The risk factors affecting the persistence of corpus callosum splenium lesions

Abstract

Background

The most compact portion of the corpus callosum (CC) is the corpus splenium (CS).

Purpose

To evaluate the connection between clinical and demographic features to determine whether neuroimaging findings will be permanent or temporary in CS patients.

Material and Methods

We enrolled 93 patients (age range = 18–86 years) with CS lesions. Demographic and clinical information were recorded. We examined the lesions depending on the location. Group 1 (n = 20) had lesions limited to the CS (egg-shaped or round); group 2 (n = 15) had “boomerang sign” lesions; and group 3 (n = 58) had splenium involvement in conditions affecting the whole brain (Boomerang sign+ plus).

Results

Group 1 had a lower mean age, shorter disease duration, and fewer persistent lesions than others (P < 0.01, P < 0.001, and P < 0.001, respectively). The mean disease onset age (in years) in group 1 was higher than that of the other groups (P < 0.045). Group 2 had lower potassium (K) (P < 0.003) and red cell distribution width levels (P < 0.029) than the other groups. Age <41.5 years (P < 0.001), age at illness initiation <48.5 years (P < 0.002), disease duration <5.5 months (P < 0.001), and eosinophil level <0.29 uL (P 0.014) all point to temporary lesions.

Conclusion

Cases with limited CS lesions have younger onset ages, lower disease onset ages, and shorter disease durations. Age, age of disease onset, disease duration, and eosinophil level are risk variables that affect whether CS lesions are permanent or temporary.

Keywords

Central nervous system hematologic magnetic resonance imaging brain brain stem

Introduction

Anatomically, the corpus callosum (CC) is a structure that provides communication between the two hemispheres. The corpus splenium (CS), which comprises fibers with wildly dissimilar axonal calibrations, is also the most compact part of the corpus callosum (1,2). The axonal fibers in this region, notably by increasing their thickness, complete their myelination for a variety of roles as the white matter continues to develop until the age of 18 years (3,4). Split brain or disconnection syndrome findings have been shown to exist, particularly in individuals who have undergone callosotomy surgery for epilepsy surgery. Split-brain syndrome occurs in approximately 25% of individuals with refractory epilepsy after callosotomy; it is often transient (5). These findings might be tactile or visual anomia, dyslexia, agraphia, neglect, apraxia, or alien hand syndrome (6). Symptoms of CS lesions on magnetic resonance imaging (MRI) might also include impaired visuospatial abilities, behavioral disorders, seizures, headache, language disorders, reading and calculating difficulties, and consciousness (3). Lesions restricted to the CS on MRI alone typically result from infections or metabolic problems and are not typically visible until 2–3 weeks after therapy (7). It has also been claimed that CS lesions on MRI only disappear after 6–9 months, probably due to the treatment's delayed start (8,9).

Patients with “boomerang sign” CS lesions have a variety of etiological reasons, including metabolic disorders, malignancies, and inflammatory diseases. The etiological causes of disorders affecting the whole brain in individuals with splenium involvement include trauma, ischemic-hypoxic encephalopathies, developmental diseases, and intracranial hypotension syndromes (1).

We did not see any research including the links between the morphological features of CC lesions and the patients’ prognosis, etiological variables, and clinical and laboratory data. Therefore, the aim of the present study was to assess the association between clinical and demographic traits, neuroimaging assessments, immune response, and prognosis in individuals with corpus callosum splenium lesions on MRI.

Material and Methods

Our investigation was conducted by the Department of Neurology, Istanbul Medeniyet University's Training and Research Hospital, Istanbul, Türkiye. A retrospective study approach was used to conduct this study. We assessed 93 patients between January 2013 and December 2021 at an outpatient clinic and service of the Neurology Department.

All the participants were aged 18–86 years. When their complaint originally appeared, all patients had their first MRI examinations done immediately in the emergency room. The control MRI in our research was done one month later since the lesions often disappear 2–3 weeks after therapy. All patients’ CS lesions were categorized based on the available research. According to the location, we investigated the lesions in three different groups: group 1 = lesions limited to the CS only (egg-shaped or round); group 2 = “boomerang sign” lesions extending from the splenium to the white matter in temporal-parietal-occipital regions; and group 3 = splenium involvement in conditions affecting the whole brain (boomerang sign + plus).

