A variety of eponymic names, including the Call-Fleming syndrome, thunderclap headache with reversible vasospasm, benign angiopathy of the central nervous system, postpartum angiopathy, migrainous vasospasm or migraine angiitis, and drug-induced cerebral arteritis or angiopathy, have been proposed to describe the same clinical-radiological syndromes. In 2007, reversible cerebral vasoconstriction syndrome (RCVS) was proposed as a unifying term. RCVS is characterized by reversible multifocal narrowing of the cerebral arteries heralded by sudden (thunderclap) headaches with or without neurological deficits, resolving within 12 weeks of presentation.1 The most severe acute headache is often accompanied by nausea, vomiting, photophobia, blurred vision, transient motor deficit, and aphasia. RCVS occurs mostly in middle-aged adults, and there is a female preponderance (64%–92%) with an increased incidence during the postpartum period.1,2 The pathophysiology of RCVS is not clearly understood. Both endogenous factors and exogenous factors such as sympathomimetic and serotonergic drugs, tumors, brain trauma, and poorly controlled hypertension may play a role.1,2 Roughly 25% to 60% of cases occur secondary to identifiable triggers.3 Despite the substantial risk of ischemic or hemorrhagic complications, permanent neurological deficits are noted in only 3% to 6% of patients.4 Mortality is estimated at <1% but it is higher in the postpartum period.2
HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is a complication of a severe form of preeclampsia.5 It can occur suddenly after a totally uneventful pregnancy, mostly at the end of third trimester. The pathogenesis of eclampsia and HELLP syndrome is also not fully understood yet. It may be caused by a disruption in implantation and placentation in early pregnancy with resultant hypoxia of the trophoblast. The only causal therapy of HELLP syndrome is expeditious delivery. However, symptoms can last for several days after childbirth. Hypertension and thrombocytopenia can significantly increase the risk of bleeding during the puerperium. The initiation of antihypertensive treatment can prevent cerebral hemorrhage. The most common neurological complication of eclampsia and HELLP syndrome are tonic-clonic convulsions caused by hypertensive encephalopathy. In rare cases, HELLP syndrome can be complicated by RCVS. In HELLP syndrome, management is focused on expeditious delivery and antihypertensive treatment. In RCVS, however, elevated blood pressure should be obtained to ensure cerebral perfusion.
Here, we report a case of a patient presenting with acute thunderclap headache as well as severe HELLP syndrome, complicated by acute respiratory distress syndrome (ARDS), postpartum uterine atony, and acute kidney failure.
A 31-year-old patient in the 38th week of pregnancy presented to a general hospital with acute right upper quadrant abdominal pain and headache. Clinical findings and laboratory tests revealed preeclampsia and incipient HELLP syndrome. Urgent cesarean delivery was performed under spinal anesthesia and the patient subsequently was admitted to an intermediate care unit (IMCU). Blood pressure on admission was 205/110 mm Hg and lowered during cesarean delivery to 150/70 mm Hg. On admission to IMCU, her blood pressure increased again to 180/95 mm Hg and a continuous intravenous (IV) application of urapidil (initial bolus of 50 mg, followed by 10 mg/h) as well as dihydralazine (5 mg/h IV) was started.
The postoperative course was complicated by an eclamptic seizure shortly after admission to IMCU, which was treated with high-dose magnesium (initial bolus of 5 g, followed by 1 g/h IV) as well as 5 mg diazepam. Nitroglycerin (1 mg/h IV) was added to control the blood pressure, which increased again to 210/105 mm Hg despite preexisting dual antihypertensive therapy. Fulminant HELLP syndrome with platelet decrease (Table 1) prompted the administration of an IV bolus of 0.6 mg desmopressin and 2 g tranexamic acid as well as an emergency-based transfer to our university tertiary referral medical center.
On admission to the emergency department, intubation was performed because of a Glasgow Coma Scale of 7. One hundred twenty-five milliliters of mannitol 20% was administered empirically to treat assumed intracranial pressure (ICP). Computed tomography (CT) scan revealed intracerebral and ventricular bleeding on the right side in the thalamus region, internal and external capsule, and parieto-occipital areas (Figure 1). Furthermore, signs of alveolar consolidations and multifocal infiltrates in the lung indicated aspiration.
Because of deranged coagulation (Table 1), 1200 mL fresh frozen plasma, 2400 mL platelets, and 1000 IU prothrombin complex concentrate were administered. Uterine atony was treated by oxytocin therapy (to a total sum of 12 IU IV) and followed by 250 µg/h sulprostone IV.
