An underdiagnosed condition

Reversible cerebral vasoconstriction syndrome has been reported in patients aged 13–70 years.3, 15 Mean age of onset is around 45 years with a female to male preponderance from between about 2 and 10:1.3, 13, 14 The exact incidence is unknown. This syndrome, although rare, is probably still underdiagnosed, particularly the pure cephalalgic form. Only three series including more than 10 patients have been published.

• A retrospective American series of 16 patients hospitalised for suspected CNS angiitis, of whom 10 had repeat angiography to assess reversibility of vasoconstriction.13

• A prospective Taiwanese series of 56 patients with recurrent thunderclap headaches of whom 22 had proven initial vasoconstriction, then a series of 32 patients (including 12 from the first series) with the proven syndrome.6, 14

• Our prospective French series of 67 cases, seen in a single institution between 2004 and 2007, who all had vasoconstriction and repeat angiography showing its resolution.3

Mechanisms and causes

Although the pathophysiology remains unknown, the prevailing hypothesis is of a transient disturbance in the control of cerebral vascular tone leading to segmental and multifocal arterial constriction and dilatation.2 This disturbance may be spontaneous (so-called idiopathic reversible cerebral vasoconstriction syndrome), while 25–60% of cases are secondary, mostly to exposure to vasoactive sympathomimetic or serotoninergic substances, and/or to the postpartum state (table 2).2, 3, 9, 13, 16

Vasoactive substances

The incriminated substances include various medications such as selective serotonin reuptake inhibitors and all α-sympathomimetics, often used as over the counter nasal decongestants, some diet pills and herbal medications, and most illicit drugs, including cannabis (which is the most frequent cause in France).2, 3, 7, 8, 16, 17 In some patients, the syndrome occurs after just a few days of exposure while in others it occurs after several months of either regular or irregular exposure to one or several of these substances, at normal or excessive doses. Acute alcoholic intoxication may be an additional precipitating factor but has only been incriminated in association with exposure to other drugs, such as cannabis and/or ecstasy/and or cocaine.3

Postpartum

Postpartum reversible cerebral vasoconstriction syndrome starts in two-thirds of cases during the first week after delivery, usually after a normal pregnancy.8, 9, 16 In 50–70% of cases, it is associated with the intake of vasoconstrictors, mostly ergots used to treat postpartum haemorrhage or to inhibit lactation (eg bromocriptine, methergine).9

Other causes

Many other causes have been reported, such as catecholamine secreting tumours, head trauma, neurosurgical procedures, carotid endarterectomy and intracranial hypotension.2, 8, 16, 18 The syndrome may also be associated with other extra or intracranial arterial lesions such as cervical artery dissection, especially postpartum, unruptured intracranial aneurysm, and arterial dysplasia.3, 16, 19 The mechanism of the link between these arterial abnormalities and the vasospastic process is unknown.

It is important to emphasise that the headaches are secondary headaches, symptomatic of the vascular disorder; they have nothing to do with migraine which is a primary headache without any underlying causal lesion.1 A history of migraine is found in only 16–20% of reversible cerebral vasoconstriction syndrome cases, no different from the prevalence of migraine in the general population.3, 14

Overlap with the posterior reversible encephalopathy syndrome

The reversible cerebral vasoconstriction syndrome may complicate severe conditions such as intravenous immunoglobulin therapy in Guillain–Barré syndrome, immunosuppression for transplantation or septic shock. In these complex cases it is almost always associated with a neurotoxic state called the “posterior reversible encephalopathy syndrome” or PRES. This clinicoradiological syndrome has similar clinical features to severe reversible cerebral vasoconstriction syndrome (acute headache, confusion, seizures, cortical blindness) but a characteristic MR imaging pattern, better visualised on FLAIR than on T2 sequences.20 There is bilateral symmetrical hemispheric junctional/boundary zone high signal affecting the cortex, and subcortical and deep white matter to varying degrees. Lesions affect mainly parietal/occipital regions (98%) but also the superior frontal sulcus, temporal–occipital junction and may also be seen in the cerebellum, basal ganglia, brainstem and deep white matter.21, 22 This vasogenic oedema is usually totally reversible in a few days. However, infarction or tissue injury with cytotoxic oedema (leading to focal areas of restricted MR diffusion) may occur in areas of severe hypoperfusion.21, 23 Haemorrhage (focal haematoma or subarachnoid blood) is seen in about 15% of cases.21

