An 81-year-old woman was admitted in June 2014 to Tseung Kwan O Hospital with aspiration pneumonia. She had temporal lobe necrosis and absence seizure after radiotherapy for nasopharyngeal carcinoma. She was prescribed lifelong oral phenytoin with no adverse reaction reported to date. Oral phenytoin was changed to intravenous, 100 mg every 8 hours, via a 22G catheter in her right wrist due to oropharyngeal dysphagia. The catheter had been changed several times due to blockage with no apparent extravasation. Erythematous swelling of the skin around previous cannula sites was treated as cellulitis by intravenous ciprofloxacin.

The following day the patient’s right hand deteriorated and showed marked circumferential purplish discolouration, swelling, and gangrenous changes to the skin (Fig 1). Similar minor changes over the left hand were noted. She was afebrile and not septic. White cell count (12.8 × 10⁹/L) was mildly elevated and C-reactive protein was elevated at 196 mg/L. Nonetheless, these results could be interpreted as being due to concurrent aspiration pneumonia.

Computed tomographic angiography revealed fluid collection in the patient’s right hand up to the right forearm with reasonable arterial supply. Intravenous penicillin G and ciprofloxacin were started. Serial clinical assessments prior to surgery showed no further deterioration. Emergency incision, drainage, and carpal tunnel release were performed. Findings were skin and fat necrosis, venous thrombosis and a large amount of clear fluid over the fascial layers of the palm and fingers. There was no turbid or dishwater discharge. The transverse carpal retinaculum was thickened and tight. Mild necrosis of the right-hand small muscles was noted. Cultures of intra-operative tissue samples were negative for micro-organisms.

On day 15 of intravenous phenytoin injection, the patient was diagnosed with purple glove syndrome (PGS). Intravenous phenytoin was stopped immediately and changed to valproate. The condition of the patient’s left-hand improved rapidly but that of her right hand continued to deteriorate (Fig 2) and necessitated below-elbow amputation. The amputation wound healed and she was referred for rehabilitation.

An 87-year-old woman with brain metastasis from lung carcinoma was prescribed oral phenytoin for epilepsy. She was admitted to Tseung Kwan O Hospital in April 2016 with fever. She was prescribed 100 mg phenytoin every 8 hours via a 22G catheter in her left hand due to potential dysphagia. She complained of painful swelling of her left hand after several doses of phenytoin. There was no extravasation of drug. The patient was afebrile and not septic. Diffuse circumferential purplish, tender swelling of the distal left forearm and left hand was noted. The patient’s hand was in intrinsic minus posture. There was no crepitation or fluctuance. The patient’s left wrist and finger movements were limited by pain. Passive stretching of the fingers exacerbated her pain. Radial pulse was palpable with good capillary refill. White cell count (12.4 × 10⁹/L) and C-reactive protein were slightly elevated (17.2 mg/L).

The patient was suspected to have PGS of her left hand complicated by compartment syndrome. Intravenous phenytoin was stopped 1 day after injection and switched to valproate. Serial clinical assessments prior to surgery revealed no further deterioration. Emergency fasciotomy and carpal tunnel release were performed. Intra-operative findings were consistent with compartment syndrome and PGS. There was no evidence of necrotising fasciitis. Cultures of intra-operative tissue samples were negative for micro-organisms. Debridement and primary wound closure were performed 12 days after fasciotomy and the patient was transferred for rehabilitation.

Subsequently, the patient developed a breakthrough seizure and was prescribed intravenous phenytoin via her right hand because the physician did not notice that the patient had previously developed PGS as a complication of this treatment. She developed PGS of her right hand complicated by compartment syndrome. Emergency fasciotomy and carpal tunnel release of the right forearm and right hand were performed. Debridement and primary closure of wounds were performed 16 days after fasciotomy. In order to avoid future complications, a note was made in her medical records that she had an adverse reaction to phenytoin.