Neurological examination revealed internuclear ophthalmoplegia (anisocoria, optokinetic nystagmus), and transcranial Doppler analysis showed hyperperfusion without signs of vasospasm. Consequently, primarily posterior reversible encephalopathy syndrome was supposed. Cranial CT scan the next day showed findings similar to the admission CT and no signs of elevated ICP.
On the second day after admission, aspiration pneumonia associated with sepsis and ARDS (Table 2) demanded catecholamine therapy (norepinephrine, maximum dose 0.17 µg/kg/min IV) as well as 2 days of intermittent prone positioning. Microbial cultures (blood, urine, abdominal puncture, bronchoalveolar lavage) were taken but remained sterile.
For the purpose of maintaining spontaneous breathing as well as tolerating prone positioning, inhalative sedation with sevoflurane was established. This had the advantage of being easily interrupted for frequent neurological examinations. For applying sevoflurane via the intensive care respirator (Evita V500, Dräger, Germany), the anesthetic conserving device (AnaConDa, Sedana Medical, Uppsala, Sweden) was used.
AnaConDa is an anesthetic gas recirculation system.6 It can administer volatile anesthetics with any intensive care ventilator. The miniature vaporizer is integrated into the respiratory circuit instead of the usual passive heat-and-moisture exchanger between the Y piece and the patient. The volatile anesthetic is applied continuously in liquid form by using a syringe pump. It is stored in a carbon layer and released into the gas mixture during the inspiratory cycle. More than 90% of the anesthetic gas is recirculated in such a way. However, 10% of the vapor gas needs to be scavenged by a residual gas filter or an anesthetic gas-scavenging system. The device eliminates the need for CO2 absorption and rebreathing techniques. Consequently, there is no concern about compound A. Acceptable levels of sedation for the intensive care unit (ICU) can be achieved with sevoflurane 0.5 to 1.0 vol%.6,7 In our case, the inspiratory and expiratory anesthetic gas concentrations were measured using an external gas monitor (Vamos, Dräger, Germany) and titrated to end-tidal doses of 0.5 to 0.8 vol%.
Daily neurological examinations confirmed internuclear ophthalmoplegia (anisocoria, optokinetic nystagmus). Concentration deficits and a mild impairment of cognitive function were interpreted as septic encephalopathy and showed rapid improvement. Regular transcranial Doppler analyses remained constant. Oral nimodipine (Nimotop, Bayer Vital GmbH, Leverkusen, Germany) therapy was started for the prevention of vasospasm.
Over the course of her ICU stay, the patient developed acute kidney injury and hypervolemia. Continuous renal replacement with citrate anticoagulation was started on day 3, aiming for a negative fluid balance.
After the patient had recovered from the critical stage of her illness, magnetic resonance imaging and magnetic resonance angiography were performed on day 6 and showed RCVS (Figure 2), as well as mesencephalic and ventricular bleeding and a subacute lacunar stroke affecting parts of the pons.
The patient was transferred to a skilled rehabilitation facility 2 weeks after her initial presentation and could be discharged home on day 30 after admission to hospital. Neuropsychological assessment showed only low restrictions in flexibility and attention, a mild reduction in physical capacity, as well as diplopic images on short focusing with a good prognosis.
No further vasospasms could be detected by transcranial Doppler examination and repeated magnetic resonance imaging scan 90 days after admission (Figure 3). She recovered fully from acute kidney injury.
The present case was complicated by multiple factors.
To rule out the differential diagnosis of aneurysmal subarachnoid hemorrhage in severe, recurrent “thunderclap” headache, vascular imaging is needed and typically shows diffuse, multifocal, segmental narrowing and dilation (string of beads) of large- and medium-sized arteries.2,8,9 Catheter angiography has been the gold standard for evaluating intracranial vessels. However, noninvasive imaging modalities such as transcranial Doppler sonography, CT angiography, and MR angiography are being used with increasing frequency for frequent follow-ups.8,9
In our case, no lumbar puncture was performed. Consequently, the differential diagnosis of primary cerebral angiitis was not excluded, but was considered unlikely. However, in doubtful cases, with unclear thunderclap headache and multifocal segmental vasoconstriction in the absence of aneurysm, cerebral spinal fluid studies or even brain biopsy may be needed.
No pharmacological treatment has gained enough evidence of efficacy in the therapy of RCVS. However, because patients are at risk of ischemic complications with a poor outcome, it seems prudent to initiate therapy with agents that have a favorable tolerability profile, especially if vasospasm is severe, or if transient neurological symptoms occur.