The posterior reversible encephalopathy syndrome was initially described in association with eclampsia or during ciclosporin treatment after transplantation, always in the setting of severe hypertension. But it is now recognised as a complication of many other conditions, including pre-eclampsia/eclampsia, immunosuppression after allogenic bone marrow or organ transplantation, autoimmune disease, high dose chemotherapy and septic shock.21, 24

Like the reversible cerebral vasoconstriction syndrome, the exact pathophysiology of the posterior reversible encephalopathy syndrome is unknown, and two hypotheses are debated.25 The most popular is that severe arterial hypertension leads to a failure of cerebral autoregulation with subsequent hyperperfusion and vasogenic oedema. In the emerging second hypothesis, T cell and/or endothelial cell activation may trigger cerebral vasoconstriction leading to hypoperfusion with subsequent brain ischaemia and vasogenic oedema. Whatever the pathophysiology, numerous recent studies have shown that:

• reversible cerebral vasoconstriction is a frequent if not a constant feature of the posterior reversible encephalopathy syndrome

• 20–30% of cases are normotensive

• normotensive cases have vasogenic oedema that is more extensive than hypertensive cases which suggests that hypertension may sometimes be a reaction to the increase in cerebral blood flow in some cases.21, 23 24 25 26

Besides the association of reversible cerebral vasoconstriction syndrome and the posterior reversible encephalopathy syndrome in the setting of severe conditions, it is important to appreciate that about 10% of the former cases are associated with the posterior reversible encephalopathy syndrome, regardless of the cause: idiopathic, secondary to a vasoactive substance or to the postpartum state, or associated with arterial dissection.3, 16

Symptoms and signs

Headache

Headache is often the only symptom, as in 75% of our French series.3 It is severe in most patients and is often of the thunderclap type—very sudden, peaking in less than 1 min and very intense.3, 6, 13, 14 Multiple thunderclap headaches recurring every day or so over 1–4 weeks are almost pathognomonic.2, 3, 6, 14 The headache is typically bilateral, with a posterior onset rather than diffuse, of severe to very severe intensity, sometimes excruciating, with agitation, shouting and yelling, often associated with nausea, vomiting, photophobia and phonophobia. Migraineurs clearly identify the thunderclap headaches as different from their usual headaches. Severe pain usually lasts 1–3 h (but ranges from a few minutes to several days) and 50–75% of patients describe a permanent mild background headache between thunderclap attacks. About 80% of patients report at least one trigger factor: sexual activity, straining, emotion, physical effort, coughing, sneezing, urinating without effort, bathing or showering and sudden head movement.2, 3, 6, 14 In some patients, all their thunderclap headaches are triggered by one or several of these factors while in others some thunderclap headaches occur at rest, and some after a trigger. In our experience in an emergency headache centre, patients presenting with recurrent sexual thunderclap headaches over a few days almost always have reversible cerebral vasoconstriction syndrome.

Some patients have a single thunderclap headache. Some patients describe acute headache attacks awaking them from sleep, a situation that does not allow them to be sure of the thunderclap onset. Rarely, the headache is more progressive and moderate. In the presence of lateral or posterior neck pain, it is important to carefully look for carotid or vertebral artery dissection.3, 19

Focal deficits and seizures

The frequency of other neurological signs and symptoms depends on how the patients are recruited into the studies and varies from 9% to 63%, and for seizures from 0% to 21%.3, 6, 13, 14 Indeed, it is the presence of such features that usually leads to extensive investigations which, by contrast, are frequently not performed when the patient has isolated headaches (even though for a thunderclap headache a normal CT scan should be followed by a lumbar puncture to look for blood in the CSF followed often by imaging of the cervical and cerebral arteries and the intracranial veins).

Deficits and seizures are of many types. Some transient focal deficits have a sudden onset like transient ischaemic attacks, while others begin progressively and successively over a few minutes, with positive visual and/or sensory symptoms mimicking migrainous auras. Persistent focal deficits are usually due to a haematoma or infarction. Impairment of consciousness is infrequent and usually mild, but coma may occur in rare severe cases with multiple strokes.

