45.1.1 Clinical Presentation

A 65-year-old female patient of Filipina-Canadian descent presented with acute-onset headache with a 10 out of 10 severity. Headache had begun acutely 4 days prior to visiting the hospital. It was characterized as diffuse and bilateral, centered at the vertex of her skull. The headache was described as different in character from the patients’ normal migraines. There were no associated symptoms such as visual symptoms, nausea or vomiting, photophobia, phonophobia, meningismus, or focal neurological deficits. The patient’s headache improved 30 to 45 minutes after taking ibuprofen, although it did not resolve completely. She continued to take ibuprofen every 4 to 6 hours over the next 4 days; however, the headache worsened. The patient went to her local hospital where a noncontrast CT of the head was performed, which showed subarachnoid hemorrhage over the left frontal convexity (Fig. 45.1). She was then transferred to a tertiary hospital and was assessed by neurology and neurosurgery; thereafter, she was admitted for treatment and further investigations. On physical examination, no focal neurological deficits were found. Laboratory investigations showed the patient to be a chronic hepatitis B carrier. Her hepatitis was not active during the course of admission. Rheumatology was consulted with working diagnosis of cerebral vasculitis versus reversible cerebral vasoconstriction syndrome (RCVS). Rheumatology blood panel was negative.

45.1.2 Imaging Workup and Investigations

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  Initial noncontrast CT of the head demonstrated a focal area of hyperdensity, compatible with subarachnoid hemorrhage, within a left frontal convexity sulcus. Subsequent CTA did not demonstrate a vascular cause for subarachnoid hemorrhage.

  
  
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  MRI of the brain exhibited sulcal hyperintensity on the fluid-attenuated inversion recovery (FLAIR) sequence and gradient echo T2 hyperintensity overlying the left frontal and parietal lobes adjacent to the central sulcus, in keeping with subarachnoid hemorrhage.

  
  
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  Catheter angiography was performed which exhibited multiple focal segmental areas of mild arterial narrowing, involving the pericallosal artery and distal cortical anterior cerebral artery branches, as well as the mid and distal middle cerebral artery branches. There were also similar findings in the distal posterior cerebral arteries more prominent on the left (Fig. 45.2).

  
  
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  Follow-up angiogram was performed four weeks after the initial catheter angiography, and there was interval resolution of the previously noted areas of arterial narrowings.

  

45.1.3 Diagnosis

Reversible cerebral vasoconstriction syndrome.

45.1.4 Treatment and Follow-up

The patient was treated with Solu-Medrol and prednisone for the working diagnosis of vasculitis, with a tapering dose over 3 months following discharge. She was also initially treated with Nimodipine and then Verapamil for possible RCVS. Acute pain service provided supportive management for pain control. She was discharged with satisfactory resolution of her headaches and returned for follow-up catheter angiogram 4 weeks following discharge.

45.1.5 Outcome

The patient remained asymptomatic on her last follow-up visit, 7 months after initial presentation.

45.2.1 Background

RCVS is a clinicoangiographic syndrome characterized angiographically by reversible diffuse-multifocal narrowing of the cerebral arteries, and typically associated with single or recurrent episodes of sudden and severe thunderclap headaches. This may be complicated by ischemic or hemorrhagic strokes and a variety of other neurological complications. ^{1 ,​ 2 ,​ 3 ,​ 4 ,​ 5 ,​ 6}

It was also previously known as Call–Fleming syndrome among other names such as thunderclap headache with reversible vasospasm, postpartum cerebral angiitis, central nervous system pseudovasculitis, and benign angiopathy of the central nervous system ^{5 ,​ 7 ,​ 8 ,​ 9 ,​ 10 ‎}

The syndrome is considered relatively rare and its exact incidence is unknown. ⁵ It appears to be more common in women than in men with a ratio of 2.4:1 and the mean age of presentation is 42 years (range: 10–76 years) with no clear ethnicity group specification. ^{‎ 2 ,​ 3 ,​ 4 ,​ 5 ,​ 11}

45.2.2 Pathology

The pathophysiology of RCVS is poorly understood. Many theories have been postulated, including sympathetic overactivity, dysregulation of vascular tone of intracranial arteries, and blood–brain barrier (BBB) breakdown. The latter was demonstrated in a study conducted by Lee et al.‎ ¹² It was based on the idea that the contrast-enhancing FLAIR MRI sequence will show gadolinium leakage into the cerebrospinal fluid (CSF) spaces and brain parenchyma secondary to a disturbed BBB. This finding was showed in two-thirds of patients with RCVS. This would suggest that the cerebral capillaries are also affected. Further studies are needed to better understand the relationship between BBB breakdown and vasoconstrictions in RCVS‎. ¹²