The first step, however, is withdrawal of any suspected exogenous triggers, including vasoactive medications and symptom relief with analgesics, blood pressure control, and seizure prophylaxis.1–3,8 In our case, the trigger of HELLP and consecutive RCVS was already terminated by delivery.
The early phase of the illness was characterized by hemorrhage and hemodynamic instability due to uterine atony, a well-known problem after cesarean delivery. Therefore, initially vasoconstrictive medication (oxytocin, sulprostone) was given. These first-line drugs do not act selectively on the uterus. The risk of worsening existing vasospasms had to be taken.
After overcoming uterine atony, vasoconstrictive medication was reduced and the calcium channel blocker nimodipine, which is contraproductive in uterine atony, was started orally. Nimodipine has been used via the oral and IV routes empirically because of its effectiveness in postaneurysmal subarachnoid hemorrhage vasoconstriction. However, open-label studies showed beneficial effects in RCVS by decreasing intensity and frequency of thunderclap headaches.10 To date, no effect of nimodipine on hemorrhagic and ischemic complications has been proven.4,8 The optimal duration of treatment is unknown.2
The choice of pharmacological strategy (vasodilatative versus vasoconstrictive) was further complicated in this case because of the patient developing septic vasoplegia. In HELLP syndrome, management is focused on antihypertensive treatment, whereas in RCVS sufficient blood pressure should be obtained to ensure cerebral perfusion. The most appropriate target blood pressure is unknown and may be a tightrope walk.
A frequent side effect of nimodipine therapy is impaired gas exchange caused by the opening of intrapulmonary shunts. Therefore, in this case of severe ARDS, oral nimodipine therapy could first be started after overcoming respiratory failure.
For the treatment of severe ARDS, early and prolonged prone positioning is beneficial.11,12 With increased ICP, elevated upper body positioning would be desirable. Spontaneous breathing is regarded to be the most protective breathing mode, but hypoventilation and associated hypercapnia are likely. In ARDS, permissive hypercapnia is tolerated, whereas ICP management requires normoventilation.
We used volatile sedation with sevoflurane via AnaConDa to preserve spontaneous breathing and patient comfort and to guarantee normoventilation simultaneously. Interruption for frequent neurological examination was possible at any time.
Volatile anesthetics have been used successfully for the purpose of sedation in intensive care since the end of the 1980s. Compared with IV sedatives, volatile anesthetic agents are associated with shorter extubation times, reduced duration of mechanical ventilation, and faster discharge from hospital.6 Sevoflurane is known to have cardioprotective, neuroprotective, and anti-inflammatory properties.7 It is likely that there are beneficial effects in ARDS patients too. It is proven to improve gas exchange, reduce alveolar edema, and attenuate pulmonary as well as systemic inflammation.13–15 However, there may be side effects. A transient increase in the measured fluoride concentration has been shown, even though it does not seem to be of clinical relevance.7 One also has to keep in mind the danger of increasing ICP as a result of cerebral vasodilation.16 In our case, there were no signs of elevated ICP.
In moderate sevoflurane dosing (< 1.0 vol%), relaxation of the uterus is unlikely. Long-time application remains an off-label use. This is, to our knowledge, the first described case of inhalative sedation in RCVS.
Negative fluid balance is assumed to be beneficial in ARDS. In our patient, the development of acute anuric renal failure prompted the initiation of renal replacement therapy. Because of intracranial hemorrhage, a bedside continuous venovenous hemofiltration with citrate-buffered replacement solution was used to prevent further intracranial bleeding.
We report a case of intracranial bleeding related to HELLP syndrome and RCVS, which was complicated by septic ARDS and acute renal failure.
To ensure prompt diagnosis and management familiarity with this, clinical entity is essential for cerebrovascular neurosurgeons, vascular neurologists, gynecologists, and critical care physicians to create the best possible patient outcome.
In HELLP syndrome, management is focused on antihypertensive treatment. Whereas in RCVS, sufficient blood pressure should be maintained to ensure cerebral perfusion.
Prone position and spontaneous breathing is known to be beneficial in ARDS but might be difficult to achieve. Inhalative sedation with sevoflurane via AnaConDa might be the road to success.
The patient has granted written informed consent for publication of the case.
The authors wish to thank Helen Engelstädter for her critical review of the English writing in this manuscript.
Name: Michael Ramming, MD.
Contribution: This author helped care for the patient and prepare the manuscript.
Name: Joachim Bansbach, MD.
Contribution: This author helped care for the patient and prepare the manuscript.
Name: Christopher Beck, MD.
Contribution: This author helped care for the patient and edit the manuscript.
Contribution: This author helped care for the patient and edit the manuscript.
This manuscript was handled by: Mark C. Phillips, MD.
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