General examination

The general physical examination is usually normal, except in complex conditions associated with the syndrome and the posterior reversible encephalopathy syndrome in the setting of eclampsia, septic shock, immunosuppression, etc. About 25–30% of patients have blood pressure surges during the thunderclap headaches and some patients also have a facial flush.

Investigations

Brain CT and MRI

Non-contrast CT brain scan is usually normal while the more sensitive MRI was abnormal in about one-third of patients in the prospective series.2, 3, 14 In our patients with purely the cephalalgic reversible cerebral vasoconstriction syndrome, MRI showed a cortical subarachnoid haemorrhage (SAH) in 20% and the appearance of posterior reversible encephalopathy in 10%; and in patients that presented with a persistent focal deficit, MRI showed an infarct or haematoma in 100%. In our 67 patients, the most frequent abnormality was a small localised cortical SAH (22%), unilateral or bilateral, visible as high signal on FLAIR in some sulci near the convexity (fig 1).3, 4, 13, 16, 27 28 29 Focal intracerebral haemorrhage occurred in 6% of our 67 cases.3 This may be single or multiple, cortical or deep and of variable volume (fig 2).3, 5, 30 Subdural haemorrhage has also been reported.30 There may be more than one type of haemorrhage in any one patient. Infarction is rare; 4% in our series.3 The infarcts may be single or multiple and often have a boundary zone distribution (fig 3).2 In 10% of patients, symmetrical high signal on FLAIR is consistent with the posterior reversible encephalopathy syndrome (fig 4).3 Finally, cervical FAT/SAT sequences are very useful to search for any associated cervical artery dissection.

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Figure 1

Cortical subarachnoid haemorrhage in reversible cerebral vasoconstriction syndrome. (A) CT brain scan showing a small right frontal haemorrhage. (B) In another patient with a normal CT scan, MRI (FLAIR) shows bilateral cortical subarachnoid haemorrhage with high signal in several sulci.

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Figure 2

CT showing intracerebral haemorrhage in the reversible cerebral vasoconstriction syndrome which may be single (A, C, D) or multiple (B), lobar (A, B, D) or deep (C), isolated or associated with cortical subarachnoid haemorrhage (B, right frontal cortical subarachnoid haemorrhage, arrows) or with an acute subdural haemorrhage (D, occipital subdural blood, arrow).

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Figure 3

Infarction in reversible cerebral vasoconstriction syndrome: MRI (FLAIR) 3 months after the acute phase showing the sequelae of bilateral occipital and left temporoparietal infarcts.

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Figure 4

Posterior reversible encephalopathy syndrome during reversible cerebral vasoconstriction syndrome: MR FLAIR high signal is mainly symmetrical and may be confluent, predominating in the occipital region (A, a postpartum case) or patchy and moderate (C, an idiopathic case) with resolution in both patients on MRI at 1 month (B, D).

Cerebral angiography

Angiography shows segmental narrowing and dilatation (string of beads) of one or more cerebral arteries (fig 5).2, 31 Non-invasive angiography (MRA or CTA) was only 80% sensitive in our series compared with the gold standard of catheter angiography which is by definition 100% sensitive (because it defines the syndrome), although nowadays rarely necessary (fig 6).3 If another condition or another lesion is very unlikely, and if the initial MRA/CTA is definitely normal, and if there is no cortical SAH and no stroke on MRI, we do not perform a catheter angiogram. But depending on the clinical state of the patient, we may repeat transcranial Doppler ultrasound (see below) with or without repeat MRA/CTA, or we simply follow-up. Of course, in these patients, no definite diagnosis is possible. The first angiogram, whatever its type, may be normal if performed very early, within 4–5 days of onset of symptoms; therefore, if the first MRA or CTA is normal, a second angiogram a few days later may be diagnostic.3

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Figure 5

Catheter angiography in the reversible cerebral vasoconstriction syndrome: multiple segmental narrowings and dilatations affecting medium sized arteries (A, B) and/or large sized arteries (B, C), from the anterior (A, C) or vertebrobasilar circulation (B).