Purple glove syndrome is an adverse reaction to intravenous phenytoin. Its incidence has been reported to range from 1.5% to 5.9%.1 Its manifestation includes pain, skin discolouration, blister formation, sloughing, ulceration, necrosis, and compartment syndrome at the injection site within hours of drug administration. Differential diagnoses include extravasation of the medication, cellulitis, peripheral vascular disease, venous thrombosis, and collagen vascular disease.2

The pathogenesis of PGS is poorly understood. It has previously been considered to be a result of extravasation of highly alkaline phenytoin (pH 12).3 4 However, PGS can occur in the apparent absence of extravasation. Histological examination has suggested thrombosis might play a role in pathogenesis.3 To further complicate the matter, PGS has also been reported to be possible following oral phenytoin administration.4 There is no literature to date to correlate any intravenous complication with previous use of oral medication.

Risk factors for PGS after intravenous phenytoin administration include older age, female sex, peripheral vascular disease, sepsis, history of chronic debilitating disease, number of doses, higher dosage (>15-20 mg/kg body weight), higher infusion rate (>25 mg/min), and use of an intravenous catheter <20G.5

Initial management includes analgesia, elevation of the affected limb, compression, massage, and gentle heat. Phenytoin should be stopped and changed to an alternative antiepileptic. Most cases of PGS are mild and can be resolved with no long-term sequelae. Management is mainly supportive. However, PGS may progress to limb ischaemia and compartment syndrome. Frequent monitoring of neurovascular status is required. Vascular study should be performed if perfusion is compromised.5 Anticoagulation, thrombectomy or thrombolysis should be considered when arterial thrombosis is identified. Emergency fasciotomy should be performed for compartment syndrome. An unsalvageable limb should be amputated. Amputation has been reported to be necessary in 10.1% of cases.5 The use of regional blockade and hyaluronidase remains experimental.5

Purple glove syndrome may be prevented by avoiding phenytoin if there is an alternative agent with similar efficacy, for example valproate. Otherwise, oral phenytoin is preferred. If intravenous phenytoin is used, it should be administered via a larger catheter into a larger vein, at the correct dosage and infusion rate, and with a post-infusion saline flush.5

All authors contributed to the concept of study, acquisition and analysis of data, drafting of the article, and critical revision for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

The authors have no conflicts of interest to disclose.

This case report received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki. The patient provided informed consent for all procedures.

1. Rajabally H, Nageshwaran S, Russell S. An atypical case of purple glove syndrome: an avoidable adverse event. BMJ Case Rep 2012;2012. pii: bcr0120125653. Crossref

2. Lalla R, Malhotra HS, Garg RK, Sahu R. Purple glove syndrome: a dreadful complication of intravenous phenytoin administration. BMJ Case Rep 2012;2012. pii: bcr2012006653. Crossref

3. Okogbaa JI, Onor IO, Arije OA, Harris MB, Lillis RA. Phenytoin-induced purple glove syndrome: a case report and review of the literature. Hosp Pharm 2015;50:391-5. Crossref

4. Bhattacharjee P, Glusac EJ. Early histopathologic changes in purple glove syndrome. J Cutan Pathol 2004;31:513-5. Crossref

5. Garbovsky LA, Drumheller BC, Perrone J. Purple glove syndrome after phenytoin or fosphenytoin administration: review of reported cases and recommendations for prevention. J Med Toxicol 2015;11:445-59. Crossref

A 62-year-old man presented to Queen Elizabeth Hospital in November 2015 with sudden-onset chest pain radiating to his back and left lower limb numbness for 3 hours. He had previously suffered a stroke from which he had made a good recovery and could walked unaided. There was decreased sensation of the entire left lower limb that was cooler than the right. All pulses over the left lower limb were absent but motor power was intact. He did not complain of abdominal pain and his abdomen was neither distended nor tender. He was haemodynamically stable, and auscultation revealed normal heart sounds.

Contrast-enhanced computed tomography (CT) scan revealed a type A dissection from the aortic root down to the left external iliac artery. No haemopericardium or pericardial effusion was noted. Celiac artery and superior mesenteric artery (SMA) originated from both a true and false lumen. The origin and proximal segment of the SMA and celiac artery were compressed by the thrombosed false lumen (Fig 1). Bowel wall was well enhanced. There was cranial extension of the dissection into the right common and internal carotid arteries. The cerebral arteries were still opacified. Computed tomography brain showed early ischaemic change in the right cerebellar hemisphere.

