Does Calcified Neurocysticercosis Affect Migraine Characteristics and Treatment Responsiveness? A Case–Control Study

ABSTRACT.

Recently, inflammation and free-radical release has been described in the surrounding brain parenchyma of seemingly inert calcified lesions of neurocysticercosis. These free radicals can induce migraine by stimulating calcitonin gene-related peptide release. This stipulated mechanism led us to hypothesize that calcified neurocysticercosis may increase migraine severity. This case–control study included patients (migraine with calcified neurocysticercosis) and control subjects (migraine without calcified neurocysticercosis) in a 1:1 ratio. Headache frequency, visual analog scale (VAS) score, and Migraine Disability Assessment (MIDAS) score were assessed at baseline and at the end of 3 months. To compare treatment responsiveness between patients and control subjects, we treated both groups identically so that difference in treatment would not confound the results. Each group comprised 78 patients. Baseline headache frequency (11.3 ± 3.3 versus 7.9 ± 3.4), VAS score (7.5 ± 1.1 versus 6.0 ± 1.2), and MIDAS score (15 ± 7.6 versus 9.6 ± 4.5) were significantly greater in patients than control subjects. Interestingly, the change from baseline to the end of 3 months in headache frequency (6.0 ± 1.7 versus 2.8 ± 1.4), VAS score (2.6 ± 0.02 versus 1.4 ± 0.01), and MIDAS score (8.3 ± 5.0 versus 3.6 ± 2.0) were significantly greater in patients than control subjects. Our study emphasizes that calcified lesions of neurocysticercosis are not inert, and cause an increase in the frequency and severity of migraine attacks. Interestingly, these patients also showed a better response to treatment with amitriptyline, possibly resulting from its anti-inflammatory action. Further studies are warranted to explore possible inflammatory mechanisms in calcified neurocysticercosis, which influences migraine physiology.

INTRODUCTION

Patients with primary headaches, when subjected to cranial imaging, occasionally, may show calcified lesions suggestive of calcified neurocysticercosis. The significance of these lesions in patients with migraine is unknown. Neurocysticercosis is a common helminthic disease that more commonly presents with seizures.¹ Calcified neurocysticercosis is the last stage of the degeneration of cysticerci in the brain parenchyma in which the parasite’s remnants take the form of the calcified nodule.² These calcified lesions are usually considered innocuous. However, recently, the association of these lesions with seizures and primary headaches have gained acceptance in the medical literature. Earlier, these calcified lesions were considered incidental findings in patients with primary headaches; however, recently many epidemiological studies have established the association of primary headaches with calcified neurocysticercosis.^3–5 Apart from this, some studies have documented inflammatory changes in brain parenchyma surrounding calcified lesions of neurocysticercosis. This inflammation causes blood–brain barrier disruption and release of free radicals.⁶ These free radicals have the potential to stimulate the release of calcitonin gene-related peptides (CGRPs), which in turn lead to the activation of the trigeminal vascular reflex and induce migraine attack.^7,8 This stipulated mechanism led us to hypothesize that calcified neurocysticercosis may increase the severity of migraine. Therefore, we compared migraine frequency, severity, and response to treatment among patients with migraine with and without calcified neurocysticercosis.

METHODS

This study was conducted in the Department of Neurology, King George’s Medical University, Lucknow, a tertiary care center in northern India. We enrolled the subjects from Feb 2020 to Nov 2021. This study was approved by the ethics committee (registration no. ECR/262/Inst/UP/2013/RR-16) of our institute (approval no. 138/Ethics/19 dated 14 Feb 2020). All participants gave written informed consent. This was a case–control study. Patients and control subjects were in a 1:1 ratio.

Inclusion criteria.

We included consecutive patients with migraine who were diagnosed per the criteria of the International Classification of Headache Disorders 3 (ICHD-3).⁹ These patients with migraine underwent cranial computed tomography (CT). During the study period, patients who showed calcified neurocysticercosis on cranial CT were included as patients in the NCC group (patients with migraine with calcified neurocysticercosis). A similar number of age- and gender-matched control subjects who had migraine but did not show any calcified lesions on cranial CT were included in the control group. Calcified neurocysticercosis was defined as rounded, homogeneous, hyperdense nodules measuring ≤ 1 cm on plain cranial CT.^5,10 The flow chart of the study is presented in Figure 1.

