The etiologies of isolated fourth cranial nerve palsy: a 10-year review of 158 cases

To identify the etiologies of isolated fourth cranial nerve palsy in Ramathibodi hospital, Thailand. Patients diagnosed with isolated fourth nerve palsy from January 1, 2009, through July 31, 2020 in Ramathibodi Hospital, were included in this retrospective, observational case series. The demographic data of patients, age at presentation, the etiologies of isolated fourth nerve palsy and neuroimaging results (if indicated) were recorded. We identified 154 unilateral and 4 bilateral cases of isolated fourth nerve palsy. Mean age at presentation was 38.89 ± 25.71 years old. Most of the unilateral cases were congenital (57.79%), with microvasculopathy (27.92%), intracranial neoplasm (8.44%) and other etiologies. Trauma with closed head injury was the most common etiology of bilateral cases (75%), followed by ruptured arteriovenous malformation (25%). Twenty-one of the 43 (48.84%) patients with microvasculopathy fourth nerve palsy underwent neuroimaging, with normal findings, and all patients’ symptoms resolved within 6 months of symptom onset. In our series, most of the isolated fourth nerve palsy cases were congenital, followed in frequency by microvasculopathy and intracranial tumor, as in many studies. In cases of microvasculopathy, the clinical signs and symptoms resolved within 6 months in all cases: observation was sufficient, with no necessity for neuroimaging. However, neuroimaging should be considered in cases with atypical presentations, such as headache, periorbital pain, or if there is rapid progression or no recovery.

series in which trauma was the most common cause. Microvasculopathy also was a common etiology. Patients who have microvascular risk factors should be closely followed medically; neuroimaging should be performed only when there is progressive clinical diplopia or there is no recovery [3].
Owing to the various common etiologies in different studies, we aimed to determine the etiologies of isolated fourth nerve palsy in our hospital, and also to focus on the necessity of neuroimaging in this disease.

Methods
This retrospective study used an electronic medical record system to identify all cases of isolated fourth nerve palsy diagnosed from January 1, 2009, through July 31, 2020 at Ramathibodi Hospital, Thailand, a tertiary referral center. The study protocol was approved by the Human Research Ethics Committee Faculty of Medicine Ramathibodi Hospital, Mahidol University and adhered to the tenets of the Health Insurance Portability and Accountability Act and the Declaration of Helsinki.

Patients
Unilateral isolated fourth nerve palsy was defined as incomitant hypertropia, underaction of the superior oblique muscle with or without overaction of inferior oblique muscle, positive unilateral head tilt test or excyclotorsion with the double Maddox rod test less than 10°. Fundus photography was performed to confirm affected eye excyclotorsion.
Bilateral isolated fourth nerve palsy was defined as underaction of bilateral superior oblique muscle with or without overaction of bilateral inferior oblique muscle, alternating hypertropia on horizontal gaze or tilt, positive bilateral head tilt test, excyclotorsion with the double Maddox rod test more than 10°or a V-pattern esotropia of greater than 25 prism diopters. Fundus photography was performed to confirm bilateral excyclotorsion.
Exclusion criteria for all patients were: a history of orbital disorders; myasthenia gravis; multiple cranial nerves disorders; and nuclear and supranuclear disorders with other paretic or restrictive causes. All patients' medical records were reviewed, to confirm their diagnosis, and to identify the medical conditions and etiologies of the isolated fourth nerve palsy. We recorded the following: demographic data, age at presentation, and the etiologies of isolated fourth nerve palsy. Not every case was confirmed the diagnosis by neuroimaging. Atypical presentations of fourth nerve palsy, such as rapidly progressive diplopia, profound headache, periocular pain, and painful eye movements, were investigated by neuroimaging and reviewed.

