Abstract
In 1988, Call and colleagues described four patients and reviewed a total of 19 patients from the literature who presented with a self-limited syndrome of recurrent, sudden, high-intensity headaches (‘thunderclap headache’) associated with nausea, vomiting, photophobia, generalized seizures (7/19), recurrent transient neurological symptoms (7/19), or permanent neurological deficits such as hemiparesis, cortical blindness (4/19) (1). Three patients became comatose and died. The common finding in all patients was the presence of diffuse segmental cerebral vasospasm involving the distal internal carotid, basilar, and major arteries of the circle of Willis which was fully reversible within weeks to months. Brain and/or cerebral blood vessel biopsies were negative in 6/19 patients and CSF examinations were mildly abnormal in five patients (three patients with elevated CSF protein 51–125), two patients with CSF lymphocytic pleocytosis (6–16 leucocytes). They felt that the segmental vasospasm was probably due to a physiological abnormality, given the lack of a structural correlate, cellular infiltrate, or hypertension in most patients.
Similar clinical–angiographic patterns (sudden severe headache and diffuse vasospasm) have been described in patients with a history of migraine, as well as after carotid endarterectomy, postpartum period, Guillain–Barré syndrome, sexual intercourse, unruptured intracranial aneurysm, exertion, severe hypertension, and after administration of serotonergic, sympathomimetic medications, and illicit drugs such as cocaine (1–8).
Nowak and colleagues describe the case of a 63-year-old woman who presented with multiple discrete thunderclap headaches over a 2-week period with delayed neurological deficits (cortical visual field loss and hemiparesis), diffuse segmental cerebral vasospasm, and bilateral occipital-parietal cerebral infarctions (9). Resolution of vasospasm was documented by transcranial Doppler 1 day after the intravenous administration of nimodipine and magnesium sulphate, only to recur after nimodipine was discontinued. Ultimately, headaches and vasospasm resolved 17 days after the initial symptoms. The authors conclude that calcium channel antagonists may be important therapeutic agents in the treatment of reversible cerebral vasoconstriction in patients with Call–Fleming syndrome. Their conclusion is supported by a similar case reported by Sturm and Macdonell, who described a similar clinical scenario in a 58-year-old woman who presented with recurrent severe thunderclap headaches over a 14-day period, diffuse reversible cerebral arterial vasospasm, and delayed bilateral watershed ischaemic stroke with cortical blindness (10). Vasospasm and clinical deterioration appeared to be halted by the use of intravenous nimodipine.
As the literature continues to grow with case reports of this unusual disorder, the clinical spectrum is becoming more refined. As these and other cases illustrate, the clinical–angiographic syndrome of recurrent thunderclap headaches, diffuse reversible vasospasm, and delayed ischaemic deficits may occur spontaneously or secondary to an underlying metabolic, haemodynamic, or biochemical (endogenous or exogenous) insult. The headaches are often occipital/posterior, and although the arteriographic evidence of vasospasm is diffuse, multisegmental, and can involve the anterior and posterior circulation, the delayed ischaemic insults often occur in either an arterial border zone or in a parietal–occipital distribution.
The frequent involvement of posterior (occipital–parietal) brain in this syndrome resembles the imaging features in patients with reversible posterior leukoencephalopathy syndrome (PLES) (11). This is a newly described neurological disorder characterized by abrupt and severe headache, nausea, vomiting, seizures, visual disturbances, focal neurological deficits and altered sensorium. PLES is often but not always associated with an abrupt rise in arterial blood pressure, and is usually seen with eclampsia, renal disease, hypertensive encephalopathy, and in patients who have received cytotoxic or immunosuppressive drugs such as tacrolimus, cyclosporin, intravenous immunoglobulin, and alpha-interferon (12). The characteristic imaging finding is bilateral symmetrically increased T2 or diffusion-weighted signal in the posterior (parietal–occipital) grey and white matter (13). Diffusion-tensor imaging changes lend support to the hypothesis of vasogenic oedema as the pathophysiological mechanism underlying this syndrome (14). However, diffuse vasospasm has been described in PLES and the overlap in clinical and imaging features highlights the need for a careful clinical evaluation, as the management may be quite different. Immediate anti-hypertensive therapy is vital in most patients with PLES, whereas similar treatment in patients with diffuse vasospasm may compromise cerebral blood flow and brain perfusion.
Although the aetiopathogenesis of the Call–Flemming syndrome is not known, the lack of an obvious precipitating factor in these cases suggests a disturbance in the neural control of vasomotor tone or the presence of an as yet unidentified circulating humoral agent. Although a number of humoral factors have been implicated in the pathogenesis of vasospasm in patients with subarachnoid haemorrhage, the presence of subarachnoid blood is felt to be integral in the pathogenesis of vasospasm in this disorder. The abrupt, spontaneous, and self-limited nature of the vasospasm in Call–Flemming syndrome would suggest a humoral mechanism is unlikely. Vasospasm, as opposed to arterial stenosis, usually reflects a reversible process consisting of a localized smooth muscle contraction of the blood vessel wall, which results in segmental luminal narrowing. Vasospasm can be provoked by mechanical, biochemical, and neurogenic stimuli. The abrupt onset of both the headache and vasospasm in Call–Flemming syndrome, together with the lack of an obvious haemodynamic, metabolic, or biochemical insult, would seem to imply a neurogenic mechanism. The perivascular and intramural portions of the intracerebral arteries are richly invested with sympathetic innervation from both extracerebral (cervical and sympathetic ganglia) and intracerebral (brainstem nuclei including locus ceruleus) origin. That vascular calibre may directly reflect adrenergic tone, and sympathetic receptor sensitivity is supported from experimental and animal models of vasospasm in subarachnoid haemorrhage (SAH) as well as the observation of similar angiographic findings in patients with pheochromocytoma and sympathomimetic drug intoxication (7, 15–17).
The cases presented above raise the possibility that calcium channel antagonists may reverse vasospasm and potentially limit or prevent the development and/or severity of the delayed neurological deficits (9, 10). The rationale for using calcium antagonists in patients with vasospasm related to SAH is based on the notion that these drugs counteract the influx of calcium in the vascular smooth-muscle cell, a mechanism which is central to the regulation of smooth-muscle contractility. Calcium antagonists, such as nicardipine and nimodipine, reduce the proportion of vasospasm-induced ischaemic neurological deficits and nimodipine improves overall outcome within 3 months of aneurysmal SAH (18). In addition to its ability to reduce angiographically detected vasospasm, nimodpine possesses neuroprotective and anti-platelet effects which may contribute to its effectiveness. Because it is unlikely there will ever be a randomized trial of calcium antagonists in this syndrome, the recommendation to administer nimodipine to patients with Call–Fleming syndrome who develop neurological symptoms or signs in the presence of diffuse vasospasm, appears to be sound medical advice. The question which begs more discussion is whether all patients with unprovoked thunderclap headache and diffuse cerebral vasospasm should receive prophylactic nimodipine, particularly in light of the fact that hypotension, which occurs in up to 15% of patients treated with nimodipine, could further compromise cerebral blood flow in these patients. However, even though not all patients develop neurological symptoms or signs, given the severe neurological sequelae which have occurred in some patients, a brief course of nimodipine may be prudent. Obviously, careful clinical observation over the initial 2–3 weeks is crucial, as most deficits appear to be delayed by 1–3 weeks.