Figure 1.

Flowchart of the study. MIDAS = Migraine Disability Assessment; VAS = visual analog scale.

Exclusion criteria.

We excluded patients with a history of seizures. We also excluded patients with aura because sometimes it is very difficult to differentiate aura from a simple partial seizure. Apart from this, patients who received any preventive medication in the past were also excluded. Patients, whose cranial CT scan showed stages of neurocysticercosis other than the calcified stage were also excluded.

Workup.

Baseline clinical and demographic details of all patients were documented. We evaluated all participants for frequency, severity, and associated features of headaches. The severity of pain was assessed by using a visual analog scale (VAS) that ranged from 0 to 10 points. Participants were also assessed for migraine-associated disability using the Migraine Disability Assessment (MIDAS). Last, we also assessed comorbid anxiety and depression using the Generalized Anxiety Disorder 7 (GAD-7) assessment and the Patient Health Questionnaire 9 (PHQ-9), respectively.

Treatment and follow-up.

Both groups were treated identically so that a difference in treatment would not confound treatment responsiveness. Preventive treatment was given in the form of amitriptyline tablets, 10 mg for 7 days, followed by 25 mg for 3 months. All patients were advised to take 500-mg naproxen tablets for abortive treatment. They were also asked to maintain a headache diary. Primary outcome measures were changed in headache frequency, VAS score, and MIDAS score at the end of 3 months. A good outcome was defined as ≥ 50% reduction in headache frequency at 3 months in comparison to baseline; < 50% reduction was defined as a poor outcome.

Sample size estimation.

Considering the prevalence of calcified neurocysticercosis in migraine as 4.7%, an alpha error of 5%, a design effect of one, and a 95% CI, the sample size was calculated to be 69. Adding for the speculated 10% loss to follow-up, the final sample size was estimated to be 76 for each arm.^2,11

Statistical analysis.

We present categorical variables as numbers and/or percentages and continuous variables as mean ± SD and/or median with interquartile range. Continuous variables were compared between two groups by unpaired Student t-test. Categorical variables were compared between two groups using the χ² test. Comparison of outcome measures between baseline and at the end of 3 months was done using the paired Student t-test. To compare the magnitude of response to treatment between the two groups, we calculated the mean difference in headache frequency, VAS score, and MIDAS score from baseline to the end of 3 months in both groups separately, and then compared them using the unpaired Student t-test. Logistic regression was applied to find the significant predictors of a good outcome. We also used the McNemar test and conditional logistic regression. For this purpose, we paired age- and gender-matched control subjects to individual patients. We used SPSS 24 (SPSS Inc., Chicago, IL) for all statistical analyses.

RESULTS

We included a total of 156 patients with migraine. Each group was comprised of 78 patients.

Baseline characteristics.

The mean age was 30 years and females constituted 65% of all patients. Baseline headache frequency was significantly greater in the NCC group (11.3 ± 3.3) compared with the control group (7.9 ± 3.4, P < 0.001). Baseline VAS score (7.5 ± 1.1 in the NCC group, 6.0 ± 1.2 in the control group, P < 0.001) and MIDAS score (15 ± 7.6 in the NCC group, 9.6 ± 4.5 in the control group, P < 0.001) were also significantly greater in in the NCC group. Both groups were similar with respect to mean GAD-7 and mean PHQ-9 scores (Table 1). Calcified neurocysticercosis was mainly found in the frontal and parietal areas (34.62% in each lobe) (Figure 2). The rest of the calcified lesions were present in the temporal (5.13%), occipital (5.13%), basal ganglia (1.28%), and interhemispheric (10.26%) regions. Bilateral calcified lesions were found in 8.97%. None of the patients had perilesional edema.

Table 1.

