OnabotulinumtoxinA injections: treatment of reversible cerebral vasoconstriction syndrome chronic daily headaches

Abstract

Reversible cerebral vasoconstriction syndrome (RCVS) is a rare condition characterised by repetitive, multifocal, vasofluctuations of cerebral arteries. A key symptom is chronic, disabling ‘thunderclap’ headaches, which are extremely difficult to treat as established medications may exacerbate the pathophysiology of RCVS. OnabotulinumtoxinA (OBT-A) injections are used for the prophylaxis of chronic daily headaches (CDH). The mechanism of action of OBT-A significantly differs from oral headache treatments. Thus, OBT-A may be an effective, safe treatment of RCVS-CDH. A 51-year-old woman with RCVS-CDH presented to outpatient clinic. This case report describes the first, believed, documented treatment of RCVS-CDH by OBT-A injections. In 2018, the consented patient received a total of 200 units of OBT-A, 155 units to the 31 approved U.S. Food and Drug Administration (FDA) sites and 45 units injected into the bilateral occipital belly of occipitofrontalis muscles. The patient reported 3 months of excellent pain relief (60% reduction). Three rounds of OBT-A injection, each 3 months apart, resulted in 80% reduction. OBT-A injections may prove a successful, novel treatment for RCVS-CDH.

Background

Reversible cerebral vasoconstriction syndrome (RCVS), first described by Call and Fleming in 1988 (Call-Fleming syndrome), but with case studies dating back to the 1960s, is a current diagnosis used to describe a group of cerebrovascular vasospasms and the resulting syndrome.^{1 2}

Historically, this disease was termed isolated benign cerebral vasculitis, postpartum angiopathy, primary thunderclap headache (TCH) and vasospasm in fatal migrainous infarction, among other names.³ The current name, RCVS, was proposed by Leonard Calabrese in 2007, being more descriptive of the pathophysiology.⁴

RCVS is characterised by segmental, multifocal vasofluctuations (constrictions and dilations) of the cerebral arteries.⁵ The main presenting symptom is TCH; other presentations and sequelae include nausea, vomiting, photophobia, phonophobia, seizures, hemiplegia, ataxia, dysarthria, aphasia and numbness.^{1 6} These presentations can make diagnosis difficult as the differential includes traumatic/anoxic brain injuries, stroke, migraines, seizures, meningitis, as well as other neurological conditions.

RCVS has a female to male ratio of 2.4:1 with an average age of onset of 42.⁷ The exact pathophysiology of both RCVS and the resulting chronic daily headaches (CDH) (greater than or equal to 15 headaches (HA)/month) is unknown. However, RCVS is believed to resolve in a period of 1–3 months.⁸ Nonetheless, the ramifications, such as HA, may be chronic. HAs in patients with RCVS prove very difficult to treat as most HA treatments are contraindicated.

Studies in RCVS are rare as much of the current knowledge base emanates from case reports. This case report presents a patient with a complex medical course, who first experienced TCH in 2013. In 2015, neurology formally diagnosed the patient with Call-Fleming syndrome with angiography showing diffuse, mild vasoconstriction. A year later, the patient presented to physical medicine and rehabilitation with intractable CDH, not responding to conventional treatments. The authors believe that this case report is the first ever documented treatment of RCVS-CDH with onabotulinumtoxinA (OBT-A) injections.

