A Rare Case of Idiopathic Reversible Cerebral Vasoconstriction Syndrome

Introduction

Headache disorders, including migraines, tension headaches, and cluster headaches, affect approximately 46% of adults worldwide and account for about 3.5 million emergency department (ED) visits annually in the United States [1]. Occasionally, headaches can manifest as the primary symptom in many serious conditions, such as primary angiitis of the central nervous system (PACNS), systemic vasculitis, and non-inflammatory intracranial vasculopathies [2–4]. Reversible cerebral vasoconstriction syndrome (RCVS) is a subset of non-inflammatory intracranial vasculopathies [2]. RCVS is classified as a condition of diffuse cerebral artery constriction and can be complicated with transient neurological deficits, seizures, ischemic strokes, and hemorrhagic strokes [5–11]. It is suggested that RCVS can account for about 3 hospitalizations per million adults [7]. However, it is believed that RCVS may be underdiagnosed as ischemic strokes or migraines [8].

A predominant characteristic of RCVS is a thunder-clap headache, which patients describe as being the worst headache they have experienced. Thunder-clap headaches present in 85% of RCVS cases [8]. About 81% of patients with RCVS have experienced multiple recurrent thunder-clap headaches over an average period of 1 week [10–13]. RCVS is classified as being idiopathic or secondary to conditions including trauma, extreme environmental changes, exertional activities, changes in hormone levels, taking of vasoactive agents, emotional stress, and/or recreational drugs [5–10]. Populations with the highest prevalence of RCVS include women (77.5–80.0% of RCVS cases), Whites (64.0–87.0% of RCVS cases), and patients with a history of hypertension (54.1% of RCVS cases) [7]. The average age of individuals affected by RCVS is about 45 years in women, with men being about 10 years younger on average when affected by RCVS [7,10].

In this case study, we present a healthy young woman who presented to the ED 3 times with concerns of severe headaches. Her third ED visit resulted in hospitalization due to seizures and acute intracranial hemorrhage (ICH). The patient ultimately received a diagnosis of RCVS during her hospitalization.

This case study will illustrate investigations that took place to help diagnose the condition and treat the patient, including the identifying features of RCVS, a brief review of the follow-up visits after the initial diagnosis of RCVS, and possible factors that could have contributed to the worsening and onset of RCVS in the patient.

Case Report

The patient was a 34-year-old Black woman who presented to the ED with a chief concern of a recurrent, severe headache. Her past medical history was significant for heart murmurs and migraines that occurred about 1 to 2 times a month and were worse in the summer, which she attributed to increased stress. The patient reported that she underwent cryotherapy for stress relief before initial evaluation in the ED. She also reported that she began having recurrent, sudden-onset headaches that initially began during cryotherapy. The patient presented to the ED 2 days after the cryotherapy treatment, twice on the same day. The patient was evaluated for the third time 3 days later.

During the first ED visit, the patient reported having a severe, sudden-onset headache that persisted for about 12 h at that time and was associated with nausea and photophobia. The patient described that the headache she was experiencing was worse than previous migraines she had experienced. A computed tomography angiography (CTA) of the head and neck that was performed at the time of this initial visit depicted no evidence of hemodynamically significant stenosis, occlusion, or aneurysmal changes. The patient tested negative for SARSCoV-2, RSV, and influenza A and B and had a non-focal neurological examination, with normal vital signs. She was treated with dexamethasone, prochlorperazine, diphenhydramine, and ketorolac and discharged home after the headache resolved.

The patient then presented to the ED again for a second time, just 4 h later, as the headache returned. She described the headache as being a sudden-onset, severe, and sharp sensation over her temples that lasted for longer than 5 min, although the nausea and photophobia had resolved. The patient had a non-focal neurological examination, and aside from an elevated blood pressure of 124/100 mmHg, all other vital signs were normal. No additional imaging was performed during this visit. The patient endorsed that she had used acetaminophen and ibuprofen for some relief prior to her visit. Diphenhydramine, metoclopramide, and ketorolac were administered in the ED, and upon re-assessment, the patient reported resolution of her symptoms. She was again discharged home.

Three days later, the patient presented to the ED once again for evaluation of a severe, sudden-onset headache. Initial vital signs were significant for an elevated blood pressure and heart rate. Shortly after arrival to the ED, the patient began having tonic-clonic activity of the upper extremities, with right eye deviation. She was treated with benzodiazepines, then became combative in her postictal state, thus requiring multiple rounds of sedatives to be administered, before she was ultimately endotracheally intubated for airway protection. Her ED evaluation included brain CT, blood work, and a lumbar puncture.