Comparison of baseline clinical characteristics among patients with migraine with calcified neurocysticercosis (NCC group) and without calcified neurocysticercosis (control group)

Characteristic	NCC group (n = 78)	Control group (n = 78)	P value
Mean age ± SD, years	26.49 ± 9.269	31.18 ± 11.20	0.5
Gender, n (% female)	46 (59.1)	56 (71.8)	0.8
Location of headache
Hemicranial	76	69	0.02
Holocranial	2	9
Associated features, n
Nausea	10	17	0.04
Vomiting	11	10
Photophobia	18	20
Phonophobia	18	6
Headache frequency, n (mean ± SD)	11.27 ± 3.29	7.88 ± 3.35	< 0.001
VAS score
Mean ± SD	7.42 ± 1.03	6.03 ± 1.17	< 0.001
Median (IQR)	8 (7–8)	6 (5–7)
MIDAS score
Mean ± SD	15.0 ± 7.66	9.58 ± 4.48	< 0.001
Median (IQR)	13 (10–18)	8 (6–12)
MIDAS grade
Mean ± SD	2.85 ± 0.63	2.24 ± 0.72	< 0.001
Median (IQR)	3 (2–3)	2 (2–3)
GAD-7 score, mean ± SD	3.962 ± 3.705	3.564 ± 3.529	0.4
PHQ-9 score, mean ± SD	7.808 ± 2.564	9.218 ± 3.758	0.4

GAD-7 = Generalized Anxiety disorder-7; IQR = interquartile range; MIDAS = Migraine Disability Assessment; PHQ-9 = Patient Health Questionnaire-9; VAS = visual analog scale.

Figure 2.

Calcified neurocysticercosis seen in cranial computed tomography.

Response to treatment.

A significant reduction in headache frequency was noted at the end of 3 months when compared with baseline in the NCC group (11.3 ± 3.3 at baseline versus 5.2 ± 1.6 at 3 months, P < 0.001) as well as in the control group (7.9 ± 3.4 at baseline versus 5.1 ± 1.9 at 3 months, P < 0.001). Similarly, the VAS scores (7.5 ± 1.0 at baseline versus 4.8 ± 1.1 at 3 months in the NCC group, P < 0.001; 6.0 ± 1.2 at baseline versus 4.6 ± 1.2 at 3 months in the control group, P < 0.001) and MIDAS scores (15.2 ± 7.8 at baseline versus 6.5 ± 2.4 at 3 months in the NCC group, P < 0.001; 9.6 ± 4.5 at baseline versus 6.5 ± 2.4 at 3 months in the control group, P < 0.001) were significantly reduced at the end of 3 months when compared with baseline both groups (Figure 3). However, after 3 months of preventive medication, there was no difference in headache frequency (5.2 ± 1.6 versus 5.1 ± 1.9, P = 0.6), VAS score (4.8 ± 1.1 versus 4.6 ± 1.2, P = 0.9), and MIDAS score (6.5 ± 2.4 versus 6.5 ± 2.4, P = 0.9) between the NCC group and the control group, respectively.

Figure 3.

Graphical presentation of mean headache frequency, mean visual analog scale (VAS) score and mean Migraine Disability Assessment (MIDAS) score at baseline (circle) and at the end of 3 months (square) in patients with migraine with calcified neurocysticercosis (NCC group) and without calcified neurocysticercosis (Control group).

When we compared the magnitude of response to treatment between two groups from baseline to the end of 3 months, the mean difference in headache frequency (6.0 ± 1.7 in the NCC group versus 2.8 ± 1.4 in the control group), VAS score (2.6 ± 0.02 in the NCC group versus 1.4 ± 0.01 in the control group), and MIDAS score (8.3 ± 5.0 in the NCC group versus 3.6 ± 2.0 in the control group) was significantly greater (P < 0.001) in the NCC group versus the control group (Table 2).

Table 2.

Comparison of change in headache frequency, visual analog scale (VAS) score, and Migraine Disability Assessment (MIDAS) score from baseline to the end of 3 months among patients with migraine with calcified neurocysticercosis (NCC group) and without calcified neurocysticercosis (control group)

Parameters	NCC group, n (mean ± SD)	Control group, n (mean ± SD)	Mean difference (95% CI)	P value
Headache frequency	6.03 ± 1.68	2.78 ± 1.41	3.25 ± 0.24 (2.75 to 3.74)	< 0.001
VAS score	2.60 ± 0.02	1.44 ± 0.01	1.16 ± 0.002 (1.15 to 1.16)	< 0.001
MIDAS score	8.30 ± 5.04	3.58 ± 1.98	4.72 ± 0.61 (3.51 to 5.93)	< 0.001