Etiological analyses of each patient were completed, and their relationships to the various types of CS lesions were investigated by categorizing the etiological reasons as infections, metabolic events, malignancies, ischemic events, demyelinating disorders, movement disorders, cognitive disorders, and trauma. Patients with reversible lesions were monitored for approximately one year, while others were still monitored at the neurology outpatient clinic. Blood samples were also obtained, and biochemical and hematological markers were assessed to evaluate the patients’ immunological responses. Long-term patients were clinically followed up every three months in the neurology outpatient clinic. MRI follow-ups were done every three, six, or 12 months, depending on the patient's condition.

The Helsinki Declaration's guiding principles were followed while conducting the study. Informed consent was obtained from all individual participants included in the study. The Ethics Committee of Prof. Suleyman Yalcin of Istanbul Medeniyet University and the Training and Research Hospital approved the research (Date of Ethics Committee and protocol number: 2021 and 0359).

Imaging protocols for MRI

MRI was performed using Optima 450w 1.5 T (GE Healthcare, Milwaukee, WI, USA) and included the following sequences: axial T1-weighted (TR/TE = 540/12 ms) and T2-weighted (T2W; TR/TE = 4640/89 ms) fast spin-echo, axial, and coronal fluid-attenuated inversion recovery (FLAIR; TR/TE = 7000/92 ms), sagittal T2W (TR/TE = 4025/106 ms) fast spin-echo with a slice thickness of 5 mm, diffusion-weighted imaging (TR/TE = 5900/98 ms; field of view = 250 × 250 mm; slice thickness = 5 mm; matrix = 128 × 128; b value = 0 and 1000 s/mm²).

Analysis of statistics

SPSS version 25.0 (IBM Corp., Armonk, NY, USA) was used to evaluate statistical studies. The Shapiro–Wilk or Kolmogorov–Smirnov test was used to compare groups to determine if the continuous numerical variables reported as findings were normal. Using Levene's test, the homogeneity of group variances was evaluated. When the parametric test's underlying assumptions were fulfilled, the standard deviations and averages were determined using the independent samples t-test. The interquartile distribution's median (25th percentile to 75th percentile) was provided in case the parametric test hypotheses were not sufficient and Kruskal–Wallis H tests were used. To present the category data, frequencies and percentages were used. Pearson chi-square tests were performed to look at how the category variables differed. The variables evaluated in the receiver operating characteristic (ROC) analysis are as follows: (i) age (years, patient’s age at the time the study was conducted); (ii) age of disease onset age (years, patient’s age at diagnosis); (iii) disease duration (months, duration of illness); (iv) glucose (mg/dL, glucose level at the time of the study was conducted); and (v) eosinophil (10 × 3 uL, eosinophil value at the time of the study was conducted). The prediction model was described using a ROC analysis. A value of P < 0.05 was required for significance.

Results

In the present study, there were 43 (46.2%) men and 50 (53.8%) women. The mean age of the patients group 1 was much lower than that of patients in the other groups, at 44 years (range = 18–76 years), compared with 69 years (range = 28–85 years) for group 2 and 56 years (range = 18–91 years) for group 3 (P < 0.01). The patients’ age of disease onset (69 years; range = 28–80) in group 2 was lower than that of group 1 (40.5 years; range = 11–74 years) and group 3 (49.5 years; range = 14–90 years) (P < 0.045). The disease duration of group 1 (1 months; range = 0.5–72)was less than group 2 (12 months; range = 0.5–265 months) and group 3 (24 months; range = 0.5–373 months) (P < 0.001). Lesions persisted for a shorter period in group 1 (mean = 5 ± 25.0 months) than in group 2 (mean = 11 ± 73.3 months) and group 3 (mean = 55 ± 94.8) (P < 0.001) (Table 1). When the distributions of symptom subgroups are compared according to groups, the percentage of patients with unconsciousness was higher in group 1 than in the other groups (P = 0014). In addition, the percentage of cognitive disorders was higher in group 2 than in the other groups (P = 0017). There was no significant difference between the groups in terms of the percentages of behavioral disorders, language disorders, and visuospatial disorders. The results are shown in Table 1. We also analyzed whether there were differences between the groups in terms of the underlying etiologies. We detected that only the percentage of infections was higher in group 1 than in groups 2 and 3 (P = 0003). The details can be seen in Table 1.

Table 1.

Clinical and demographic characteristics of the patients.

