Is elevated serum homocysteine in isolated ischemic cranial nerve palsies a predictor of stroke?

Abstract

BACKGROUND

Isolated third, fourth, and sixth cranial nerve palsies (CNP) in elderly people occur commonly due to microvascular ischemia. Ischemic isolated CNP share several atherosclerotic risk factors that are responsible for stroke which include hypertension, diabetes mellitus and dyslipidemia. Hyperhomocysteinemia is atherogenic and hence is also considered as an independent risk factor for stroke. So indirectly, elevated homocysteine in CNP may act as a risk factor for stroke.

AIM

To determine the incidence of isolated ischemic CNP secondary to elevated serum homocysteine (predisposing them to a greater risk of stroke), and if serum homocysteine levels need to be checked routinely in all isolated CNP by neuro-ophthalmologists.

METHODS

This is a retrospective case study, in which 66 patients diagnosed with ischemic isolated CNP were enrolled. Informed written consent was obtained from all who participated in this study. Data of these patients were collected from the electronic medical records and were analyzed. Complete anterior, posterior segment and neuro-ophthalmic examinations were done, in addition to routine blood investigations and serum homocysteine.

RESULTS

The mean age was 55 years old. Gender wise, 74.24% affected were males and 25.76% were females. The sixth nerve was affected in 68.18% cases. Of 66 patients, 37 cases (56.06%) had elevated serum homocysteine. In patients > 40 years and without any systemic risk factors, 63.2% had elevated serum homocysteine. In patients < 40 years and without systemic risk, 66.7% had high serum homocysteine levels.

CONCLUSION

In cases without systemic risk factors, serum homocysteine may indirectly act as a risk factor for developing stroke in patients having isolated ischemic CNP. According to our study, patients with or without risk factors and those above 40 years, 56.06% patients with isolated ocular motor palsy had elevated serum homocysteine. This implies that the level of elevated serum homocysteine was statistically significant (P < 0.05) in these patients; thus, indirectly showing a greater predilection towards developing a stroke. In this small pilot study, we show that even in neuro-ophthalmology serum homocysteine should be routinely checked for all patients with isolated ischemic CNP. This might reduce the incidence of patients developing a stroke.

Key Words: Cranial nerve palsy; Homocysteine; Stroke; Ischemia

Core Tip: This retrospective study of 66 patients with isolated ischemic cranial nerve palsies found elevated serum homocysteine in over half the cases, including those without traditional vascular risk factors. The findings suggest homocysteine may be an independent risk factor for stroke, supporting routine testing in such patients which may help identify stroke risk early and guide preventive care.

INTRODUCTION

Ischemic ocular cranial nerve palsy (CNP) is most commonly seen in the elderly population, the major cause being microvascular ischemia[1]. The risk factors are mainly diabetes, hypertension, dyslipidemia, cardiovascular diseases, cerebrovascular accidents, smoking, and elevated hematocrit levels[2,3]. Third nerve CNP is associated with multiple risk factors[4,5]. Only a few cases of CNP in the young have been reported.

Hyper homocysteinemia is also considered as an independent risk factor for other systemic and ocular vaso-occlusive disorders, including nonarteritic ischemic optic neuropathy (NAION), central retinal artery occlusion (CRAO), and central retinal vein occlusion (CRVO), especially in young patients without any other systemic risk factors[6,7]. Several studies showed the association of hyperhomocysteinemia and nonarteritic anterior ischemic optic neuropathy[8-10].

In a study conducted by Mishra et al[11], hyperhomocystenemia can also be considered as an independent risk factor for ischemic CNP. Homocysteine is a metabolic product of methionine breakdown. Its further metabolism needs vitamins B12, B6, folic acid and methylenetetrahydrofolate reductase (MTHFR) enzyme. It is a potent atherogenic risk factor leading to the formation of the free radicals and causes smooth muscle proliferation[6]. It has a deleterious effect on vascular endothelium causing aggregation of platelets, thrombus formation and there by increases the risk of vascular occlusion. Toxicity to endothelium is due to conversion of homocysteine to a chemically reactive molecule homocysteine thiolactone[7]. Loewenstein et al[12] studied the prevalence of genetic mutation in the enzyme MTHFR. This MTHFR enzyme helps in the conversion of 5,10 methylenetetrahydrofolate to 5 methylteterahydrofolate. The impaired activity of this enzyme may lead to hyperhomocysteinemia. Ischemic ocular CNP share several atherosclerotic risk factors for stroke. Hyperhomocysteinemia, being atherogenic, is considered as an independent risk factor for stroke. So indirectly, elevated homocysteine in CNP might probably be a risk factor for stroke. The risk of stroke is highest during the first year with a hazard ratio of 5.96. The highest risk of stroke occurred after third nerve palsies with a hazard ratio of 3.37[13,14].

MATERIALS AND METHODS

A retrospective study was done at a tertiary eye care center in South India. Electronic medical records data was collected from December 1, 2021 to March 31, 2022 (4 months). Approval from our institutional review board was obtained (RET202100385). Patients presenting with only isolated single nerve palsies were considered for this study. Though 157 cases with isolated ischemic nerve palsies (3^rd, 4^th, 6^th cranial nerves) were documented during these 4 months, only 66 patients were included in the study as they consented and could afford the cost of testing the serum homocysteine levels. Elevated serum homocysteine was defined as any value more than 15 μmol/L. Multiple cranial nerve palsies were excluded. Enquiry regarding the history of potential risk factors like diabetes mellitus, hypertension, dyslipidemia, cerebrovascular accident and cardiac disease were made. Best corrected visual acuity, anterior and posterior segment examination, diplopia and HESS charting and routine blood investigations (hemoglobin, complete blood count, erythrocyte sedimentation rate, routine blood sugar, total cholesterol) were done. Apart from this, serum homocysteine was also done. Neuroimaging was done in patients < 40 years of age and those who were > 40 years but without any systemic risk factors. Data was entered in excel sheet and statistical analysis was done. Demographic and baseline variables were presented with frequency, measures of central tendency and dispersion. Categorical variables were presented with frequency and percentage, whereas continuous variables were presented with mean and standard deviation or median with Inter quartile range. Age was categorized into two groups. viz, "< 40 and > 40". A univariate analysis to find the association between categorical variables was done with Fisher's exact test. A Wilcoxon rank sum test was used to find if there exists any association between systemic illness and the average homocysteine levels between 2 groups of age. For all the statistical analysis, a p-value of less than 0.05 were considered statistically significant. Stata, the statistical software version 17.0, StataCorp, LLA, Texas was used for statistical analyses.