Arterial blood gas analysis and serum lactate level were normal. Transthoracic echocardiography detected an intimal flap at the aortic root. Mild aortic regurgitation was present. Left ventricular function was good.

The patient had a type A aortic dissection with left lower limb acute ischaemia. Emergency interpositional ascending aortic grafting was performed to close the entry site of the ascending aorta dissection and to re-expand the true lumen. Postoperatively, the patient was haemodynamically stable and all left lower limb pulses reappeared.

A new CT scan of the abdomen revealed improved perfusion to the celiac artery. Nonetheless, the SMA remained severely stenotic with only a thin line of contrast enhancement evident in the true lumen. Enhancement of the jejunal wall was decreased. The SMA had both restricted inflow at the orifice and outflow due to compression by the thrombosed false lumen.

Emergency endovascular stenting and open fenestration of the SMA was performed in the hybrid operation theatre. A 5-French arterial sheath was inserted into the right common femoral artery. The true lumen orifice of the SMA was cannulated with a 5-French Yashiro Glidecath catheter (Terumo, Japan) and a 0.035-inch hydrophilic guidewire (Terumo, Japan). The 0.035-inch hydrophilic guidewire (Terumo, Japan) was exchanged for a Rosen guidewire (Cordis, US). The 5-French arterial sheath was exchanged for an 8-French Arrow-Flex guiding sheath (Arrow International, US). A 10-mm × 12-mm Genesis balloon expandable stent (Cordis, US) was deployed at the SMA orifice. Arteriogram showed improvement of flow at the SMA orifice only (Fig 2). Laparotomy was performed. The small and large bowel were not infarcted but lacked peristalsis. The SMA distal to the middle colic artery was bluish in appearance due to thrombosis. Longitudinal arteriotomy was made. All the thrombus in the false lumen was removed. Longitudinal fenestration was made at the dissection flap. The true lumen circulation was re-established with thrombectomy using a 3-French Fogarty catheter. The arteriotomy was closed with a saphenous vein patch. The small bowel appeared healthy after revascularisation. On-table duplex ultrasonography revealed good flow along the SMA.

The patient was transferred to the intensive care unit and extubated 4 days after surgery. He had no neurological deficits or abdominal symptoms. All distal pulses were normal. He recovered well and was discharged from hospital on aspirin 42 days after admission.

Serial follow-up CT scans after the operation showed a patent SMA and celiac artery. The patient remained asymptomatic at a follow-up examination 2 years later.

Acute dissection is one of the most lethal surgical emergencies of the aorta. It results from a tear in the aortic wall intima that extends into the media to create a false lumen and a dissection flap. It is categorised according to the Stanford classification. Visceral malperfusion occurs in 16% to 33% of cases1 due to anterograde propagation of the dissection from the ascending aorta to the level of the aortic visceral branches. This leads to mesenteric ischaemia, organ dysfunction, and systemic metabolic abnormalities. Although the results of surgical treatment for acute type A aortic dissection have improved due to technical advances, mortality remains as high as 89% in the presence of visceral ischaemia.2 It has been suggested that unless pericardial tamponade is present, restoration of visceral perfusion by endovascular techniques should take precedence, especially in cases with a high degree of mesenteric ischaemia and metabolic disturbance.3 This can improve metabolic status and reduce the intra-operative risk of subsequent dissection repair. However, the extent of intestinal malperfusion is difficult to assess since clinical signs typically present late: 75% of patients have no clinical evidence at presentation, as in our patient. This can delay diagnosis and management contributing to the high mortality. The use of biomarkers such as serum lactate has been suggested as potentially useful indicators of mesenteric ischaemia.4 5 If the initial lactate level is high with no other cause and radiological or clinical evidence of bowel ischaemia is present, revascularisation using percutaneous endovascular techniques should be performed first to alleviate intestinal ischaemia, followed by serial measurements of lactate level to look for improvement in peripheral perfusion.3 If the lactate level is persistently high, surgical revascularisation must be considered.