A brain CT depicted a focal parenchymal hemorrhage within the paramedian left parietal lobe (Figure 1) and posterior left occipital lobe (Figure 2), with trace subarachnoid extension adjacent to the left paramedian parietal hemorrhage. CT venography was negative for acute dural venous sinus thrombosis.

The complete blood count, peripheral smear, and cerebral spinal fluid all showed an elevated white blood cell (WBC) count (Table 1). A urine rapid drug screen, as shown in Table 2, depicted that the patient was positive for tetrahydrocannabinol. Due to the patient’s condition and elevated WBC count, there was ongoing concern for meningitis/encephalitis. She was treated with broad-spectrum antibiotics and admitted to the Surgical/Trauma Intensive Care Unit for neurosurgery and neurology consults and ventilation management.

The following day, the patient had magnetic resonance imaging (MRI) completed, which depicted 2 parenchymal hematomas, with one in the left occipital lobe and the other in the left parietal lobe. Figure 3 depicts the one in the left parietal lobe, which did not differ from the results noted previously on the CT scan performed the day prior (Figure 1). No etiology was identified on the MRI to explain the hematomas, and there was no evidence of vascular malformation or dural venous sinus thrombosis. The patient also had a digital subtraction angiography performed, which showed multifocal irregularities of the left middle cerebral artery branches; hence, with this diffuse vasoconstriction, vasculitis vs RCVS remained in the differential diagnosis (Figure 4).

The next day, the results of her encephalitis/meningitis PCR panel returned and were negative (Table 3); therefore, an infectious process as the etiology was ruled out. She also tested negative for the MTHFR C.1286A>C mutation and was heterozygous for the MTHFR C.665C>T mutation, which was significant, as individuals that are homozygous for MTHFR mutations are at an increased risk for having ischemic strokes at a young age [14].

The neurology team’s leading diagnosis was RCVS, as there were no ischemic changes noted on the MRI, and the patient’s initials symptoms started during cryotherapy. The patient noted that she was undergoing the cryotherapy for increased emotional and work-related stress at the time, which can increase vasoconstriction. The patient was extubated during her second day of admission and had labile blood pressure readings, which were intermittently hypertensive. She was treated by the nephrology team for blood pressure management. Table 4 outlines the patient’s treatment plan during her admission and the medication regimen she was discharged with. At the time of discharge, the patient was noted to not have any focal neurological deficits and was advised to discontinue the use of herbal supplements and vitamins that she reported having previously used.

At her 1-month follow-up appointment with the neurology team, the patient reported ongoing difficulties concentrating, mild to moderate headaches, which were relieved by her medication regimen, and fatigue, but overall felt that her condition had improved. The patient also denied having had any seizures since being discharged. The neurology report did note that the patient had 4 out of 5 weakness to her right upper extremity, but otherwise no other focal neurological signs or symptoms were noted. She was advised to continue to avoid possible triggers for RCVS, such as marijuana use, illicit drug use, herbal supplements, overexertion, Valsalva maneuver, antihistamines, and decongestants, which can increase intracranial pressure and lead to a reoccurrence of RCVS.

At the 3-month follow-up appointment, a CTA of the head and neck showed no vascular malformations, venous anomalies, changes to suggest vasculitis, or aneurysms and that the previously noted parenchymal hematomas had resolved, with no new hemorrhage identified (Figure 5). This finding is in line with earlier research conducted, where the hallmark sign of RCVS is that the previously noted CTA abnormalities resolve within 1 to 3 months, which is consistent with the timeline shown in Figure 6 [10].

Discussion

There are many challenges in diagnosing RCVS. Reasons include that its symptoms overlap with many other vasculopathies, and the timing between headache onset and abnormal image findings are inconsistent, varying over a period of about 8 days [3,12]. Although most affected patients with RCVS are women, White, and have an average age of 45 years, the patient discussed in this case study was younger and Black [7,13]. The patient did not have a previous history of any vascular risk factors that are usually correlated with a higher risk for RCVS, such as coronary artery disease, hypertension, and diabetes [7]. Prior history of migraines has been shown to correspond with an increased risk for RCVS as well, which the patient in this study did report [13]. Some studies have also shown a correlation between COVID-19 and RCVS; however, this patient had a negative PCR test for SARS-CoV-2 [8].