Classification of etiologies of isolated cranial palsy
Congenital fourth nerve palsy was diagnosed based on the infant's photographs with facial asymmetry, or on a history of vertical misalignment or abnormal head posture, presence of large vertical fusional amplitudes (more than 5 prism diopters) [6,7] and absence of subjective torsion.
Traumatic fourth nerve palsy was defined as the presence of fourth nerve palsy following head trauma.
Microvasculopathy was defined as medical hypertension, diabetes mellitus, dyslipidemia, or a combination thereof, measured within 1 year before or after the onset of isolated fourth nerve palsy and requiring management. Laboratory investigations (complete blood count, fasting blood glucose and lipid profile) were performed. Hypertension was diagnosed using the criteria of the Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, that is, systolic or diastolic blood pressure elevated to more than 140/90 mm Hg on presentation [8]. Diabetes mellitus was defined using the 2020 American Diabetes Association criteria [9]. The criterion for a diagnosis of dyslipidemia was the presence of at least one of the following: more than 200 mg/dL total cholesterol, more than 130 mg/dL of low-density lipoproteins, or more than 150 mg/dL of triglycerides [10]. Patients with microvasculopathy were followed, and their diagnosis confirmed, when ocular misalignment resolved within 6 months.
Intracranial neoplasm was diagnosed if the isolated fourth nerve palsy was a direct result of a neoplasm identified based on clinical symptoms and neuroimaging.
Other etiologies in our study included post-neurosurgery causes, arteriovenous malformation (AVM), brain aneurysm and hemorrhagic stroke.

Etiologies
Our study identified 154 unilateral (97.47%) and 4 bilateral (2.53%) cases of isolated fourth nerve palsy ( Table 1). We excluded 3 patients who presented at their first visit with superior oblique palsy and changed over time to having other cranial nerve palsies or ptosis. The diagnosis in each of those cases was confirmed to be myasthenia gravis, based on a positive acetylcholine receptor antibody test.
Most of unilateral cases were found to be congenital in origin (57.79%), followed by microvasculopathy (27.92%) and intracranial neoplasm (8.44%). Other causes of unilateral isolated fourth nerve palsy were the effects of neurosurgery, AVM and aneurysm, and hemorrhagic stroke, at 0.65% each.
Bilateral isolated fourth nerve palsy was much less frequently found in our study. The most common cause of bilateral fourth nerve palsy was trauma (75%), followed by ruptured AVM (25%).
Twenty-one of the 43 (48.84%) patients with microvasculopathy fourth nerve palsy underwent neuroimaging. The results were normal in all cases. The diagnosis for all of the microvasculopathy patients was confirmed when the misalignment symptoms resolved within 6 months.

Age at presentation
The mean age at presentation with fourth nerve palsy was 38.9 ± 25.7 years. The etiologies varied by age of presentation (Fig. 1). Eighty-nine patients, with a mean age (± standard deviation) of 24.1 ± 23.0 years, were classified as congenital cases. For the 9 trauma patients, the mean age was 40.8 ± 15.4 years. The 43 microvasculopathy patients presented symptoms in the sixth decade (61.3 ± 10.8 years). The 13 patients with an intracranial neoplasm also presented with symptoms in the sixth decade (60.7 ± 9.8 years).