Our patient had no clinical or biochemical signs suggestive of bowel ischaemia. Therefore, interpositional ascending aortic grafting was performed first, since proximal extension of the dissection would be dangerous and entry site closure may improve blood flow along the SMA. The left lower limb pulses reappeared after surgery. However, CT did not show similar improvement in the SMA; on the contrary, the jejunum showed decreased enhancement. Superior mesenteric artery revascularisation was indicated. An anterograde approach was adopted for endovascular stenting of the SMA orifice, followed by open fenestration and closure with vein patch distally. No bowel resection was required. The successful outcome in this patient demonstrates good treatment prioritisation, prompt decision making, and multidisciplinary cooperation in the management of type A aortic dissection with peripheral malperfusion.

The authors have made substantial contributions to the concept or design of this study, acquisition of data, analysis or interpretation of data, drafting of the article, and critical revision for important intellectual content. The authors had full access to the data, contributed to the study, approved the final version for publication, and takes responsibility for its accuracy and integrity.

The authors have disclosed no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki. The patient provided informed consent for all procedures.

1. Okita Y, Takamoto S, Ando M, Morota T, Kawashima Y. Surgical strategies in managing organ malperfusion as a complication of aortic dissection. Eur J Cardiothorac Surg 1995;9:242-6. Crossref

2. Girardi LN, Krieger KH, Lee LY, Mack CA, Tortolani AJ, Isom OW. Management strategies for type A dissection complicated by peripheral vascular malperfusion. Ann Thorac Surg 2004;77:1309-14. Crossref

3. Slonim SM, Nyman U, Semba CP, Miller DC, Mitchell RS, Dake MD. Aortic dissection: percutaneous management of ischemic complications with endovascular stents and balloon fenestration. J Vasc Surg 1996;23:241-51. Crossref

4. Muraki S, Fukada J, Morishita K, Kawaharada N, Abe T. Acute type A aortic dissection with intestinal ischemia predicted by serum lactate elevation. Ann Thorac Cardiovasc Surg 2003;9:79-80.

5. Murray MJ, Gonze MD, Nowak LR, Cobb CF. Serum D(-)-lactate levels as an aid to diagnosing acute intestinal ischemia. Am J Surg 1994;167:575-8. Crossref

A 44-year-old woman presented to the emergency department in December 2014 with acute severe right-sided headache that began at the occipital region and spread to the right temporal and frontal regions. Pain was only partially relieved by analgesics. The patient had no history of altered mental state or focal neurological deficits. Her medical history was unremarkable except for a road traffic accident a few months previously ago with consequent right lower limb trauma. Neurological assessment revealed no gross abnormality. An urgent non-contrast brain computed tomography (CT) scan showed no intracranial haemorrhage or other abnormalities. Due to persistence of symptoms the patient underwent brain magnetic resonance (MR) imaging at a private centre. A small skull lesion was evident on the right basiocciput for which further imaging study was requested at our hospital. A contrast 3-T MR scan with angiography sequences revealed that the previously reported lesion corresponded to a 0.7-cm T1-weighted isointense and T2-weighted hyperintense structure located at the right hypoglossal canal, which was expanded. It exhibited intense contrast enhancement and was in direct continuity with the inferior petrosal sinus and the internal venous plexus around the foramen magnum, all findings suggestive of a venous lake at the right hypoglossal canal (Fig 1).

Additionally, an anomalous vessel arising from the left internal carotid artery at C2 level was noted, entering the cranium through the left hypoglossal canal and joining the basilar artery. This anomalous vessel corresponded to a left persistent hypoglossal artery (PHA; Figs 1 and 2). The bilateral cervical vertebral arteries were diminutive in calibre and did not serve as major arterial supplies to the basilar artery. No intracranial aneurysms were detected and no infarction or other abnormality was noted. The patient’s symptoms later substantially improved with symptomatic treatment.

Bony venous lakes of the skull are common and asymptomatic, and they are typically parasagittal in location. In CT scans, they appear as lucent lesions with corticated/sclerotic margins. In MR imaging, they exhibit the same signal characteristics as veins. However, it is rare to find venous lakes located at the hypoglossal canal, and other entities must be excluded such as a neurinoma or even a dural arteriovenous fistula of the hypoglossal canal, another rare but potentially symptomatic condition that may follow head trauma.1 In this case, there was no apparent arteriovenous shunt detected in the MR angiography sequences.