Although RCVS is a subset of non-inflammatory intracranial vasculopathies, it is the most notable mimicker that should be distinguished from the other similar-presenting vasculopathies, notably PACNS and posterior reversible encephalopathy syndrome (PRES) [2,3,10,15]. The presentation of thunder-clap headache along with the complications of seizures and intracranial hemorrhage presents not only in RCVS, but also in PACNS and PRES [2–4,10,15]. However, in RCVS, headaches are commonly recurrent and have sudden onset (81%), while in the other mentioned vasculopathies, headaches are more chronic in nature [3,8,13]. As an inflammatory vasculopathy, PACNS requires a treatment course different from that of PRES and RCVS [2,3,10,15]. Administering the treatments usually given to a patient with PACNS, such as glucocorticoids and immunosuppressive agents, can exacerbate RCVS and PRES [2,3,8,10,15,16].

Seizures present more often in PRES, about 60% to 75% of the time, and are less common in RCVS [8]. However, seizures still occur more in patients with RCVS than in patients with PACNS [2]. The patient in this case study did have 2 intraparenchymal hemorrhages and evidence of mild subarachnoid extension, which is consistent with existing literature, as intracranial hemorrhage is more prevalent in RCVS and rarely noted in PRES [5,7,8]. PRES is also more associated with chemotherapy, autoimmune diseases, and prior history of hypertension, which were not present with this patient [9,15]. Although PRES and RCVS differ in their underlying cause, they can occasionally occur at the same time [15]. However, both PRES and RCVS require similar courses of treatments [15].

Although the pathological process of RCVS is unknown, some studies that suggest a dysfunction of cerebral vascular tone and abnormalities in the blood-brain barrier can be the cause of RCVS [6]. However, there are 2 factors that have been linked to a higher risk for RCVS: use of vasoactive substances and the post-partum state [8,9]. Vasoactive substances linked to being likely triggers and/or worsening agents of RCVS include adrenergic agents, such as epinephrine, antidepressants (SSRI/SNRI), blood products, chemotherapy drugs, pseudo-ephedrine, and even anti-migraines drugs, such as ergot derivative drugs, non-steroidal anti-inflammatory drugs, and trip-tans [3,5,7–10]. Some recreational drugs that have also been linked to a higher risk of RCVS, having even led to fatal cases of RCVS when combined with other vasoactive substances, include amphetamines, cannabis, cocaine, ecstasy, and nicotine [8,9]. The other factor that has been connected to an increased risk for developing RCVS is the post-partum state [8,9]. The patient in this case study had a normal human chorionic gonadotropin test result, but the urine rapid drug screen was positive for tetrahydrocannabinol. Emotional stress has also been thought to be a causative factor for RCVS, and this patient did note that she had an increased workload during the time period she had RCVS [12].

For PRES and PACNS, there are usually autoimmune or inflammatory markers, such as evidence of pleocytosis, principally leukocytes and monocytes, and this patient had an elevated WBC count [8,17]. However, upon further investigation, this patient was found to be negative for many infectious agents and had no history of autoimmune factors contributing to her condition. Although, diagnostically, increased levels of emotional stress are listed as a trigger for RCVS, the inpatient neurology team believed that the patient’s undergoing cryotherapy could have contributed to the patient developing RCVS. There are studies reporting that exposure to extreme temperature changes, including full-body cryotherapy, can be possible triggers for RCVS [9,18]. Earlier studies have shown that glucocorticoids, non-steroidal anti-inflammatory drugs, and diphenhydramine are linked with worsening outcomes in RCVS [15,16]. Aside from the patient herself taking ibuprofen prior to her initial ED visits for her headache, glucocorticoids and diphenhydramine were administered in the ED during the 2 initial visits preceding the main visit discussed in this study. However, it is unclear if they contributed to the exacerbation of RCVS.

In terms of long-term outcomes, about 88% of patients with RCVS report improvement of their symptoms. However, over 53% of patients that had previously resolved RCVS continued to have chronic headaches [10,13]. About 13% of patients with RCVS had long-term, severe impairment, and 8% had recurrences of RCVS [10,13]. It was also reported that pain, anxiety, and depression are frequent in RCVS patients, with symptoms being exacerbated by chronic headaches [13].

Conclusions

RCVS is an underdiagnosed condition that is characterized by a sudden-onset, severe headache that can often be misdiagnosed as a migraine. It is important to note that complications including intracranial hemorrhage, subarachnoid hemorrhage, and seizures can arise not just from other vasculopathies but from RCVS as well; hence, an early diagnosis is critical. It is especially important to further evaluate patients who present to the ED for recurrent, severe headaches, even if recent past imaging shows no acute abnormalities. Furthermore, although cryotherapy is not a formally listed cause for RCVS, there are studies suggesting that extreme temperature changes are correlated with an increased risk for RCVS development.