Journal of Neurology https://doi.org/10.1007/s00415-018-8888-6 ORIGINAL COMMUNICATION Haemorrhagic stroke related to the use of 4-fluoroamphetamine C. H. W. Wijers1 · M. C. Visser2 · R. T. H. van Litsenburg3 · R. J. M. Niesink1,4 · R. B. Willemse5 · Esther A. Croes1 Received: 15 January 2018 / Revised: 15 April 2018 / Accepted: 30 April 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Introduction The use of the new psychoactive substance 4-fluoroamphetamine (4-FA) and the number of 4-FA-related intoxications substantially increased in The Netherlands in recent years. We describe two patients with severe 4-FA-related complications and the characteristics of a large sample of 4-FA-intoxicated patients. Methods Information on patients with 4-FA-related intoxications between January 2009 and June 2017 was available from the Monitor Drug-related Incidents. Detailed clinical information was obtained of two patients with haemorrhagic stroke after toxicologically confirmed 4-FA use. Results We report on two patients who presented with headache and mild hypertension after 4-FA use. Patient A developed one-sided weakness and decreased consciousness after a few hours. A computed tomography scan showed a left-sided intracerebral haemorrhage. Because of life-threatening cerebral herniation, haematoma evacuation was performed. Postoperatively, she suffered from a right-sided hemiparalysis and severe aphasia, requiring clinical rehabilitation. Patient B had a subarachnoid haemorrhage without neurological deficits. In total, 939 4-FA-intoxicated patients were registered. These patients used 4-FA alone (44%) or in combination with alcohol (13%) and/or other drugs (43%). Discussion Patients using 4-FA are at risk for life-threatening health problems, including intracranial haemorrhage. Additional brain imaging should be considered in 4-FA-intoxicated patients, not only in the presence of neurological deficits, but also in the case of severe headache. Keywords 4-Fluoroamphetamine (4-FA) · Drugs · Intoxication · New psychoactive substance · Stroke Introduction In recent years, the use of the new psychoactive substance 4-fluoroamphetamine (4-FA) considerably increased in The Netherlands [1, 2]. In the Comprehensive 2016 Night Life Study, an online survey among almost 5000 Dutch * Esther A. Croes ecroes@trimbos.nl 1 Department of Drug Monitoring and Policy, Netherlands Institute of Mental Health and Addiction (Trimbos Institute), 725, 3500 AS Utrecht, The Netherlands 2 Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands 3 Event Medical Service, Uden, The Netherlands 4 Faculty of Management, Science and Technology, School of Science, Open University of the Netherlands, Heerlen, The Netherlands 5 Department of Neurosurgery, VU University Medical Centre, Amsterdam, The Netherlands nightlifers, a quarter of the participants reported 4-FA use in the past year. Although their representativeness is unknown, 4-FA use was equal to cocaine and amphetamine use [2]. Initially, 4-FA was found as an adulterant in amphetamine and ecstasy, but, since 2009 users increasingly buy 4-FA on purpose [1, 3, 4]. The popularity is probably due to its legal status until May 2017 and its effects that are experienced as relatively mild [3]. Users describe these effects as an intermediate between amphetamine and ecstasy, and tend to call it ‘ecstasy light’ [3]. Since 2009, a substantial increase has been observed in the number of 4-FA-related intoxications, including patients with life-threatening complications, which we summarized in Wijers et al. [5]. 4-FA induces the release of dopamine, serotonin, and noradrenalin, and inhibits their reuptake [6, 7]. Although neuropharmacological effects seem most similar to amphetamine and ecstasy in animals [7, 8], toxicological studies in humans were not performed. Scientific literature on complications after the use of 4-FA was mainly limited to case reports. Three case 13 Vol.:(0123456789) Journal of Neurology reports reported patients with complications after analytically confirmed 4-FA use were reported previously, suffering from acute cardiomyopathy described as Takotsubo syndrome, and sympathomimetic toxic syndrome, including hyperthermia [9–11]. Knippels et al. reported on three young patients with 4-FA-intoxications, who developed (1) a tonic–clonic seizure, bruxism, mydriasis, and rhabdomyolysis, (2) severe confusion and a desire to die, and (3) tachycardia, hypertension, and hyperthermia [12]. Recently, a small cohort of 45 patients who experienced adverse effects after 4-FA use