A PHA results from failure of regression of a primitive hypoglossal artery, one of the several anastomoses that exist between the carotid and vertebrobasilar arteries during embryogenesis. Although rare, it is the second most common persistent carotid-vertebrobasilar anastomosis after the trigeminal artery, with a prevalence of up to 0.29%,2 usually representing an incidental finding. However, diagnosis of PHA is important because it is often the only blood supply to the basilar trunk, as vertebral arteries are usually hypoplastic. Moreover, PHA is associated with intracranial arterial aneurysms, ischaemic cerebrovascular attacks, subarachnoid haemorrhage and arteriovenous malformations.3 Recognition of PHA is extremely important before any endovascular procedure, carotid endarterectomy or skull base surgery is performed. Exposure of the basilar trunk to an unusual haemodynamic stress could be the underlying mechanism that predisposes an individual to the development of aneurysms.4 On the contrary, there is an increased risk of ischaemia caused by embolism from the internal carotid artery to the posterior circulation through the PHA.5

Both vascular anomalies in this patient were most likely incidental findings; however, owing to the reported association of PHA with intracranial aneurysm development and ischaemic events, any new episode or the development of neurological symptoms should have triggered immediate imaging study.

To the best of our knowledge, this is the first report of a PHA with a contralateral hypoglossal canal venous lake, both representing rare vascular variants.

All authors contributed to the concept of study, acquisition and analysis of data, drafting of the article, and critical revision for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This case report received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki. The patient provided informed consent for all procedures.

1. Manabe S, Satoh K, Matsubara S, Satomi J, Hanaoka M, Nagahiro S. Characteristics, diagnosis and treatment of hypoglossal canal dural arteriovenous fistula: report of nine cases. Neuroradiology 2008;50:715-21. Crossref

2. Uchino A, Saito N, Okada Y, et al. Persistent hypoglossal artery and its variants diagnosed by CT and MR angiography. Neuroradiology 2013;55:17-23. Crossref

3. Srinivas MR, Vedaraju KS, Manjappa BH, Nagaraj BR. Persistent primitive hypoglossal artery (PPHA)—a rare anomaly with literature review. J Clin Diagn Res 2016;10:TD13-4.

4. Terayama R, Toyokuni Y, Nakagawa S, et al. Persistent hypoglossal artery with hypoplasia of the vertebral and posterior communicating arteries. Anat Sci Int 2011;86:58-61. Crossref

5. Conforto AB, de Souza M, Puglia P Jr, Yamamoto FI, da Costa Leite C, Scaff M. Bilateral occipital infarcts associated with carotid atherosclerosis and a persistent hypoglossal artery. Clin Neurol Neurosurg 2007;109:364-7. Crossref

Lysergic acid diethylamide (LSD) is a powerful hallucinogenic drug that was first synthesised in 1938.1 Although LSD is considered a conventional drug of abuse, cases of LSD intoxication are scarce in Hong Kong. The Hospital Authority Toxicology Reference Laboratory—the only tertiary referral laboratory for toxicological analysis in Hong Kong, established in 2004—did not encounter cases of LSD intoxication until 2015. Between 2015 and 2018, eight cases of LSD-associated intoxication were identified at five acute hospitals in Hong Kong when LSD and its metabolites were detected in patient urine samples. Details of these eight patients (7 male, 1 female; age range, 16-25 years) are presented in the Table. The most common presentation of LSD intoxication in these patients was agitation (63%), followed by erratic behaviour (50%) and violent behaviour (38%). Impaired level of consciousness (75%) and apparent sympathomimetic toxidrome (75%) were documented in most patients. History of LSD use was elicited in all cases. However, only four patients were willing to volunteer the sources of LSD: one bought LSD from the Internet, one obtained LSD at a party, and two obtained LSD from friends. The most common co-ingestant was cannabis, which was detected in three cases. Amphetamine and methamphetamine were detected in one case. In one patient, phenibut (3-phenyl-4-aminobutyric acid), a central nervous system depressant structurally related to gamma-aminobutyric acid, was detected. Two cases were complicated by rhabdomyolysis and one of them required intensive care unit admission. The clinical details of these two cases are presented below.