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Figure 6

MR angiography in the reversible cerebral vasoconstriction syndrome performed 8 days after headache onset: multiple narrowings (arrows) of the right middle cerebral artery and both posterior cerebral arteries, with segmental dilatation of the left middle cerebral artery (large arrow) (A). Resolution of abnormalities at 3 months (B).

Calibre irregularities may affect the anterior as well as the posterior cerebral circulation, and are mostly bilateral and diffuse; large arteries such as the basilar or the carotid siphon may also be involved.10 The narrowings are not fixed, and a repeat angiogram after a few days may show the resolution of some with new zones of constriction often involving more proximal vessels.

The syndrome may be associated with single or multiple unruptured cerebral aneurysms (6% in our French series which is not that much more frequent than in the general middle aged population, but these patients had no red blood cells in the CSF and no extravasation of contrast on catheter angiography), arterial dysplasia, and vertebral or carotid dissection.3, 16 The association with dissection seems more frequent in females, particularly postpartum.3, 19

Ultrasound

Cervical ultrasound examination is usually normal except in cases associated with arterial dissection. Transcranial Doppler on the other hand is very useful for monitoring the temporal evolution of cerebral vasoconstriction. In the prospective Taiwanese study of 32 patients, the maximal mean flow velocity in the middle cerebral artery exceeded 80 cm/s in 81% of patients and 120 cm/s in 47%, but never exceeded 200 cm/s.6 Sequential studies are more sensitive than a single investigation because velocities may be normal during the first few days, then begin to increase and reach a peak at the end of the third week after headache onset.3, 6 Transcranial Doppler is also useful to monitor the vasospam but may not be sufficient to reliably assess reversibility which still requires a repeat angiogram. Moreover, some patients still have raised velocities at the end of the third month, even when their MRA has returned to normal.6

Cerebrospinal fluid

There are mild abnormalities in more than half of the patients with an excess of white blood cells (5–35/mm³) and red blood cells (with or without visible subarachnoid blood on MRI) and increased protein levels up to 1 g/l.2, 3 If the lymphocytic reaction exceeds 10 cells/mm³, it is better to repeat the lumbar puncture after a few weeks to make sure it is normal and exclude chronic meningitis.

Other investigations

Blood tests are usually normal but may show a moderate and transient inflammatory response, notably in patients with oropharyngeal infections who took nasal decongestants. Urine toxicology can be useful (cannabis, cocaine, amphetamines, ecstasy). If there are blood pressure surges during the headache phase, urinary amines have to be tested for pheochromocytoma.

Temporal clinicoradiological course

One of the main characteristics of reversible cerebral vasoconstriction syndrome is the temporal pattern of the clinical features and the associated arterial abnormalities (table 3).3 The first symptom is usually a thunderclap headache that recurs during the first week, with the last attack at a mean of 7–8 days after onset. Mild background headache may then persist in about 75% of patients, and finally all significant headaches have gone by about 3 weeks.3, 6 Any intracranial haemorrhage and posterior reversible encephalopathy are early complications during the first week while ischaemic complications (transient ischaemic attacks and infarction) occur later, at the end of the second week, sometimes when the headaches have improved or even resolved.3, 6, 14

Moreover, as already stressed, vasoconstriction may not be disclosed by early angiography but found only later on repeat investigation. Maximal intracranial flow velocities are reached at a mean of 22 days after onset; these velocities are thus maximal when the headache has disappeared.6 The temporal course of the clinical and radiological features suggests a dynamic process starting in distal arteries not visualised on angiography, which progresses towards moderate to large calibre arteries.

Diagnosis

The diagnosis should be suspected in all patients with thunderclap headache, with or without other neurological symptoms, after the exclusion of all other causes (table 4).1, 32 With the current diagnostic criteria, it is impossible to make the diagnosis in the absence of headache. However, reversible cerebral vasoconstriction syndrome without headache or with very minimal headache does probably exist. We had a young women with multiple infarcts and minimal headache, smoking cannabis, with a characteristic MRA and transcranial Doppler which were both normal again at 2 months, and no other cause to better explain her illness.