was described, including eight patients with severe toxicity [13]. Severe toxicity included two fatalities, four patients with haemorrhagic stroke, two patients with inverted Takotsubo’s cardiomyopathy, one patient with myocardial infarction, and one patient with acute heart failure. The current article describes two patients who developed haemorrhagic stroke after 4-FA use in detail and the characteristics of a large number of 4-FA-intoxicated patients who were registered in the monitor drug-related incidents. Methods The monitor drug-related incidents (MDI) was initiated in 2009 and collects anonymous data on patients presenting with acute health problems related to recreational drug use at a selection of Dutch ambulance services, hospital emergency departments, forensic medicine services, and first-aid stations (FAS) at large-scale (dance) events in The Netherlands (http://www.drugsi​ ncide​ nten.​ nl) [14]. Qualified staff reports data, such as birth year and sex of the patient, and severity of intoxication, via a standard entry form. Information on substances used is based on self-report and (seldom) on toxicological screening. The severity of intoxication is classified as ‘mild’ (well-responsive and drug use slightly noticeable), ‘moderate’ (insufficiently responsive and drug use clearly noticeable), or ‘severe’ [disturbed vital parameters and/or non-responsive due to (sub)unconsciousness or agitation]. Recently, the MDI received remarkable reports of two patients with severe complications after the use of 4-FA. Detailed clinical information of these patients was obtained and toxicological analyses in their urine samples were performed using LC–MS (Bruker Toxtyper). Written informed consent was received from both patients. In addition, we extracted data on all patients who presented with 4-FA-related intoxications at one of the largest Dutch FAS organizations between January 2009 and June 2017 from the MDI database for this study. The local ethics committee confirmed that analyses of the anonymous data from the MDI database do not require separate ethics approval. 13 Results Case reports Patient A A 23-year-old female tourist with no previous medical history collapsed at a large dance event. On arrival at the local FAS, she was alert and reported use of a 4-FA tablet 4 h earlier and use of cannabis 7 h earlier. She had no previous experience with recreational drug use. Her vital signs at presentation were: ­SaO2, 98%; respiration, 12 breaths/minute; HR, 60 bpm; BP, 133/86 mmHg; capillary refill time < 2 s; isocoric reactive pupils; glucose level, 7.1 mmol/L; normal skin colour; and T, 36 °C. In addition, no neurological deficits were present, but she was sleepy and complained about headache. After 1.5 h observation, her situation deteriorated rapidly as the level of consciousness decreased, BP increased to 151/104 mmHg, and weakness of the right arm and leg was observed. The patient was transported to hospital by ambulance. At presentation, her vital signs were: respiration 19/minute; HR 57 bpm; BP 153/95 mmHg; and T 36 °C. Neurological examination showed reduced consciousness (E2M5V2) with isocoric responsive pupils, right-sided hemiparalysis, and left-sided localization. A plain computed tomography scan (CT-scan) showed an intracerebral haemorrhage in the left hemisphere (Fig. 1a). CT-angiography did not reveal an underlying vascular malformation. Re-evaluation of the neurological status after the CT-scan showed a dilated non-responsive right pupil (false localising sign). An acute neurosurgical intervention was performed with haematoma evacuation and removal of the bone flap due to persistent intraoperative brain swelling. Postoperatively, she regained consciousness with normal reactive pupils, but with a right-sided hemiparalysis and severe aphasia. The further clinical course was uneventful and she was transferred to a clinical rehabilitation unit. The autologous bone graft was replaced after 4 months without complications. At that moment, neurological examination showed that she was able to talk in her native language and to walk with supportive measures (right leg grade four paresis; right arm grade three paresis). The use of 4-FA was toxicologically confirmed in a urine sample of the patient. No traces of cannabis or other drugs were found. Patient B A 23-year-old female with no medical history presented with severe headache at the emergency department of a Journal of Neurology Data from the monitor drug‑related incidents Fig. 1  Plain computed tomography scans (CT-scans) of