	Whole group (n = 93)	Lesion location			P
	Whole group (n = 93)	Group 1 (n = 20)	Group 2 (n = 15)	Group 3 (n = 58)	P
Age (years)	55 (18–91)	44 (18–76)	69 (28–85)	56 (18–91)	<0.01*
Sex (female)	50 (53.8)	9 (45.0)	9 (60.0)	32 (55.2)	0.638^†
Marital status					−
Single	3 (3.2)	−	−	3 (5.2)
Married	90 (96.8)	20 (100)	15 (100)	55 (94.8)
Educational status					−
Uneducated	1 (1.1)	−	1 (6.7)	−	−
Primary school graduate	54 (58.1)	8 (40)a	6 (40)a	40 (69)b	0023^†
High school graduate	32 (34.4)	9 (45)a	8 (53.3)b	15 (25.9)b	0072^†
University graduate	6 (6.5)	3 (15)	−	3 (5.2)	−
Age at disease onset (years)	50 (11–90)	40.5 (11–74)	69 (28–80)	49.5 (14–90)	<0.045*
Disease duration (months)	12 (0.5–373)	1 (0.5–72)	12 (0.5–265)	24 (0.5–373)	<0.001*
Etiologies					−
Infections	21 (20.4)	10 (47.6)a	1 (5.9)b	10 (15.4)b	0003 ^†
Metabolic causes	13 (12.6)	3 (14.3)	4 (23.5)	6 (9.2)	0264^†
Tumors	9 (8.7)	−	2 (11.8)	7 (10.8)	0253^†
Ischemic events	32 (31.1)	5 (23.8)	4 (23.5)	23 (35.4)	0389^†
Demyelinating diseases	23 (22.3)	3 (14.3)	3 (17.6)	17 (26.2)	0396^†
Movement diseases	2 (1.9)	−	2 (11.8)	−	−
Cognitive disorders	1 (1.0)	−	1 (5.9)	−	−
Trauma	2 (1.9)	−	−	2 (3.1)	−
Lesion persistence (permanent)	71 (76.3)	5 (25.0)	11 (73.3)	55 (94.8)	<0.001^†
Symptoms
None	4 (3.6)	−	1 (6.3)	3 (4.3)	−
Unconsciousness	37 (33.6)	14 (56)a	4 (25)b	19 (27.5)b	0014 ^†
Disconnection signs	5 (4.5)	2 (8)	−	3 (4.3)	−
Behavioral disorders	22 (20)	3 (12)	1 (6.3)	18 (26.1)	0066^†
Language disorders	10 (9.1)	3 (12)	−	7 (10.1)	0334^†
Visuospatial disorders	16 (14.5)	2 (8)	4 (25)	10 (14.5)	0383^†
Cognitive disorders	16 (14.5)	1 (4)a	6 (37.5)b	9 (13)a	0017 ^†

Statement marked bold were statistically significiant.

Values are given as n (%) or median (range).

Group 1 = lesions are limited to corpus splenium only; group 2 = “boomerang sign” lesions extend from the splenium to the white matter in temporal-parietal-occipital regions; group 3 = splenium involvement in conditions affecting the whole brain.

^aThe study that produced a statistically significant difference between the three groups.

^bThe study with no significant difference.

*Kruskal–Wallis H test.

†

Chi-square test.

It was discovered that group 2 had a higher mean serum potassium (K) level (4.95 mmol/L; range = 4.1–5.4 mmol/L) than groups 1 and 3 (P < 0.003). We found that the mean red cell distribution width (RDW) in group 2 (15.6%; range = 12.3%–44%) was higher than that of groups 1 and 3 (P < 0.029) (Table 2).

Table 2.

Analysis of biochemical and hematological parameters.