As already stressed, recurrent thunderclap headaches over a few days immediately suggests the syndrome as does non-aneurysmal subarachnoid haemorrhage and/or cryptogenic stroke, notably when the patient has severe headache as well.3, 28 Appropriate investigations, including transcranial Doppler, CTA, MRA or eventually catheter angiography should be performed to demonstrate the typical angiographic pattern. The definitive diagnosis can however only be confirmed when the reversibility of the arterial abnormalities is assessed at 12 weeks from onset although complete resolution may be slower in some patients.2 Indeed, in the Taiwanese series of 32 patients, although two-thirds had complete normalisation of their vessels on MRA at 3 months, only marked improvement was noted in the rest.6

Differential diagnosis

Thunderclap headache revealing subarachnoid haemorrhage

Every thunderclap headache must be considered symptomatic and requires immediate investigation which will reveal an underlying cause in half of the patients, mainly a vascular disorder (table 4).32, 33 The most important cause is SAH. Therefore, a non-contrast CT scan, followed by CSF analysis for blood products if the scan is normal, is mandatory in all patients. Aneurysmal rupture is the most frequent cause of SAH (85%) while other less frequent causes include reversible cerebral vasoconstriction syndrome itself which of course can be confusing.3, 28 However, several features help to distinguish one from the other.2 3 4 4, 29 The crucial point is that cortical SAH due to reversible cerebral vasoconstriction syndromes does not correlate with the site and severity of vasospasm in contrast with aneurysmal SAH which does correlate with the site and severity of vasospasm. Indeed, SAH due to reversible cerebral vasoconstriction syndrome is typically localised, overlying the lateral or superior cortical surface, with only a minimal or moderate amount of blood, while the vasoconstriction is widespread and multifocal, affecting medium and large arteries remote from the site of bleeding. Moreover, the typical angiographic pattern of reversible cerebral vasoconstriction syndrome includes, in addition to the multifocal vasoconstriction, multifocal segmental dilatations that are easily seen and sometimes large, producing the characteristic “string of beads” or “sausage-string” appearance. By contrast, aneurysmal haemorrhage tends to be more obvious near the ruptured aneurysm where it directly triggers the vasospasm, which is thus not multifocal but affects only one or two medium sized arteries close to the site of bleeding.

Other causes of thunderclap headache

Besides SAH, thunderclap headache may be the presenting symptom of several other vascular and non-vascular disorders.32, 33

• Other intracranial haemorrhages, notably cerebellar or intraventricular, are responsible for 5–10% of thunderclap headaches, and the diagnosis is easily made by CT scan.

• Rarely infarcts, notably cerebellar infarcts, may present with an isolated thunderclap headache with a normal CT scan within the first few hours, MRI (diffusion sequences) being much more sensitive. Some cerebellar infarcts present with “pseudo SAH” without even vertigo, and it may be difficult to examine patients for gait ataxia who are vomiting and have a very severe headache.

• Several other vascular disorders may present with isolated thunderclap headache: cervical and intracranial arterial dissection, intracranial venous thrombosis, giant cell arteritis, pituitary apoplexy and some symptomatic but as yet unruptured aneurysms (although bleeding may be visible within the wall on MRI). A number of these causes have a normal CT brain scan and CSF, making it mandatory to perform brain MRI with cervical and cerebral angiography and venography (table 4).

• Finally, an isolated thunderclap headache may be the presentation of several non-vascular disorders including acute sinusitis, meningitis or meningoencephalitis, acute tumoral or non-tumoral intracranial hypertension, and CSF hypotension.32, 33

The problem of primary cerebral angiitis

The rare severe forms of reversible cerebral vasoconstriction syndrome raise the possibility of cerebral angiitis, notably primary angiitis of the CNS,2, 12, 13, 34, 35 when it is crucial to start steroids and immunosuppressants as early as possible. On the other hand, in reversible cerebral vasoconstriction syndrome it is important not to expose the patient to the risks of a brain biopsy and prolonged immunosuppression. Of course, in the acute phase it may be impossible to distinguish the two conditions on the basis of angiography (see below) but there are some distinguishing features:

• Clinically, reversible cerebral vasoconstriction syndrome has an acute onset followed by a monophasic course usually without any new complications after 4 weeks3; this can only be a retrospective criterion.

• Onset in the postpartum phase or after exposure to vasoactive substances is very suggestive of reversible cerebral vasoconstriction syndrome.