A 25-year-old man who had a history of childhood asthma presented to Princess Margaret Hospital, Hong Kong, in September 2018 with agitation after sublingual use of LSD on a stamp at a party. At presentation, his Glasgow Coma Scale was 13/15 (E4, V4, M5). The patient’s blood pressure was 116/80 mm Hg, heart rate was 150 beats per minute, body temperature was 39.2℃, and pupil sizes were 5 mm bilaterally. Biochemical investigations showed a peak creatine kinase (CK) value of 6260 U/L, and urine myoglobin was positive. The patient was intubated and treated with alkaline diuresis in the intensive care unit. The urine specimen was analysed in the Toxicology Reference Laboratory, where LSD, its metabolite (2-oxo-3-hydroxy-LSD), diazepam, nordiazepam, temazepam, midazolam and propofol were detected.

An 18-year-old man who enjoyed good past health presented to United Christian Hospital, Hong Kong, in April 2016 with erratic behaviour after sublingual use of LSD on a stamp obtained from his friends. At presentation, his Glasgow Coma Scale was 13/15 (E4, V4, M5). The patient’s blood pressure was 127/50 mm Hg, heart rate was 167 beats per minute, body temperature was 38.7℃, and pupil sizes were 6 mm bilaterally. Biochemical investigations showed metabolic acidosis, a peak CK value of 14 732 U/L, and urine myoglobin was positive. In the urine specimen, LSD, its metabolite (2-oxo-3-hydroxy-LSD), and lidocaine were detected.

Classically described as a psychedelic or hallucinogenic agent, LSD is structurally similar to serotonin (5-hydroxytryptamine), an important neurotransmitter in the central nervous system. It acts as a serotonin receptor agonist in the central nervous system and may produce prominent visual hallucinations, audiovisual synaesthesia, and derealisation. Significant sympathomimetic stimulation has also been observed.2 The effects typically begin within 30 to 60 minutes, peak at around 2 hours and can last for up to 12 hours after intake.2 These effects are consistent with the current findings that most patients presented with apparent sympathomimetic toxidrome, characterised by tachycardia, hypertension, mydriasis, and pyrexia.

There is a general impression promulgated over the Internet and by celebrities that LSD is harmless and even beneficial to personal development. Recently, LSD has re-emerged as a micro-dosing psychedelic. People consume regular low doses of LSD in an attempt to boost their creativity.3 However, this practice, also described as the Silicon Valley trend, lacks scientific evidence. These factors appear to have misled the public into underestimating the potential sequelae of LSD abuse. In contrast, our case series clearly demonstrates that LSD intoxication is associated with severe sequelae. In both cases complicated with rhabdomyolysis, no other stimulant-class drugs of abuse were detected, including conventional and emerging drugs of abuse.4 No better alterative causes of rhabdomyolysis were identified from the medical or drug history and biochemical investigations; LSD intoxication was the major contributing factor to rhabdomyolysis in both cases. Other cases of LSD-associated rhabdomyolysis have been reported in the literature.5 6 Fortunately, all patients in our series recovered uneventfully. However, at least one fatal case has been reported elsewhere.7

Frontline clinicians should be aware that LSD has re-appeared, disguised as a “safe” drug of abuse associated with multiple local intoxication cases with severe sequelae including rhabdomyolysis. Thorough investigations and serial monitoring are required to detect complications. Urine toxicology is useful to confirm the exposure to drugs of abuse. However, owing to its high potency, the dosage of LSD taken is small (in micrograms) and urine levels may be very low.2 A sensitive analytical system is required to detect the presence of LSD and its metabolite. Public education on the dangers or LSD abuse, and effective regulatory control by the government sectors are recommended.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Concept or design of study: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the article: C Li, MHY Tang, TWL Mak.
Critical revision for important intellectual content: All authors.

All authors have disclosed no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval for this study was granted by the Hong Kong Hospital Authority Kowloon West Cluster Research Ethics Committee (Ref KW/EX-19-003). The Committee exempted the study group from obtaining patient consent.