RCVS-CDH clinically differ from migraine, tension, cluster, hormonal, caffeine withdrawal, exertion, hypertension, rebound and postconcussive HA in mechanism, frequency, intensity and treatment. These acute TCH, reaching peak severity by 1 min and lasting at least 5 min, are a common symptom of unruptured cerebral aneurysms and vasospasms.^{9 10}

There exists an array of established treatment options for CDH in patients without RCVS. These fall under two categories: therapeutic and prophylactic. In the former are analgesics such as acetaminophen, triptans (sumatriptan, rizatriptan, almotriptan), ergot alkaloids (dihydroergotamine, ergotamine), antinausea (chlorpromazine), opioids (hydrocodone, oxycontin) and glucocorticoids (prednisone, dexamethasone). In the later, prophylactic medications include beta blockers (propranolol, metoprolol), calcium-channel blockers (verapamil), tricyclic antidepressants (amitriptyline) and antiseizure drugs (valproate, topiramate). OBT-A injections have been shown to work as a prophylactic treatment of CDH.¹¹ Furthermore, alternative, but mild, treatments for CDH include acupuncture, butterbur extracts, low sound/light environments, ice packs and supplements (magnesium, riboflavin). However, many of these established CDH medications and treatments (eg, triptans are potent vasoconstrictors) are contraindicated in patients with RCVS as they may contribute to vasofluctuations and thus aggravate this syndrome.^{12 13}

The triggers and pathophysiology of RCVS vasospasms are currently unknown.^{1 8} It is thought that RCVS is due to a transient disturbance in the control of cerebrovascular tone, and alterations in such have been shown to be a key underlying mechanism.^{1 3} Medications, procedures and treatments that may cause alterations in cerebral vascular tone are contraindicated in RCVS, as they may lead to disturbances in blood flow and therefore aggravate RCVS and trigger TCH. Contraindicated vasoactive, non-therapeutic and therapeutic, substances in RCVS include cannabis, cocaine, 3,4-Methyl​enedioxy​methamphetamine (MDMA), amphetamines, Lysergic acid diethylamide (LSD), binge drinking, ergot and ergoline derivatives, sympathomimetics, nasal decongestants, selective serotonin reuptake inhibitors (SSRI), triptans, immunosuppressants, interferon-α, ginseng and nicotine patches.⁸ More specifically, the following are also contraindicated: trazodone, orgasms, valsalva maneuver, hot showers, decongestants, non-steroidal anti-inflammatories, cold/cough medications and epinephrine.

Most HA treatments are contraindicated in RCVS; however, an extensive literature search did not yield any study into the contraindication or use of OBT-A in RCVS. Hence, the mechanism of action of OBT-A was seriously analysed prior to use in this patient, and did not seem to contribute to vasofluctuations.

A series of OBT-A injections repeated every 3 months has been found to be a safe and effective treatment for the prophylaxis of CDH.¹⁴ OBT-A is a sterile, vacuum-dried purified botulinum toxin type A, produced from fermentation of Hall strain clostridium botulinum type A intended for intramuscular use.¹⁵ OBT-A is purified to a complex of the neurotoxin and accessory proteins.¹⁵ This complex is administered by intramuscular injection into the glabellar, frontal, temporal, bilateral trapezius and suboccipital regions of the head and neck.¹⁴ The complex binds to motor nerve terminal acceptor sites and inhibits acetylcholine release in vivo, thus blocking neuromuscular transmission.¹⁵ OBT-A inhibits acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) at the C-terminal of the protein.¹⁶ SNAP-25 is an integral protein relating to the docking and release of acetylcholine from vesicles within the nerve endings.¹⁵ Thus, by cleaving SNAP-25, OBT-A results in muscle chemodenervation.

In summary, OBT-A works to inhibit the release of acetylcholine from presynaptic motor neurons at the neuromuscular junction, thus causing partial muscular paralysis. It is crucial to note that this process seems to function independent of blood flow alterations and vasofluctuations. Most importantly, the mechanism of action of OBT-A differs dramatically from triptans (potent vasoconstrictors) and SSRI agents in that it does not stimulate serotonin, or other neurotransmitters, in order to encourage the reduction of inflammation and dilation of blood vessels.^{12 13 17} Thus, from a neurochemical perspective, OBT-A injections appear to be a fitting treatment for RCVS-CDH.

