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Abstract
Background: The Call–Fleming syndrome (CFS) comprises acute severe recurrent (thunderclap) headaches, occasional transient or fluctuating neurological abnormalities and reversible segmental cerebral vasoconstriction. It is a benign condition with an excellent prognosis, yet because it is often clinically and radiologically similar to a number of commonly encountered conditions, diagnostic difficulties may arise, leading to inappropriate, and even potentially harmful, investigative and therapeutic approaches.
Cases: Three personal cases are presented to highlight the occurrence of subarachnoid haemorrhage (SAH) as part of CFS. In two patients with a positive CT head, SAH involved the sulci in the upper cerebral convexity, an unusual location in aneurysmal SAH.
Results: SAH is not an uncommon feature of CFS, occurring in approximately 25% of reported cases, and may pose a diagnostic challenge. CFS has a relatively characteristic spectrum of features, allowing a confident diagnosis in most cases, even when atypical features such as SAH are present.
Conclusions: Recognising the spectrum of abnormalities seen in CFS, including particularly SAH, allows a sound approach to a safe diagnosis.
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The Call–Fleming syndrome (CFS)1 refers to a clinico-angiographic entity comprising: (i) acute severe recurrent headaches, (ii) occasional fluctuating neurological abnormalities and (iii) reversible segmental vasoconstriction affecting several cerebral arteries in multiple territories. Cases of reversible cerebral vasoconstriction syndrome had previously been described under various names, including postpartum angiopathy2 3 and benign angiopathy of the CNS, 4 5 yet probably represent the same syndrome as CFS. The benign nature of CFS makes it important to recognise to avoid exposing patients to potentially harmful investigations and therapies. One potentially confusing feature of CFS is subarachnoid haemorrhage (SAH).
This article reports three new cases of SAH associated with CFS, and highlights the clinical, radiological and laboratory features that should be considered to arrive at the diagnosis.
CASE REPORTS
Case No 1
A 50-year-old female had a past history of menstrual headaches and occasional high blood pressure (BP) over the past 20 years, treated for brief periods only. She had recently been taking red clover (a herbal remedy containing isoflavones and phytoestrogens) for hot flushes. The family history was positive for headaches in one brother.
In September 2002, during a “very stressful” business meeting, she developed an occipital headache that built up over 10 min and was associated with vomiting. The headache lasted for 2 h and then resolved completely after taking oral paracetamol. The following day, the headache recurred but was excruciating and reached its peak over seconds; it was not associated with vomiting or nausea, and resolved spontaneously over 1 h. It recurred 2 days later and the patient presented to the emergency room. Clinical examination was normal apart from BP of 195/90.
A CT scan of the head showed definite but minimal SAH over the lateral hemispheric convexity bilaterally, and digital subtraction angiography (DSA) revealed typical segmental vasoconstriction in the anterior and posterior circulations bilaterally but no aneurysm or vascular malformation (fig 1). She received simple analgesia, nimodipine and atenolol and her symptoms resolved completely within 48 h. Laboratory tests, including erythrocyte sedimentation rate, C reactive protein and a vasculitis screen were negative. Biochemical and imaging investigations for pheochromocytoma were repeatedly negative. A repeat cerebral DSA 12 days later showed partial resolution of the earlier findings and a follow-up MRI scan 2 months later was entirely normal.
The patient remains well since that episode with stable BP on atenolol and no recurrence of any symptoms as of October 2007.
Case No 2
A 33-year-old female had a past history of monthly migraine, bronchial asthma and untreated borderline hypertension. In September 2004, she presented to the emergency room with a severe agonising headache. Three days earlier, she had an upper respiratory tract infection for which she was taking a pseudoephedrine based medication (Sudafed). She had developed a mild frontal headache on the day before presentation and the next day woke up with a left-sided frontal headache that suddenly increased in severity and rapidly spread bilaterally and backwards. This was associated with vomiting and photophobia, and later on dysphasia, blurred vision and tingling in the angle of the mouth and hand and mild distal weakness of the upper extremity, all on the right.
In hospital, clinical examination confirmed mild right hand weakness and normal BP. CT and MRI scans of the head revealed SAH overlying the left superior frontal region that was localised to a single cortical sulcus with a haematoma filling the sulcus and apparently diffusing into the neighbouring cortex (fig 1). DSA revealed widespread segmental vasoconstriction in the arteries of the anterior cerebral circulation bilaterally, but no aneurysm or vascular malformation (fig 1). Laboratory tests, including a vasculitis screen, were unremarkable.
The patient received paracetamol, cyclizine, tramadol, pethidine and nimodipine. Her headaches decreased in frequency and her other symptoms gradually improved over the following weeks. She continued to have brief episodes of face tingling and “odd” speech while in hospital. An EEG showed some left frontal slowing but no epileptiform abnormalities. A repeat MRI in March 2005 showed resolution of the haematoma but no underlying vascular malformation. She has since remained well and had a successful uncomplicated pregnancy in 2005.