both patients. a Patient A with a deep-seated intracerebral haemorrhage in the left hemisphere with compression of the left lateral ventricle and midlineshift. b, c Patient B with subarachnoid haemorrhage in the right frontal area (arrows) hospital. She reported the use of four units of alcohol and a capsule of 110 mg 4-FA the night before. Five hours later, she experienced an acute severe headache and nausea, followed by vomiting. These symptoms were progressive during the day. She regularly uses a similar dose of 4-FA, but did not experience any complications before. She was alert and her vital signs were: S ­ aO2 99%; HR 65 bpm; BP 165/95 mmHg; and T 37.2 °C. Pupils were isocoric and reactive. No signs of weakness and changes in sensation or vision were observed, but the patient reported dizziness and photophobia. Partly triggered by the experience with the previous patient, a CT-scan was made, which showed a small subarachnoid haemorrhage at the right frontal side (Fig. 1b, c). No subsequent CT-angiography was performed. Due to the peripheral frontal localization of the subarachnoid haemorrhage and the exclusion of head trauma, the haemorrhage was interpreted to be 4-FA-induced. She was discharged after 24 h. At an out-clinic visit, she reported that the headache lasted for weeks, but gradually declined. She also experienced cognitive problems and was referred to a rehabilitation centre. After several months, she was still not be able to work. The use of 4-FA was toxicologically confirmed in a urine sample of the patient. No traces of other drugs were found. In total, 13,035 patients with drug-related intoxications were registered by the FAS organization between January 2009 and June 2017. Of these, 939 patients used 4-FA, either alone (44%) or in combination with alcohol (13%) and/or other drugs (43%). The majority of these patients (93%) were registered between 2015 and 2017. Previously, we showed a substantial increase in the number of patients with 4-FA-related intoxications at the FAS organization: none of the registered patients presented with 4-FA-related intoxications between 2009 and 2011, < 1% in 2012 and 2013, 2% in 2014, 11% in 2015, and 16% in 2016 [5]. Additional data of 2017 showed that 15% of the registered patients presented with 4-FA-related toxicity between January and June 2017. Female patients were found to encounter more often health problems after single use of 4-FA; male patients more often after combined use of 4-FA with alcohol and/or drugs (Table 1). The majority of registered patients were young (median 21 years, range 15–59 years). 4-FA was most commonly combined with ecstasy (60%), followed by amphetamine (23%) and GHB (17%). Patients who combined 4-FA had more often moderate or severe intoxications (37%) than patients who used 4-FA alone (12%). (Severe) headache was reported by at least four out of seven patients with severe intoxications after the use of 4-FA without other drugs and alcohol. Discussion We showed that 4-FA-related complications do not seem to be uncommon and may be life-threatening, including haemorrhagic stroke, which add evidence to the existing literature. It seems difficult to predict who will develop acute health problems after 4-FA use as both males and females, young and old, and first (patient A) as well as experienced (patient B) users encountered complications. The two presented patients, who were described in detail, developed an intracerebral and a subarachnoid haemorrhage. Haemorrhagic stroke has also been related to the use of other recreational drugs, such as cocaine and amphetamines [15, 16]. Proposed potential mechanisms included severe elevations of blood pressure or hypertensive spikes that enhance vascular rupture, often in association with preexisting cerebrovascular malformations, such as underlying aneurysm; vasculitis; vasospasm; and haemorrhagic transformation of embolism [15, 16]. The exact mechanism in the presented 4-FA-intoxicated patients remains unclear. CT-angiography did not show preexisting vascular malformations in patient (A). In patient B, CT-angiography was not performed as an aneurysmal bleeding was considered unlikely given the amount and the distribution of the haemorrhage. A form of vasculitis 13 Journal of Neurology Table 1  Characteristics of patients with intoxications related to 4-FA use Sex Male Female Age (years) < 18 18–24 25–29 ≥ 30 Tourist Combined with alcohol Combined with other ­drugsc Ecstasy Amphetamine GHB Cocaine Ketamine Cannabis Combined with 1 other ­drugd 2 other ­drugsd ≥3 