Discussion
Fourth cranial nerve palsy, the most common cause of binocular vertical diplopia, can present in any age group [1]. Previously reported etiologies of isolated fourth nerve palsy were congenital causes, trauma, microvasculopathy, intracranial neoplasm and undetermined causes [1][2][3][4][5]. Our study, which reported the etiology of isolated fourth nerve palsy at Ramathibodi Hospital, Thailand, demonstrated frequencies of etiologies that were comparable to those in earlier studies, even though some of those studies reported the etiologies of fourth nerve palsy including isolated palsy and fourth nerve palsy in conjunction with other cranial nerve palsies. Unilateral isolated fourth nerve palsy was much more common than bilateral palsy in our study (97.47%). Most of the isolated fourth nerve palsy cases in our study were congenital, similar to results in previous studies [2,3]. Most congenital cases showed the onset of symptoms within the first decade (42.70%). However, more than half of such cases reported the onset of symptoms in adulthood, which is consistent with another study [11]. The delayed onset of symptoms is due to decompensation of control over time, and the increase in presbyopia which gradual loss of fusional amplitudes. Dosunmu et al. [11] reported the downgaze for reading when wearing presbyopic spectacle might exacerbate the symptoms.
The second-most common cause of fourth nerve palsy in some studies [2,3,12,13] has reported that trauma was more common whereas in our study was microvasculopathy, which is the same as in Rush and Younge [14]. Microvasculopathy in our study accounted for 27.22% of isolated fourth nerve palsy cases, which were associated with hypertension (25.58%), diabetes mellitus (9.30%), dyslipidemia (9.30%) and combined conditions (55.81%). Most microvascular cases presented the onset of symptoms at the sixth decade (range from the fourth to the ninth decade). Among the microvasculopathy patients, 48.84% had microvascular risk factors, but had indeterminate history such as headache, periorbital Fig.1 The etiologies of isolated fourth nerve palsy varied by age of presentation pain or unable to recognize onset of symptoms suspected to have other life-threatening diseases. Those patients underwent neuroimaging; all had normal findings. All of the patients had recovered from the misalignment symptoms within 6 months.
On the basis of increased early neuroimaging, identification of atypical presentations and close follow-up of all cases in our center, we reported intracranial neoplasm in 8.23% of cases, which is the same as Rucker's result [5], but much more common than in other studies [2-4, 4, 14]. Meningioma (38.46%) was the most common intracranial neoplasm in our study, followed by schwannoma (23.08%), brain metastasis (15.38%), pituitary adenoma (15.38%) and arachnoid cyst (7.69%). There have been various reports of isolated fourth nerve palsy associated with intracranial neoplasm, with the age of presentation between the fourth and seventh decades [15][16][17][18][19]. Our patients with microvasculopathy and intracranial neoplasm presented with symptoms in the sixth decade. Patients with intracranial neoplasm also had microvascular risk factors (46.15%). Atypical presentations were common in our patients, with cases of: diplopia with headache (69.23%), periorbital pain (46.15%), and conjunctival injection (23.08%). Barton [20] suggested that patients with an atypical presentation, such as a history of pain or progressive diplopia, and clinical symptoms such as proptosis or ptosis, should undergo urgent imaging. Elmalem et al. [15] found that 23% of their patients experienced headache as a presenting symptom in cases of fourth nerve schwannoma. In our study, the fourth cranial nerve palsy was accompanied by periorbital pain. Orbital signs such as chemosis, proptosis and conjunctival injection might be the result of lesions occupying the orbit and causing fourth nerve palsy. Therefore, atypical presentations, as mentioned, warrant neuroimaging without delay.
The other cases of isolated fourth nerve palsy in our study included one that was post-neurosurgery, and one each of AVM and brain aneurysm, and dorsal midbrain hemorrhagic stroke. One patient underwent left temporal craniotomy developed left hypertropia consistent with left fourth nerve palsy. The ruptured aneurysms in our study were located at superior cerebellar artery and posterior communicating artery.
Bilateral isolated fourth nerve palsies are reportedly uncommon [21], as we also found in our study. Only 2.53% of the cases in our population were bilateral; among those, closed head trauma was the most common cause (75.00%). Because of the longest intracranial course and thin structure of the fourth cranial nerve and the only nerve which exit the brainstem dorsally, it is susceptible to damage in closed head trauma. For head trauma cases, the most common presentation was in the third decade of life. The incidence of traumatic fourth nerve palsy in head trauma cases ranged from 0.23 to 13.00% [22]. Guichen et al. [22] reported the incidence of traumatic cranial nerve palsy was 3.20%. Trauma in our study accounted for 5.70% of isolated fourth nerve palsy cases.
One limitation of this study is the fact that Ramathibodi Hospital is a tertiary eye referral center. Thus, these data may not be entirely representative of the general population. Another limitation is that, because of our retrospective review of medical records, some information may have been incomplete, including histories of trauma.

Conclusions
The most common cause of isolated fourth nerve palsy at Ramathibodi Hospital was congenital abnormality, followed by microvasculopathy, which all resolved within 6 months of symptom onset, and intracranial neoplasm. All neuroimaging performed in the microvasculopathy cases was negative. Patients with isolated fourth nerve palsy who are diagnosed with presumed microvasculopathy can be observed without the necessity of neuroimaging, but it should be considered, especially, in cases of atypical presentation, such as diplopia with headache, periorbital pain, rapidly progressive symptoms or no recovery.
Declaration of Helsinki in view of the retrospective nature of the study and all the procedures being performed were part of the routine care.