	Whole group(n = 93)	Lesion location			P*
	Whole group(n = 93)	Group 1(n = 20)	Group 2(n = 15)	Group 3(n = 58)	P*
Serum level
Na (136–145 mmol/L)	138 (121–150)	138 (122–145)	140 (136–143)	138 (121–150)	0.077
K (3.5–5.1 mmol/L)	4.5 (2.3–5.6)	4.53 (2.3–5.14)	4.95 (4.1–5.4)	4.35 (3.1–5.6)	0.003
Creatine (0.7–1.3 mg/dL)	0.81 (0.4–9.28)	0.89 (0.55–2.24)	0.83 (0.58–9.28)	0.8 (0.4–8.82)	0.853
CRP (0–5 mg/L)	3.06 (0.01–303)	5.39 (0.01–303)	1.13 (0.2–24.77)	3.5 (0.01–213)	0.238
Glucose (74–109 mg/dL)	103 (68–322)	95 (70–133)	96 (79–178)	110 (68–322)	0.108
WBC (4–10 10 × 3uL)	8.02 (3.16–18.6)	7.8 (4.7–18.6)	8 (3.6–10.33)	8.05 (3.16–17.1)	0.864
Eosinophil (0.02–0.5 10 × 3 uL)	0.27 (0–14)	0.11 (0–2.5)	0.45 (0.01–14)	0.3 (0–11.5)	0.178
Lymphocyte (0.8–4 10 × 3 uL)	1.8 (0.38–35)	2 (0.44–35)	1.75 (0.4–5.5)	1.8 (0.38–29.3)	0.531
Neutrophil (2.00–7.00 10 × 3 uL)	5285 (2.08–61.8)	5.26 (2.55–14.5)	4.49 (2.22–8)	5.4 (2.08–61.8)	0.423
NLR	2705 (0.6–710)	2.32 (0.1–26.29)	2.59 (0.4–11.42)	3.06 (0.06–710)	0.105
Platelets (100–400 10 × 3uL)	2445 (59–666)	198 (65–666)	224 (146–449)	266 (59–452)	0.105
PLR	125.97 (1.58–7789)	106.15 (6.11–503)	120 (29.09–655)	1404 (1.58–7789)	0.186
RDW (11%–16%)	13.9 (12.1–49)	13.4 (12.1–43.9)	15.6 (12.3–44)	13.8 (12.2–49)	0.029
MCV (80–100 fL)	87 (28.1–1084)	88.7 (61.3–97)	87.6 (78.1–94.2)	85.2 (28.1–1084)	0.057
MPV (6–12 fL)	87 (28.10–1084)	10.2 (8.5–12.7)	10.35 (9.1–12.5)	10.1 (7.6–14.5)	0.412

Statement marked bold were statistically significiant.

Values are given as n (%) or median (range).

*Kruskal–Wallis H test.

CRP, C-reactive protein; RDW, red cell distribution width; MCV, mean corpuscular volume ; MPV, mean platelet volume; NLR, neutrophil-lymphocyte ratio; PLR, platelets-lymphocyte ratio; WBC, white blood cell.

ROC analyses were carried out for the hematological and biochemical data, as well as the clinical and demographic features. The factors that were determined to be more significant and valuable than the others were age, age at onset of disease, disease duration, ischemic events, and eosinophile value under the curve and P values. More likely to be temporary if the patient is aged <41.5 years (P < 0.001), the age of disease onset is <48.5 years (P < 0.002), the disease duration is <5.5 months (P < 0.001), presence of ischemic events (P < 0.02), and the blood eosinophil level is <0.29 uL (P < 0.014) (Table 3, Fig. 1). Table 4 provides a summary of the patients’ radiological follow-ups at the start and end of their visits. Fig. 2 shows the images of lesions in groups 1, 2, and 3.

Table 3.

“Cutoff” values of some predictive parameters in the development of permanent lesions in patients.

	AUC	SE	P*	95% CI		Cutoff^†	Sensitivity	Specificity
	AUC	SE	P*	Lower	Upper	Cutoff^†	Sensitivity	Specificity
Age (years)	0.776	0.056	<0.001	0.666	0.886	41.5 (years)	0.845	0.636
Age of disease onset (years)	0.716	0.058	<0.002	0.603	0.828	48.5	0.620	0.727
Disease duration (months)	0.794	0.055	<0.001	0.687	0.901	5.5	0.746	0.864
Presence of ischemic events	0.668	0.064	0.025	0.543	0.793	-	0.42	0.91
Glucose (74–109 mg/dL)	0.646	0.047	0.065	0.525	0.766	123.5	0.338	1.000
Eosinophil (0.02–0.5 10 × 3 uL)	0.682	0.064	<0.014	0.557	0.807	0.29	0.557	0.800

Statement marked bold were statistically significiant.

*P value for AUC.

†

While making the cutoff value decision, it was decided according to the highest j values (Youden's J statistic).

AUC, area under the receiver operating characteristic curve; CI, confidence interval; SE, standard error;

Table 4.

Long-term follow-up of the clinical characteristics of the patients.

	Group 1	Group 2	Group 3	P
Existence of lesion on the first visit	20	15	58
Lesion persistence (permanent) on the last visit	5 (25.0)	11 (73.3)	55 (94.8)	<0.001*

Statement marked bold were statistically significiant.

Values are given as n (%).

*Chi-square test.

Discussion

Since the CS links the two hemispheres, even if its complete range of roles has not yet been fully understood, its loss can result in disconnection findings, high cortical dysfunctions, conscious abnormalities, and behavioral alterations (1). There are case reports of H. influenzae, COVID-19, rotavirus, and Neisseria meningitidis among the infectious diseases (10 –14).