• In primary angiitis of the CNS, the onset is more insidious, and the headache is not of the thunderclap type, but rather subacute and progressive, then accompanied by transient deficits, and eventually multiple infarcts.

• MRI is often normal in reversible cerebral vasoconstriction syndrome (70%) but is abnormal in most cases of primary angiitis of the CNS (90%) showing small, multiple, deep or superficial infarcts of different ages, with or without associated white matter abnormalities.

• The CSF is markedly abnormal in most cases of primary angiitis of the CNS (>95%) showing an inflammatory reaction, while it is normal (40–80%) or shows only mild abnormalities in reversible cerebral vasoconstriction syndrome.

• Catheter angiography is frequently normal in primary angiitis of the CNS while it is by definition always abnormal in reversible cerebral vasoconstriction syndrome. Some aspects are suggestive of angiitis and are not observed in reversible cerebral vasoconstriction syndromes: irregular and asymmetrical arterial stenoses or multiple occlusions.2, 34

If there is persistent uncertainty it may be best to wait a few days; reversible cerebral vasoconstriction syndrome should stabilise and improve quickly with regression of the vasoconstriction while any arterial irregularities in primary angiitis of the CNS do not improve so fast. Treatment with immunosuppressants should be reserved for patients with biopsy proven vasculitis (a few patients with reversible cerebral vasoconstriction syndrome and persisting diagnostic uncertainty have had to have a brain biopsy but this did not show vasculitis).5, 13, 36, 37

Prognosis

The eventual prognosis is determined by any stroke which occurred in 6–9% of cases in the prospective series.3, 6, 14 Higher percentages have been reported in retrospective series and literature reviews2, 9, 13 but are probably an overestimate because of publication bias, recruitment of severe cases in stroke units, and because cases with headache only might have been overlooked. However, a few fatal cases have been published, notably postpartum.9 During the months following the acute phase, one-third of the patients report persistent mild headaches often with fatigue. Some patients develop depression. Relapses do occur but without long term follow-up studies the rate is unknown.27

In our series of 67 patients followed for a mean of 3.2 years (range 26–62 months), we have so far not observed any angiographically proven recurrence. However, 3 years after a severe attack complicated by an occipital haemorrhage, one patient had a recurrence of multiple thunderclap headaches over 1 week, after smoking cannabis. He did not seek medical advice and it was thus impossible to make a firm diagnosis. In another patient not included in our first case series, who had a proven syndrome, multiple sexual thunderclap headaches recurred 6 months later, 2 days after starting a selective serotonin reuptake inhibitor. He did not seek medical attention but remembered our recommendation, stopped the antidepressant and had no more thunderclap headaches.

Treatment

Symptomatic treatment includes analgesics (sometimes even morphine), antiepileptic drugs for any seizures, monitoring blood pressure, hospitalisation in an intensive care unit in severe cases, and rest for all other patients for a few days to a few weeks according to the severity of their headaches. Patients having triggered thunderclap headaches should be advised to avoid the trigger, such as sexual activity and any other physical effort for 1 or 2 weeks. Finally, it is important to search for all possible vasoactive substances (repeated questioning is sometimes necessary), stop them and firmly suggest to the patient that he or she avoid these kinds of drugs and medications in the future.

In the absence of any randomised trial, empirical treatment is based on nimodipine, started when the typical angiographic pattern is demonstrated.2, 14, 38, 39 This may be given intravenously for a few days, in the same doses as for aneurysmal SAH (1–2 mg/kg/h with monitoring of blood pressure). More often, nimodipine is given orally, the dose varying from 60 mg every 4–8 h, for 4–12 weeks. The effect this has on the various symptoms and complications is unclear. Thunderclap headaches seem to stop within 48–72 h but transient ischaemic attacks or even infarction have been reported in patients treated for several days.3, 38 Moreover, in our experience, some patients have an increase in their background headaches on nimodipine, and rarely a thunderclap headache triggered by a nimodipine tablet. Finally, nimodipine should be avoided in patients with low blood pressure and in patients with an associated dissection with haemodynamic compromise.

Steroids are not recommended. In a severe case without improvement on nimodipine, Canadian authors have tried intra-arterial milrinone with a good outcome.40