RESULTS

Of the 66 cases of isolated CNP (3^rd, 4^th, or 6^th) included in the study, 37 (56.06%) cases had elevated levels of homocysteine. Seven cases were below 40 years and 59 cases were above 40 years (Table 1). The abducent nerve was affected most, 45 cases (68.18%), of which 27 cases had elevated levels of homocysteine; followed by trochlear (16.67%) and oculomotor nerves (15.15%) (Table 2).

Table 1 Elevated levels of serum homocysteine in patients with and without systemic illness, n (%).

Age (years)	No systemic illness			With systemic illness
	Elevated	Normal	Fisher's exact test P value	Elevated	Normal	Fisher's exact test P value
> 40	12 (63.2)	7 (36.8)	1.00	20 (50)	20 (50)	1.00
≤ 40	4 (66.7)	2 (33.3)		1 (100)	0
Total	16	9		21	20

Table 2 Percentage distribution of cranial nerves, n (%).

Cranial nerve	Normal homocysteine level	Elevated homocysteine level	Total	Fisher's exact test P value
3	5 (50)	5 (50)	10	0.65
4	6 (54.5)	5 (45.5)	11
6	18 (40)	27 (60)	45

CNP were commonly seen in males (74.24%) and 25.76% females. The mean age affected was 55 ± 11.6 years.

Those with elevated serum homocysteine were categorized as with and without systemic risk factors. The most common risk factor affected in these patients were diabetes (57.58%) followed by hypertension (27.27%), dyslipidemia (12.12%), coronary artery disease (10.61%) and cerebrovascular accidents (9.01%).

The mean homocysteine level was 16.5 ± 7.89. Of the 7 cases of patients aged less than 40 years, 4 patients with no systemic risk factors had elevated homocysteine. In patients above 40 years, 12 cases with no systemic risk factors and 20 cases with systemic risk.

factors had elevated homocysteine. The mean homocysteine levels were compared in patients aged below and above 40 years and between those with and without systemic risk factors and was found to be statistically significant in patients above 40 years with P = 0.0359 (Table 3).

Table 3 Comparison of serum homocysteine in patients with and without systemic risk factors aged below and above 40 years, mean ± SD.

Age	Risk factors	Homocysteine	Wilcoxon rank-sum (Mann-whitney) test
< 40 years	No systemic risk factors (n = 6)	13.9 ± 4.3	0.5714
	With systemic risk factors (n = 1)	18.9
> 40 years	No systemic risk factors (n = 19)	20.9 ± 11.5	0.0359
	With systemic risk factor (n = 40)	14.7 ± 5.1

DISCUSSION

In a major review, Shew et al[15] suggested that isolated ischemic CNP was associated with a higher risk of developing stroke, posing a greater hazard ratio than any other single stroke risk factor alone. The risk being highest within the first year with a hazard ratio of 5.96 and also was found to be highest after 3^rd CNP with a hazard ratio of 3.37[15]. This was attributed to the fact that a portion of the 3^rd nerve lies in the watershed zone where the vascular supply relies entirely on the intraneural vascular plexus. This vulnerability in the 3rd nerve vascular supply may explain the increased susceptibility to ischemic palsy[14].

There are studies proving that increased homocysteine levels predispose to subsequent strokes. In the study by Kalita et al[14], 60.6% of patients with ischemic strokes had hyperhomocysteinemia. Cases without systemic risk factors with increased homocysteine levels, can indirectly act as a risk factor for developing stroke in patients having isolated ischemic CNP. According to our study, patients with or without risk factors were statistically significant (P < 0.05); 56.06% isolated had elevated serum homocysteine, thus showing a great predilection towards developing a stroke. Multiple ocular conditions like NAION, CRVO, CRAO, etc. are routinely investigated for elevated homocysteine levels. Some of the drawbacks of our study is its retrospective nature, a small sample size and vitamin B12 and folate levels were not done mainly because of cost constraints. However, serum homocysteine is almost never done in isolated ischemic cranial nerve palsies, as there are very few studies on the same. In our study we show that 56.06% of the cases of isolated ischemic CNP had elevated homocysteine levels; which suggests that this blood investigation should also be done routinely in all cases of isolated CNP. There are a number of studies showing that isolated ischemic CNP have a hazard ratio (towards developing stroke) that is higher than any individual ischemic risk factor. So indirectly, we postulate that there is a correlation between the three - ischemic isolated cranial nerve palsies have a high probability of increased serum homocysteine, which in turn is responsible for a greater chance of developing stroke. This could pave the way for future larger prospective studies to test this hypothesis.

CONCLUSION

In conclusion, this small pilot study shows that even in the neuro-ophthalmology clinic, serum homocysteine should be routinely checked for all patients with isolated ischemic CNP. This might reduce the incidence of patients developing a stroke in the future. However, larger prospective studies are recommended to substantiate this hypothesis.