other d­ rugsd Severity of intoxication Mild Moderate Severe 4-FA without alcohol or other drugs (n = 409)a N (%)b 4-FA with alcohol without other drugs (n = 124)a N (%)b 4-FA with other drugs (n = 405)a N (%)b 176 (43) 233 (57) 74 (60) 50 (40) 253 (62) 152 (38) 20 (5) 306 (75) 53 (13) 29 (7) 6 (1) n/a n/a 4 (3) 83 (67) 23 (19) 13 (11) 9 (7) 124 (100) n/a n/a n/a 11 (3) 314 (78) 56 (14) 21 (5) 23 (6) 106 (26) 405 (100) 244 (60) 93 (23) 69 (17) 40 (10) 40 (10) 19 (5) 341 (88) 39 (10) 7 (2) 83 (75) 23 (21) 4 (4) 314 (78) 64 (16) 27 (7) 241 (62) 118 (30) 29 (7) a Numbers do not add up to the total number of 939 4-FA-intoxicated patients as combined use of alcohol was unknown in one patient who used 4-FA without other drugs b Numbers may not add up to the total numbers due to missing values (< 1% missings in age and combined with alcohol and 6% in severity of intoxication) c d Numbers do not add up to the total number as 4-FA may be combined with more than one other drug Excluding alcohol cannot be excluded as histopathology was not performed. As vasculitis is associated with chronic amphetamine use [15, 16], an association with the haemorrhage in patient A (unexperienced user) does not seem likely. Hypertension or possible hypertensive spikes may have resulted in damage and ruptures of (small) cerebral blood vessels. Finally, another explanation for haemorrhagic stroke, particularly in patient B, may be the reversible cerebral vasoconstriction syndrome (RCVS), that often occurs after exposure to vasoactive drugs [17, 18]. This syndrome is characterized by severe headaches with or without other symptoms and reversible segmental vasoconstriction of cerebral arteries. Severe headache was present in the presented patients, as well as in other 4-FA-intoxicated patients registered in the MDI database [5]. A limitation of our study is the absence of a formal angiography or a magnetic resonance imaging scan with T2* and susceptibility-weighted imaging, to 13 confirm or exclude RCVS in both patients and to exclude other causes of convexity subarachnoid haemorrhage, such as venous thrombosis, arteriovenous malformation (AVM), mycotic aneurysm, or bilateral carotid stenosis, in patient (B). However, the absence of other non-contrast CT-scan features, including sinus hyperdensity (venous thrombosis), calcifications (AVM), the natural history (mycotic aneurysm), or increased age (bilateral carotid stenosis), may possibly exclude the other causes of convexity subarachnoid haemorrhage. The MDI database provided data on the largest number of 4-FA-intoxicated patients reported to date. Data on the type of drug(s) used were limited by self-report of the patients, which may have resulted in misclassification as patients may not report on all types of drugs used and/or may not know the actual content of the drug(s) used. The drug information and monitoring system (DIMS), which monitors the content Journal of Neurology of drugs at the Dutch drug market, however, showed that, in approximately 90% of the samples that were sold as 4-FA in 2016, this substance was actually detected [1, 14]. In addition, toxicological confirmation of 4-FA use was performed in both presented patients. Despite the reported cannabis use in patient A, no traces of cannabis were found in the urine sample. Therefore, we consider it doubtful whether the use of cannabis contributed to the observed symptoms. In conclusion, patients may present with life-threatening and long-lasting problems after 4-FA use, including intracranial haemorrhage. Symptoms may start mildly with headache and mild hypertension that may turn into severe complications unexpectedly rapid. This shows the difficulty for medical professionals to recognize 4-FA-intoxications. Appropriate diagnostics seem essential, which may include additional brain imaging for 4-FA-intoxicated patients, not only those with neurological deficits, but also in patients with severe headache. Acknowledgements We are grateful to the patients for giving their consent. We also thank E. J. P. Franssen, Head of the Department of Clinical Pharmacy, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands, for analysing the urine samples of the patients. The Monitor Drug-related Incidents is financially supported by the Dutch Ministry of Health, Welfare, and Sport. Compliance with ethical standards Ethical standards The local ethics committee confirmed that analyses of the anonymous data from the MDI database do not require separate ethics approval. 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