1. Nichols DE, Grob CS. Is LSD toxic? Forensic Sci Int 2018;284:141-5. Crossref

2. Dolder PC, Schmid Y, Steuer AE, et al. Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects. Clin Pharmacokinet 2017;56:1219-30. Crossref

3. Anderson T, Petranker R, Rosenbaum D, et al. Microdosing psychedelics: personality, mental health, and creativity differences in microdosers. Psychopharmacology (Berl) 2019;236:731-40. Crossref

4. Tang M, Ching CK, Tse ML, et al. Surveillance of emerging drugs of abuse in Hong Kong: validation of an analytical tool. Hong Kong Med J 2015;21:114-23. Crossref

5. Mercieca J, Brown EA. Acute renal failure due to rhabdomyolysis associated with use of a straitjacket in lysergide intoxication. Br Med J (Clin Res Ed) 1984;288:1949-50. Crossref

6. Berrens Z, Lammers J, White C. Rhabdomyolysis after LSD ingestion. Psychosomatics 2010;51:356-356.e3. Crossref

7. Fysh RR, Oon MC, Robinson KN, Smith RN, White PC, Whitehouse MJ. A fatal poisoning with LSD. Forensic Sci Int 1985;28:109-13. Crossref

An 80-year-old woman presented to our hospital with mild headache in November 2015. She had a history of hypertension, diabetes mellitus, and hyperlipidaemia. She was febrile (38.6°C) but did not appear septic. Abdominal examination revealed mild splenomegaly but no hepatomegaly and there were no focal neurological signs or suggestions of other organ involvement. A full blood count showed leukocytes 124.0 × 10⁹/L (neutrophils 120.3 × 10⁹/L, lymphocytes 2.5 × 10⁹/L, monocytes 1.2 × 10⁹/L); haemoglobin 7.8 g/dL, mean corpuscular volume 89.1 fL; and platelets 384 × 10⁹/L. The blood film showed marked neutrophilia, occasional myelocytes, and absolute basophilia but no blasts. The neutrophils showed toxic granules and were not dysplastic (Fig 1). Plain radiographs of the chest, kidney, ureter, and urinary bladder did not reveal any abnormalities. Bacterial cultures of the blood and urine did not reveal any septic foci. Because of the marked neutrophilia, the patient was initially treated for bacterial sepsis with empirical intravenous amoxicillin with clavulanic acid. Subsequent ultrasonography of the abdomen confirmed the splenomegaly (15.1 cm) but no other space-occupying lesions. The low-grade fever soon subsided after admission and she remained afebrile and non-septic, although the marked neutrophilia persisted.

A bone marrow biopsy revealed marked hypercellularity, primarily due to markedly increased granulopoiesis with left-shift in maturation but no increase in blasts. Erythropoiesis was active and normoblastic. Megakaryocytes were moderately increased with some being large and hyperlobulated. No overt dysplasia was seen. Cytogenetic karyotyping showed a normal karyotype. Reverse transcription polymerase chain reaction (PCR) for BCR-ABL1 and allele-specific PCR for Janus kinase 2 (JAK2) V617F mutation analysis were negative. In view of the clinical and laboratory picture of a possible myeloproliferative neoplasm, and the lack of a clonal marker detected by the molecular tests, we sought to utilise a next-generation sequencing (NGS) panel (TruSight Myeloid Sequencing Panel; Illumina, San Diego [CA], United States) to look for possible mutations in selected exons of 54 different genes commonly implicated in myeloid neoplasms, in accordance with a previously published protocol.1 Deep sequencing by this panel returned three pathogenic mutations: colony-stimulating factor 3 receptor (CSF3R) c.1853C>T; p.Thr618Ile or T618I at variant allele frequency (VAF) of 43.9% (Fig 2a), serine/arginine-rich splicing factor 2 (SRSF2) c.284C>T; p.Pro95Leu (NM_003016.4) or P95L at VAF of 49.6%, and additional sex combs like 1 (ASXL1) truncating mutation c.1934dupG; p.Gly646Trpfs*12 (NM_015338.5) at VAF of 34.1%. The CSF3R T618I mutation was further confirmed by Sanger sequencing (Fig 2b), thus prompting the diagnosis of chronic neutrophilic leukaemia (CNL). Although the CSF3R mutation rendered the disease amenable to ruxolitinib, the patient deteriorated rapidly and died of sudden severe gastrointestinal bleeding 12 days after admission and before specific therapy could be contemplated.