Dysregulation of intracranial vascular tone leading to vasoconstriction is believed to be the key pathophysiologic mechanism. It occurs secondary to spontaneous or evoked sympathetic overactivity by a release of exogenous or endogenous factors like vasoconstrictive drugs and female hormones among other immunologic and biochemical factors. This is supported by the absence of histologic changes in brain biopsy such as active inflammation or vasculitis. ^{1 ,​ 2 ,​ 3 ,​ 8 ,​ 13 ,​ 14 ,​ 15 ,​ 16}

Serotonin-producing tumors and serotonin-enhancing medication have been found to be associated with RCVS, which suggests that serotonin plays an important role in the pathophysiology of RCVS.‎ ⁹

Several triggers for RCVS have been identified, including early puerperium, late pregnancy, preeclampsia, vasoactive drugs (phenylpropanolamine, pseudoephedrine, ergotamine, tartrate, methysergide, bromocriptine, lisuride, selective serotonin reuptake inhibitors, sumatriptan, and isometheptene), recreational drugs (cocaine, ecstasy, marijuana, and amphetamines), tacrolimus, cyclophosphamide, pheochromocytoma, and carcinoid. ^{5 ,​ 17 ,​ 18 ,​ 19 ,​ 20 ,​ 21}

45.2.3 Presentation

RCVS is most commonly a monophasic self-limiting condition. The most prominent symptom is a severe thunderclap headache reaching its peak intensity within seconds. Up to 80% of the patients have a thunderclap headache; thus, less severe, subacute, or even absent headache is rare. In 70 to 80% of the patients, it is the only presenting symptom. The thunderclap headaches can recur up to three weeks and may occur spontaneously or be triggered by coughing, orgasm, physical exertion, acute stressful or emotional situations, straining, sneezing, bathing, or swimming. ^{1 ,​ 5 ,​ 8 ,​ 9 ,​ 10 ,​ 18}

Other focal neurological symptoms can be associated with RCVS. Most commonly, these are visual symptoms; however, aphasia and sensory symptoms have also been reported. They can mimic transient ischemic attacks or migraine auras. ^{1 ,​ 5}

45.2.4 Diagnosis

The diagnostic criteria in Box 1 were proposed by Calabrese et al.‎ ² The new International Classification of Headache Disorders, 3rd edition (ICHD-3; beta version) has proposed the diagnostic criteria shown in Box 2 for headaches attributed to RCVS and headache probably attributed to RCVS‎. ^{6 ,​ 14}

45.2.5 Differential Diagnosis

The diversity of the RCVS clinical and imaging features carries a wide range of differential diagnoses. Thunderclap headaches can also indicate a variety of serious threatening conditions such as aneurysmal subarachnoid hemorrhage, parenchymal hemorrhage, cerebral artery dissection, and cerebral venous sinus thrombosis. Typical precipitants of RCVS can also trigger headache in primary (such as primary thunderclap headache, primary exertional headache, and orgasmic and migraine headache) or secondary headache disorders other than RCVS. ^{3 ,​ 5 ,​ 7 ,​ 9 ,​ 11}

Migraine should be cautiously considered in the sitting of severe headache and migraine-related stroke, because treating it inappropriately with agents such as sumatriptan may exacerbate vasoconstriction and stroke. ^{4 ,​ 13 ,​ 18}

The most challenging and difficult to exclude differential diagnosis is the primary angiitis of the central nervous system (PACNS), given the close sharing and common overlapping of the clinical and radiological features in both conditions. RCVS has the favor of stable or improving clinical course early on in comparison with continuous deterioration in PACNS. The presenting features of explosive recurrent thunderclap headaches with normal CSF findings and normal brain imaging suggest a diagnosis of RCVS. Also, the presence of history of common triggers and associated cofactors may provide clues to the diagnosis. Other characteristic radiological features that may guide the RCVS diagnosis in the appropriate clinical setting are the absence of brain lesions on initial imaging and the presence of cortical convexal subarachnoid hemorrhages as well as the angiographic findings “string of beads” appearance. ^{13 ,​ 33 ,​ 34 ,​ 35 ,​ 36}