There have also been reported cases of hypoglycemia-induced reversible CS lesions that manifest as impaired consciousness (8). We did not find any difference among groups in terms of glucose levels.

To assess the immune response in patients, we employed “inflammatory markers,” which are often used in various illnesses in the literature. As a dependable and accessible marker of immunological response to numerous viral and non-infectious stimuli, the neutrophil-lymphocyte ratio (NLR) is now routinely employed across practically all medical specialties. In adults, readings >3.0 and <0.7 are abnormal; the NLR range is 1–2. NLR values in the range of 2.3–3.0 may serve as a preliminary sign of a pathological occurrence (15). The NLR and platelet-lymphocyte ratio (PLR) are commonly utilized to forecast the course of acute inflammatory and prothrombotic events as well as their prognosis (16,17). Our research did not support NLR and PLR as immunological markers.

According to research, the CS myelination continues to develop until the age of 18 years, allowing for the development of higher cortical functions such as reading and visuospatial information transfer (2,18). Lesions of the CS have a variety of names, including reversible spenial lesion syndrome (RESLES), cytotoxic lesions of the corpus callosum (CLOCCs), and mild encephalopathy with reversible splenium lesion (MERS) (19 –21).

Various etiological causes can lead to corpus splenic lesions, which can sometimes be visible and reversible and other times permanently. Hyponatremia results from inappropriate secretion of antidiuretic hormone (ADH) brought on by brain injury. Sodium (Na) enters the cell, cytotoxic edema forms, and potassium (K) exits the cell. The literature has recorded cases of hypernatremia and normonatremia, except for RESLES cases that developed consequent to hyponatremia (20,22). Hypo/hypernatremia did not differ between any of the groups in our research. We did not find an association between hyponatremia and the development of CS lesions, even though this is the predominant physiopathology described in the literature. However, we found that the K and RDW levels in group 2 patients were statistically greater than the other groups. Although there are authors that discuss the variations in etiological reasons depending on where the lesion is located, we were unable to find any articles that looked at the correlation between other demographic variables and the site of the lesion (23 –25).

In patients with a low present age, a younger age at disease onset, and a brief disease duration, we discovered that the development of group 1 type lesions was more prevalent. In line with the literature, we discovered that patients in group 1 had more transient lesions than those with other lesion localizations (23,25).

It has been demonstrated that CS has a role in a variety of disorders, including MS, Susac syndrome, aquaporin-4 disease, and Alzheimer's disease (26,27). There have been reports in recent years indicating that COVID-19 infections can cause reversible lesions in CS (28). The use of hazardous chemicals can also result in CS lesions (29). In addition, it has been suggested that as people age, some alterations are selectively exposed to the posterior part of the CC (24). Our analysis revealed that infections were the most frequent etiological factor of group 1 lesions. We also found that unconsciousness was the most common symptom in the group 1 lesions, whereas cognitive impairment was the most common symptom in the group 2 lesions.

Due to the lack of information in the literature to date, we also looked at the possibility of temporary CS lesions in this study. Our study reported that the condition if more likely to be reversible if the patient is aged <41.5 years, the onset age is <48.5 years, the disease duration is <5.5 months, and the blood eosinophil level is <0.29 uL. Eosinophils play a significant role in the control of inflammation and the healing of damaged tissues and are mostly secreted in allergic inflammatory diseases (30). This investigation demonstrated that elevated eosinophil counts are a sign of severe inflammation and that they provide a risk for the development of persistent lesions.

It is well known that there are many vascular irrigation branches across the whole CC (1). The development and durability of lesions in various CC regions may be influenced by the severity of the disease processes, the emergence of distinct collaterals, and the various consequences of distinct underlying pathological processes. We are limited by the small sample size and the retrospective nature of our study design, which resulted in some data loss. We believe that much more thorough information may be obtained from future trials with a much bigger patient population and prospectively conducted investigations.

Clinical symptomatology in RESLES disease can vary between asymptomatic cases and the presence of severe symptoms (9). When these patients are being followed and treated for CS, it is evident that it is critical for physicians informed of the RESLES risk. Therefore, we believe that this study is highly helpful in identifying the clinical characteristics and risk factors of the lesions in CC lesions.

In conclusion, we have demonstrated that cases with lesions that are only present in the CS present at younger ages, have a lower age of disease onset, and have shorter disease durations. If the patient is aged < 41.5 years, the disease does not start until they are aged < 48.5 years, the illness does not last more than 5.5 months, and the blood eosinophil level is < 0.29 uL, the condition is more likely to be transitory.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Asuman Orhan Varoglu

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