On univariate analysis, the presence of neurocysticercosis (P < 0.001; odds ratio [OR], 37.40; 95% CI, 15.13–92.45), younger age (P = 0.02; mean difference, 3.98; 95% CI, 0.76–7.20), greater baseline headache frequency (P < 0.001; mean difference, 3.61; 95% CI, –4.64 to –2.58), higher baseline VAS score (P < 0.001; mean difference, 1.13; 95% CI, –1.50 to –0.75), higher baseline MIDAS score (P < 0.001; mean difference, 4.22; 95% CI, –6.29 to –2.16), and higher baseline PHQ-9 score (P = 0.02; mean difference, 1.20; 95% CI, 0.18–2.23) were significantly associated with a good outcome (≥ 50% reduction in headache frequency at 3 months in comparison to baseline). On multivariate analysis (logistic regression), only the presence of neurocysticercosis (P < 0.001; OR, 26.57; 95% CI, 8.83–79.93) and greater baseline headache frequency (P = 0.001; OR, 1.38; 95% CI, 1.15–1.65) predicted good outcome independently.

As mentioned, paired patients with age- and gender-matched control subjects. This led to 34 pairs of matched patients and control subjects. This showed that the NCC group was significantly associated with a good outcome (P < 0.001, McNemar test; paired matched OR, 25.00; 95% CI, 3.39–184.50). Details are given in Table 3. A conditional logistic regression was also applied to know the factors associated with neurocysticercosis. Patient/control subject was taken as the dependent variable; baseline headache frequency, VAS score, GAD-7 score, and PHQ-9 score were taken as independent variables. A backward stepwise elimination procedure was used. It was found that greater baseline headache frequency was the only significant predictor of neurocysticercosis (P = 0.042; OR, 1.21; 95% CI, 1.01–1.46).

Table 3.

Comparison of good outcome and poor outcome among patients with migraine with calcified neurocysticercosis (NCC group) and without calcified neurocysticercosis (control group) by the McNemar test

Control group	NCC group
	Good outcome	Poor outcome	Total
Good outcome	5	25	30
Poor outcome	1	3	4
Total	6	28	34

Each number represents a case and control pair of exactly the same age and gender.

DISCUSSION

Our study demonstrates that migraineurs with calcified neurocysticercosis experience more frequent and severe migraine than migraineurs without calcified lesions. Interestingly, these patients showed a better response to treatment than patients with normal CT scans.

In a population-based study, Del Brutto et al.⁵ found that lifetime headache prevalence was more common in subjects with calcified neurocysticercosis in comparison to control subjects (OR, 4.18; 95% CI, 1.79–9.75; P = 0.001). They also found that current headaches and intense headaches were more common in subjects with calcified neurocysticercosis in comparison to control subjects (current headaches: OR, 4.19; 95% CI, 1.92–9.16; P < 0.001; intense headaches: OR, 9.47; 95% CI, 2.88–31.19; P < 0.001). Our study results are in concordance with those of Del Brutto et al.,⁵ as we also found a greater frequency and intensity of headaches in patients with calcified lesions. However, our study differs from that of Del Brutto et al.⁵ in that theirs was a population-based study whereas we included patients with migraine who fulfilled ICHD-3 criteria for migraine. In addition, we also used MIDAS to assess migraine-associated disability properly in our patients.

In our study we included only those patients who had not undergone any prior preventive treatment. This allowed us to compare baseline characteristics without any confounding effect of preventive medications on migraine course. In addition, we gave the same preventive and abortive treatment to both groups which removed any drug-specific influence on migraine outcomes and allowed us an unbiased comparison of response to treatment between both groups. In another study, Pradhan et al.¹² found a greater headache frequency in patients without calcified lesions in comparison to patients with calcified lesions which is contrary to our results. This can be explained by the difference in patient selection. Their patients were apparently on preventive treatment, which would have affected their results. Interestingly, in our study also, after 3 months of preventive medication, there was no difference in headache frequency, VAS score, and MIDAS score between the two groups (Figure 2). In addition to that, they included patients whose imaging was already available, and imaging as a part of their study protocol was not done. On the contrary, we included patients based on diagnostic criteria of migraine by ICHD-3 and did cranial imaging as part of our study protocol. Usually, cranial imaging is not recommended in patients with typical migraine.¹³ It is required only in select patients with migraine who also have seizures, focal neurological deficits, or any other atypical features.¹³ This could have introduced a selection bias in their study toward patients with atypical migraine. Moreover, unlike us, they also included patients with epilepsy on antiepileptic treatment, which might have influenced their results further.