Case presentation

In 2016, a 51-year-old Caucasian, right-handed woman, presented to outpatient clinic for lability and ‘stroke, traumatic brain injury and brain haemorrhage’. The patient also showed other crucial medical symptoms (HA, neuropathy, insomnia, decreased balance, anxiety and possible hallucinations). Because the patient had been previously diagnosed with RCVS in 2015, the medical issues were more complex than initially thought.

Prior to the patient’s RCVS diagnosis, her medical history included three successful childbirths, hypothyroidism, hypovitaminosis D, gastro-oesophageal reflux disease, hysterectomy, colostomy reversal, appendectomy, lumbar degenerative arthritis, lower cervical fusion, right adrenal adenoma and migraine HA experienced from childhood through adulthood. The patient had no known allergies and a non- contributory social and family history.

In early 2015, the patient went to the hospital for abdominal pain and had a nasogastric tube inserted. During her stay, she had a fall, could not hold a glass and had a TCH.

Two days later, her husband noticed right facial drooping. She was diagnosed with a large right temporal increasing haematoma which measured approximately 6 cm with surrounding oedema and a small subarachnoid haemorrhage with effacement of right-sided sulci and midline shift. She underwent a large right frontal temporal parietal decompressive craniectomy. Neurosurgery then diagnosed her with vasculitis. On the same day, CT angiography of head reported ‘…There are a few, scattered focal regions of narrowing within the ACA and MCA branches bilaterally.’ On the following day, cerebral angiography reported ‘… diffuse multiple predominantly mild to moderate, mid and distal cerebrovascular arterial stenosis’. Interventional radiology angiogram of the head and neck reported ‘There is a prominent pattern of tandem stenosis involving the mid and distal branches of the right ACA territory more than the right MCA territory giving an undulating contour. These are particularly prominent in the right ACA internal frontal territory where they are moderate to severe’.

Despite radiology not formally stating the pathognomonic beading of RCVS, it can be inferred that the above demonstrates this phenomena.¹⁸ The patient stated that immediately following the above, she began experiencing TCH. A month later, neurology formally diagnosed her with RCVS.

From 2015 to 2018, the patient reported a TCH occurring every week, which was described as 4-day long (Wong-Baker scale 10/10) thunderclap, throbbing, with right-sided pressure radiating posteriorly with a continuous baseline.¹⁹ These HAs were associated with facial numbness, nausea, occasional vomiting, blurred vision, phonophobia, photophobia and auditory hallucinations. They were exacerbated by valsalva manoeuvre, orgasms (both acting as immediate triggers), stress, anger and physical movement. They were relieved by hydrocodone/acetaminophen, right-sided temporal applied pressure, occiput ice pack, and a low noise/light environment.

During this period, despite being treated with nimodipine (shown in past research to treat TCH) metoprolol, divalproex sodium, topiramate, nortriptyline and hydrocodone/acetaminophen, HAs were intractable and unchanged, which resulted in multiple hospitalisations.³

Treatment

After exhausting established treatments, OBT-A was discussed with the patient. An extensive literature search was performed to find prior studies and potential side effects, due to the patient’s RCVS. The search showed no known documentation of the use of OBT-A for treatment of CDH in RCVS; likewise, given the mechanism of action of OBT-A there was no apparent contraindication. The patient was informed of the above and all potential side effects as well as benefits were explained. The patient gave both written and verbal consent for procedure.

In 2018, 200 units of OBT-A was reconstituted using 4 mL of preservative free normal saline and 4 syringes prepared. Using tuberculin needles, 155 units were injected in the 31 U.S. Food and Drug Administration (FDA)-approved sites; the remaining 45 units were injected bilaterally into the occipital belly of occipitofrontalis muscles. All sites were cleansed with alcohol prior to injection. The patient tolerated the procedure well and there were no side effects other than a temporary right eyebrow raise.