Case No 3 (previously published in the French literature6)
A 60-year-old female had a past history of migraine without aura and untreated mild mitral and aortic rheumatic valve regurgitation; she was on Lecainide for a single episode of atrial fibrillation and hormonal replacement therapy and had received dexfenfluramine for treatment of obesity up until 11 days before her neurological event. Just prior to the latter she had been treated for 2 days with aspirin, quinine, phenacetine, naphtonone and cinnamaverin for upper respiratory tract infection.
In December 1990, she suddenly screamed from fear when she saw her car slide towards a ditch in the Alps, and immediately developed a sudden severe bilateral headache. This lasted for 2 h and then improved partially over the following 6 h. It recurred that night and she was seen by a physician who found a BP of 190/90 mmHg and prescribed nifidepine, which provided some relief. The following day, the headache recurred acutely on straining and required admission to another hospital. Her BP fluctuated, but clinical examination was normal. An enhanced CT scan of the head was unremarkable and she was discharged. In the subsequent 6 days she had two further recurrences of the acute excruciating headache and was admitted under our care. A lumbar puncture, performed 10 days after onset, produced a pinkish fluid with numerous red blood cells, protein content of 0.44 g/l and positive xanthochromia. DSA showed widespread segmental vasoconstriction (sausage-string appearance) in the arteries of the anterior and posterior circulation, but no aneurysms or vascular malformation (fig 1). All blood tests, including a vasculitis screen, were normal except for elevated cholesterol at 6.4 mmol/l. She received oral nimodipine and the headaches improved, although still recurred several times over the ensuing month, especially during physical activity or defecation. Two MRI scans and magnetic resonance angiography obtained during the following 3 years were all normal, and she remains well as of October 2007.
DISCUSSION
CFS preferentially affects young adults, but has been reported in patients as young as 10 years4 and up to 66 years.7 It affects women three times more frequently than men.4 It may arise spontaneously, but is more often associated with a trigger, particularly sympathomimetic over the counter remedies and other vasoactive substances, such as pseudoephedrine,8 phenylpropanolamine,9 ergot derivatives,10 cocaine11 and drugs that modulate the dopamine or serotonin systems.12–14 Non-pharmacological triggers include childbirth,2 3 porphyria,15 pheochromocytoma,16 carotid endarterectomy17 and intravenous immunoglobulins.7
Headache is a hallmark of CFS and is usually localised around the occiput or vertex. It is often very sudden in onset and severe (ie, thunderclap headache), warranting investigations to exclude aneurysmal SAH. The headaches typically wax and wane, and recurrences are frequently caused by straining or physical exercise and gradually decrease in intensity and duration over a few days to weeks. Minor and transient or fluctuating neurological symptoms or signs are not uncommon and are often delayed relative to the headache. Visual symptoms are common14 18 and are mostly attributable to preferential development of vasogenic oedema in the occipitoparietal regions, a pattern similar to that seen with the posterior reversible encephalopathy syndrome.19
The main radiographic abnormality, and a necessary diagnostic criterion, is the segmental vasoconstriction of the cerebral arteries contributing to and arising from the circle of Willis and their branches. This may produce the so-called “sausage-string” or “beading” pattern, especially as the post-stenotic segments may show dilatations. In the majority of cases, both the anterior and posterior cerebral circulations are involved, and the abnormalities are conspicuous; however, they can also be subtle or questionable, especially on magnetic resonance angiography and should be documented on DSA. Demonstration of reversibility of vasoconstriction on repeat imaging (recommended at approximately 4–6 weeks later) is usually required unless the clinico-radiographic picture is typical. Although some radiological aspects of the CFS overlap with isolated angiitis of the CNS20—an exceedingly rare disorder21—the widespread abnormalities on DSA, usually a clear trigger and negative blood screen should lead to the correct diagnosis and avoid recourse to a brain/meningeal biopsy and potentially harmful immunosuppression.
The three cases reported here were potentially misleading because of the associated SAH. However, SAH is not infrequently encountered in CFS, perhaps in up to 1 in 4 cases,4 22 23 and typically overlies the lateral–superior cortical surface, 3 7 24 as documented in two of our cases This topography is highly unusual in aneurysmal SAH, and should raise the suspicion of CFS. In CFS, SAH is usually minimal or moderate in amount and should not be considered the cause of the segmental vasoconstriction, which affects arteries remote from the site of bleeding. In contrast, SAH in aneurysm rupture tends to predominate close to the site of the aneurysm, and locally trigger the vasospasm.
Complete recovery is the rule in CFS (>95% of cases), and recurrence of the syndrome has never been reported. Cessation of any suspected vasoconstrictor agent is imperative, and so is careful control of BP. Relief of headaches is usually achieved with simple analgesics, but calcium channel blockers (nimodipine or verapamil) are commonly used.25 Magnesium sulphate has also been tried, especially in cases with a postpartum onset, with some apparent benefit.3
REFERENCES
Footnotes
Competing interests: None.
Ethics approval: Ethics approval was obtained.