The mechanism of increased headache frequency and severity in patients with calcified neurocysticercosis is not clearly understood. Calcified neurocysticercosis is the end stage of cysticerci in the brain parenchyma and is largely considered innocuous. However, it has been demonstrated in various histopathological and neuroimaging studies that calcified cysticerci contain antigenic remnants of parasitic membranes.^6,14,15 These antigens have intermittent interaction with the host immune system as a result of remodeling mechanisms during the calcification process. This causes inflammatory changes in surrounding brain tissue, which further leads to blood–brain barrier disruption, edema formation, and release of free radicals such as nitric oxide. These free radicals can stimulate the release of CGRPs, which lead to the activation of the trigeminal–vascular reflex and induce migraine.^7,8,16,17

Despite a greater baseline headache frequency, VAS score, and MIDAS score, patients in the NCC group showed a better treatment response in comparison to control subjects. This is an interesting finding in our study and can be explained by the anti-inflammatory action of amitriptyline in addition to its anti-migraine action. Amitriptyline is a dual serotonergic and noradrenergic reuptake inhibitor and is used in the treatment of migraine, chronic pain conditions, and depression. The anti-inflammatory action of amitriptyline has been documented in various experimental studies.^18–20 This anti-inflammatory action may be a result of the reduction in nitric oxide production or a decrease in inflammatory mediators such as substance P, prostaglandin E2, interleukin 1, and tumor necrosis factor-α.^21,22 Among these, the role of substance P in particular has been studied in neurocysticercosis. Robinson et al.²³ conducted an immunostaining study on brain biopsies of patients with neurocysticercosis and found that substance P positive cells were only present near the lesions and were not present at distant brain regions. By suppressing inflammation in surrounding parenchyma, amitriptyline eliminated the difference in headache frequency and severity between the two groups at the end of 3 months in our study.

We found a significant difference in baseline headache frequency in patients and control subjects, but at the 3-month follow-up, this difference disappeared. This can also be explained by the phenomenon of regression to the mean. However, this does not entirely negate the impact of neurocysticercosis on outcome. On multivariate analysis, a good outcome was predicted independently by the presence of neurocysticercosis also, along with greater baseline headache frequency. However, the OR for the presence of neurocysticercosis (OR, 26.57) was much greater than the baseline headache frequency (OR, 1.38).

In our study we made efforts to remove confounding factors such as concomitant seizures and the effect of preventive medicines. This allowed us an unbiased comparison of baseline frequency and severity of migraine among migraineurs with calcified neurocysticercosis and without calcified neurocysticercosis. In addition, ours is a prominent tertiary care center in northern India that caters to the population of Uttar Pradesh as well as other surrounding states such as Bihar and Madhya Pradesh, which enhances the generalizability of our results.

There are certain limitations to our study. We did not do any advanced neuroimaging to determine whether perilesional edema could have represented perilesional inflammation. We also did not do any biopsy or histopathological examination to demonstrate inflammatory changes in brain parenchyma surrounding the calcified lesions in our patients. Nonetheless, performing a biopsy on patients with migraine is very challenging and may raise ethical concerns. We also did not determine CGRP levels in our patients, which could have shed additional light on the pathophysiology of increased frequency of migraine in the patients. Apart from this, our study design was such that it did not allow any blinding, which might introduce some bias to our results. We excluded patients with aura because sometimes aura can occur as a result of epileptogenic focal cerebral lesions, and it becomes difficult to differentiate whether it is a migraine aura or aura secondary to lesions.²⁴ Nonetheless, because of this, we could not see the impact of neurocysticercosis on aura.

Our study emphasizes that seemingly inert calcified lesions of neurocysticercosis influence the course of migraine by increasing the frequency and severity of headaches in patients with migraine. Further studies are warranted to explore possible inflammatory mechanisms in calcified neurocysticercosis that influence migraine physiology. Studies with advanced neuroimaging protocols such as dynamic, contrast-enhanced magnetic resonance imaging,²⁵ along examination of CGRP levels in peripheral blood may pave the way to a better understanding of the mechanisms behind the increased severity of migraine in patients with calcified lesions.