma, juxtasellar meningioma, intracranial invasion of nasopharyngeal cancer, and posterior fossa epidermoid cyst. ‘Other’ causes included postoperative complications after neurosurgery, Miller–Fisher’s syndrome, herpes zoster ophthalmicus, meningitis occurring after nerve block, mild subarachnoid haemorrhage, Tolosa-Hunt syndrome, and Wegener's granulomatosis.

A total of 108 patients had their first ocular exam within a month of palsy onset and followed for at least 6 months. Of these, 92 patients (85.2%) showed at least partial recovery. Overall recovery (at least partial recovery) and complete recovery rates of each nerve group or aetiological group are shown in Table 2. Overall recovery rate was highest in patients with traumatic cause (100.0%), followed by vascular cause (86.7%) and undetermined cause (86.2%).

Table 2 Overall recovery (at least partial recovery), complete recovery rates, and initial deviation angle of each cranial nerve, and aetiological group for 108 patients, who had their first ocular exams within a month of palsy onset and at least 6-months follow-up

Full size table

Complete recovery was seen in 73 patients (67.6%) and their average time interval from onset to complete recovery of the angle of deviation and ocular motor restriction was 3.5 months (range, 1–13 months). Further subgroup analysis for 151 patients who was first seen within 3 months of onset revealed overall recovery rate of 71.5% (108 of 151) and complete recovery rate of 55.6% (84 of 151).

Of seven patients who underwent treatments for intracranial mass or aneurysm, such as gamma knife surgery, radiotherapy, or aneurysm embolization with detachable coil, only one patient with internal carotid aneurysm showed reduction in size after embolization and the third nerve palsy partially recovered. Although remaining patients did not show mass size reduction confirmed by image study after treatment, two patients with intracranial aneurysm and brainstem glioma, having initial eyeball deviation of less than 20 PD, showed recovery during their follow-up period. Of the patients with ‘other’ causes, most cases caused by inflammatory or infectious disease showed recovery after control of primary disease process, in spite of severe initial eyeball deviation larger than 40 PD.

Pupillary involvement was found in 15 patients, 13 of whom had the third nerve palsy. At final visits, only one patient showed complete resolution of pupillary defect after treatment of Tolosa–Hunt syndrome. Ptosis was found in 29 of 48 third nerve palsy patient (60.4%) and of the 15 patients who received first ocular exam within 3 months of onset, 12 (80%) showed recovery of ptosis.

In comparison between the patients with and without complete recovery, no significant differences were found in the gender, average onset age, palsied nerve, aetiology and ocular motor restriction (Table 3). Only deviation angle on first visit showed significant difference (P=0.007). Complete recovery pattern of 108 patients according to aetiology and deviation angle on the first visit is shown in the Figure 1 and patients with smaller deviation angle are more likely to completely recover across all the aetiological groups.

Table 3 Comparison between the patients with and without complete recovery for 108 patients who had their first ocular exams within a month of palsy onset and at least 6-months follow-up

Full size table

Figure 1

Complete recovery distribution of 108 patients who had their first ocular exams within a month of palsy onset and at least 6-month follow-up according to initial deviation angle and aetiology.

Full size image

Discussion

Our data confirmed the palsied nerve distribution reported in the previous studies, which usually found the sixth cranial nerve palsy as the most common, accounting for 40.0–57% of total cases and the fourth nerve palsy as the least frequent.1, 2, 3, 4, 5, 6 However, onset age of 48.1 was somewhat younger than 52.3 or 62.5 years of two reports, which included the three types of cranial nerve palsy altogether and described the onset age in detail.5, 6 In the previous studies, aetiology distributions were various: vascular, undetermined cause, and neoplasm have been reported to be the most common.1, 2, 3, 4, 5, 6, 7, 8 The most common aetiology had changed even along the four successive reports from the same institute.1, 2, 3, 4