Outcome and follow-up

After initial OBT-A, the patient reported no HA, 4 out of every 7 days, with the remaining 3 days having a baseline HA ranging from 1–2/10 (a decrease from the initial 3–4/10) but no TCH. She additionally reported a decrease in frequency and intensity of TCH from ‘almost constant’ to ‘almost none’ with a decrease in pain from 10/10 to 7/10 in any occurring TCH. Subjectively, she stated overall improvement of 60% ‘within 3–4 days after injections’ lasting approximately 3 months. The patient reported no resultant HA from orgasm, despite saying that pre OBT-A orgasms would trigger TCH.

Following the FDA-approved protocol, the patient underwent second round of OBT-A injections 3 months later. However, this time the sites above right eyebrow were not injected. Two months postprocedure, the patient reported 30% overall improvement in HA. Three months later, she underwent third round of OBT- A injections with injection to the right eyebrow sites just as in the first round. She reported 80% overall improvement a month later.

Discussion

Due to the pathophysiology of RCVS, treatment of the severe, prolonged TCH presents multiple challenges. In this disease, most established HA treatments are contraindicated as they exacerbate vasofluctuations. As research is limited, case studies have proven an important tool in the treatment and knowledge base of TCH in RCVS. In 2007, Calabrese and colleagues created the term RCVS as a diagnostic criteria to group all similar cases into one category.³ Since then, a large collection of case studies has been published, serving to innovate the treatment and knowledge of RCVS. Here, we present the first, believed, documented treatment of RCVS-CDH with OBT-A injections.

Initially, the patient presented with polypharmacy, having been treated with standard medications such as metoprolol, amlodipine, senna, keppra, topiramate and norco. The patient’s CDH proved resistant to these treatments. Nimodipine was given as a vascular smooth muscle stabiliser to treat RCVS as it has been suggested for TCH treatment.^{3 20} Unfortunately, CDH remained unaltered and TCH persisted for a 3-year period. After great consideration, multiple literature reviews and patient consent, OBT-A was successfully used, resulting in remarkably decreased CDH and increased quality of life. In addition to subsiding HA, quality of life improved as patient’s orgasm-triggered TCH abated post-OBT-A. Furthermore, OBT-A usage can minimise polypharmacy, medication side effects and drug interactions.

While OBT-A was found to be an effective treatment for RCVS-CDH, other emerging options should be considered. These novel potential treatments include erenumab-aooe (a monthly biological monoclonal antibody), whose mechanism of action appears to not influence cerebral vasofluctuations. Cotreatment options can include physical therapy and biofeedback.

According to existing literature, RCVS and TCH are self-limiting.⁸ However, in this patient, this may not be the case. The patient had migraines since childhood; childhood migraines can result from early RCVS.^{21 22} Furthermore, after formal RCVS diagnosis, the patient continued to have TCH over a 3-year period, during which OBT-A could have been used as a prophylactic treatment. Given the chronicity of symptoms in the described patient, the authors believe that RCVS in some cases may be better termed chronic cerebral vasoconstriction syndrome.

Learning points.

• Reversible cerebral vasoconstriction syndrome (RCVS) is a rare condition characterised by repetitive, multifocal, vasofluctuations of cerebral arteries commonly resulting in the key symptom of thunderclap headaches.

• Headaches prove near impossible to treat in patients with RCVS due to the pathophysiology of the disease; most oral headache medications are contraindicated. The authors believe that this case presents the first known treatment of RCVS chronic daily headaches with onobotulinumtoxinA injections.

• Three rounds, each 3 months apart, of a series of onobotulinumtoxinA injections to the 31 FDA-approved sites, and to the occipital belly of occipitofrontalis muscles, resulted in 80% overall improvement of headaches in a patient with RCVS. Frequency and intensity of the thunderclap headache went from ‘almost constant’ to ‘almost none’.

• Demonstrated by the chronicity of RCVS symptoms in the described patient, the authors hypothesise that RCVS in some cases may be better termed chronic cerebral vasoconstriction syndrome.