Several clinical features in this patient hinted at differential diagnoses other than bacterial infection or acute inflammation. Apart from fever, there were no other clinical features related to the presenting symptom of headache. Splenomegaly, a common feature of myeloproliferative neoplasms, was present. The absolute neutrophil count was very high, yet no clinical features of sepsis were found on physical examination or from investigations.

Since 2013, understanding of the molecular genetics of CNL has been dramatically changed by the discovery of CSF3R mutations in around 80% of cases.2 The CSF3R encodes a transmembrane receptor for granulocyte colony-stimulating factor 3, and plays a crucial role in the differentiation and maturation of neutrophils.2 The CNL-associated mutations in CSF3R activate the receptor and promote the proliferation and differentiation of neutrophils, leading to the marked neutrophilia that characterises the CNL disease phenotype.3 There are two major types of CSF3R mutations in CNL. The first encompasses point mutations in the extracellular or transmembrane domains, of which the T618I mutation is the most common and comprises the majority of mutations in CNL. The second type of CSF3R mutation comprises nonsense or frameshift mutations leading to a premature stop codon and truncation of the cytoplasmic domain of the receptor.2

Mutations of other genes have also been reported in CNL. These can be grouped as SET binding protein 1 (SETBP1) mutations, spliceosome mutations (eg, SRSF2), epigenetic modifier mutations (eg, ASXL1), and signalling mutations (eg, JAK2).3 One previous study found that SRSF2 mutations occurred in three of 14 cases of CNL (21%). The SRSF2 mutations were previously associated with a worse prognosis in chronic myelomonocytic leukaemia, but its effects on CNL are unclear.3 A significant proportion of CNL patients have been shown to harbour ASXL1 (30%-60%). Similar to mutations in other myeloid malignancies, ASXL1 mutations in CNL have been shown to confer a poor prognosis.3

Although these other mutations have not been incorporated into the World Health Organization 2016 diagnostic criteria for CNL, these data suggest that some may show prognostic value. Additionally, different CSF3R mutations may allow different therapeutic approaches (see below). Because Sanger sequencing of an increasing number of genes leads to substantial increases in the required time, resources, and necessary amount of DNA, we sought to explore an NGS panel to interrogate these genes simultaneously more efficiently and cost-effectively. Of note, the panel includes genes that are important for the diagnosis of myeloproliferative neoplasm (JAK2, calreticulin [CALR] and myeloproliferative leukaemia protein [MPL]), plus genes that are frequently reported in CNL (CSF3R, SETBP1, SRSF2, ASXL1). Therefore, compared with Sanger sequencing, NGS panels are a more efficient and powerful means to enable comprehensive genomic profiling of individual CNL cases, utilising a smaller amount of DNA.

With recent discoveries in the molecular pathogenesis of CNL, new therapeutic approaches that target the CSF3R signalling pathway–related SRC family and JAK-kinase pathways have emerged. The SRC signalling pathway is activated by truncation mutations of CSF3R leading to sensitivity to dasatinib, while the JAK-STAT pathway is activated by membrane proximal mutations of CSF3R leading to sensitivity to ruxolitinib.2 Although there are few reported cases of these agents,2 4 they represent significant breakthroughs in the management of CNL. This case of a rare myeloproliferative neoplasm demonstrates how advances in understanding of the molecular pathogenesis of a disease open up new routes for the development of effective novel therapeutic strategies.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Concept and design of study: WWL Choi.
Acquisition of data: KY Mak, CH Au, TL Chan, ESK Ma, SY Lin, WWL Choi.
Analysis or interpretation of data: KY Mak, CH Au, TL Chan, ESK Ma, WWL Choi.
Drafting of the manuscript: KY Mak, WWL Choi.
Critical revision for important intellectual content: CH Au, TL Chan, ESK Ma, EYD Chow, SY Lin.

All authors have no conflicts of interest to declare.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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3. Maxson JE, Tyner JW. Genomics of chronic neutrophilic leukemia. Blood 2017;129:715-22. Crossref

4. Stahl M, Xu ML, Steensma DP, Rampal R, Much M, Zeidan AM. Clinical response to ruxolitinib in CSF3R T618-mutated chronic neutrophilic leukemia. Ann Hematol 2016;95:1197-200. Crossref