This variety of the aetiology distribution may be attributable to ambiguous inclusion criteria for vascular cause. Differential diagnosis between a vascular and an undetermined aetiology may be challenging, and is usually based on the presence of vascular risk factors.5 In studies that considered only hypertension, diabetes, and ischaemic heart disease as vascular risk factors, vascular aetiology made up only 10.7–15.4% of total cranial nerve palsy patients.1, 2, 3, 4 However, 40% of patients were attributable to vascular aetiology in another study that adopted hyperlipidemia, smoking, findings of microangiopathy, or lacunar infarction on brain imaging as additional vascular risk factors.6 Despite the introduction of useful diagnostic tools such as MRI, undetermined cause still occupy 17.7–35% of total cranial nerve palsy patients even in the reports after 1990.1, 5, 6 In previous reports, recovery rates of patients with undetermined cause (51.0–84.0%) were similar to those of patients with vascular cause (70.9–100%) and greater than other aetiological groups, as is in our study.1, 4, 5, 6 This suggests that a large portion of the undetermined aetiology group might share a same cause with the vascular group, such a kind of microvasculopathy undetectable by laboratory and imaging tests.1, 5

We eval‎uated recovery only in 108 patients with their first ocular exam within 1 month of onset, and at least 6 months of follow-up. Patients with longer latency to their first exam might have experienced recovery during the intervening period, resulting in bias toward a lower recovery rate.9 Lower recovery rate in another subgroup analysis for 151 patients seen within 3 months of onset supports this idea. This also suggests that recovery starts as early as within 1 month of onset and those who were first seen between 1 and 3 month of onset might have less latent potentiality for further recovery than those seen within a month.

Previous studies reported the cranial nerve palsy recovery rates of 38.0–80%.1, 4, 5, 6, 10 Wide ranges of recovery rates is thought to result from variable criteria for recovery among the studies and criteria that are often not well defined. The use of objective criteria like ours, based on eyeball deviation and motor restriction in patients who visited the clinic shortly after onset, may be helpful to obtain more consistent recovery rates. In some studies, recovery data were collected using follow-up letters or telephone calls in certain patients, not by ophthalmologic exam, but this might have led to inaccurate recovery rates. As to referral pattern, because most of patients first seen at local ophthalmologic clinics were referred to us as soon as possible for brain image study, referral practice pattern is not thought to have had effect on our recovery results.

Univariate analysis revealed that the deviation angle on the first visit was the only significant factor affecting recovery. Holmes et al,11 in their study on treatment outcome of the sixth nerve palsy, also mentioned that patients who showed spontaneous recovery had smaller deviation angles, but they could not rigorously test their hypothesis because of small sample size. Although insignificant, vascular and undetermined groups showed higher overall recovery rate than other aetiological groups except trauma, as revealed in previous studies.1, 4, 5, 6 Overall recovery rate of 100% in trauma group might have resulted from that trauma patients seen within a month in this study had smaller deviation angle than others, as shown in Figure 1. However, aetiology is thought to have been confounding factors in previous studies. Our results show that vascular or undetermined groups have smaller initial eyeball deviation (Table 2). We postulate that lower recovery rates in grave aetiological groups in previous studies might have resulted from the larger initial deviation and motor restriction in these groups. Even patients with neoplasm recover well without treatment or mass size reduction if their initial deviations were small.

In addition to the initial deviation, successful management of treatable underlying disease is thought to be another factor affecting recovery from cranial nerve palsy. After size reduction of intracranial mass or aneurysm and after control of underlying inflammation and infection, severity of eyeball deviation, and motor restriction turned out to improve.

The results of this study are limited by its retrospective nature and relatively small sample size. However, this is the first study to eval‎uate the recovery of third, fourth, and sixth cranial nerve palsy with objective criteria based on deviation angle and to identify factors affecting recovery. With an attempt to minimize the bias toward a lower recovery rate, we observed overall recovery rate of 85.2% for the entire third, fourth, and sixth cranial nerve palsy. Our analysis suggests that deviation angle on first ocular examination and successful management of treatable underlying disease are important factors affecting recovery from cranial nerve palsy.

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