Acute appendicitis is a common surgical emergency that can cause severe complications if diagnosis and management are delayed.1 Necrotising fasciitis (NF) is a necrotic infection involving deeper layers of the skin and subcutaneous tissue that spreads rapidly along the fascia, progressing to systemic sepsis. It is most commonly induced by injury and is an extremely rare complication of acute appendicitis. In this article, we present a case of perforated appendicitis complicated by right thigh and scrotal NF. Since the condition runs a fulminant clinical course, prompt diagnosis and early surgical intervention are crucial to reduce mortality.

A 60-year-old man with good past health presented to the Accident and Emergency Department of Queen Elizabeth Hospital, Hong Kong, in December 2015 with a 6-day history of fever and lower abdominal pain.

His vital signs on presentation were as follows: systolic blood pressure 97 mm Hg; diastolic blood pressure 59 mm Hg; pulse 90 beats per minute; and body temperature 38.3°C. Physical examination revealed lower abdominal and right thigh tenderness without subcutaneous emphysema. Laboratory data showed leucocytosis (15.5 × 10⁹/L) with neutrophilia (neutrophils 88.7%) and evidence of acute kidney injury (estimated glomerular filtration rate 38 mL/min/1.73 m², serum creatinine 171 μmol/L).

Abdominal, pelvic, and right hip radiographs were unremarkable. Urgent abdominal and pelvic computed tomographic (CT) scan revealed a dilated retrocaecal appendix with heterogeneous wall enhancement, compatible with acute gangrenous appendicitis. There was rupture at the appendiceal tip, contiguous with a 2.8- × 4.5- × 8.0-cm gas-containing abscess posterolateral to the ascending colon and caecum (Fig 1). Increased peri-appendiceal and pericaecal stranding and free gas were noted. Multiple smaller pelvic abscesses were also observed. An incidental finding of abnormal swelling of the right upper thigh was noted in the limited coverage of the thigh in the original CT scan. Another CT scan including the whole right thigh was performed by the on-site radiologist. Abnormal high-density fluid and fat stranding were noted in the subcutaneous layer and intermuscular fascial planes in the anterior, adductor, and posterior compartments of the right thigh (Fig 2). The thigh muscles were swollen without discrete abscess formation. No gas density was detected along the fasciae. The initial overall imaging diagnosis was ruptured acute appendicitis with peri-appendiceal abscess, complicated by right thigh NF.

Subsequent urgent laparotomy revealed a ruptured inflamed retrocaecal appendix and an 8-cm retrocolic abscess. Appendectomy and abscess drainage were performed. These were followed by exploration of the right thigh that revealed oedematous and necrotic subcutaneous and deep soft tissues mainly involving the adductor compartment. Multiple intramuscular abscesses were seen with turbid fluid tracing along the femoral neurovascular bundles proximally to the pelvic region. Overall features were compatible with NF. Right above-knee amputation with excisional debridement was performed in view of the patient’s poor general condition and extensive involvement.

Culture of the debrided muscle and fascial tissue yielded Escherichia coli, Bacteroides fragilis, and Streptococcus milleri. A combination of antibiotics was given, including amikacin, ampicillin, levofloxacin, linezolid, meropenem, and penicillin G. However, septic shock persisted with development of multi-organ dysfunction despite multiple inotropes. Another CT scan of the abdomen and pelvis was performed on postoperative day 1, revealing a grossly swollen scrotum with hydrocoele (not shown). No intrascrotal gas density was detected. In view of the patient’s clinical deterioration, urgent scrotal exploration was performed and revealed extensive scrotal skin necrosis with copious serous fluid draining from the perineum.

After the second surgery, the patient had persistent multi-organ failure with clinical deterioration despite supportive management. He developed acute respiratory distress syndrome with respiratory failure and disseminated intravascular coagulation with severe anaemia, further complicated by acute coronary syndrome. The patient succumbed on the fourth day of hospital admission.

The incidence of NF has risen recently owing to an increased prevalence of patients who are immunocompromised secondary to diabetes mellitus or treatment for malignancy or human immunodeficiency virus infection.1 The mortality rate for NF is high, despite significant advances in antibiotic treatment, owing to its rapid progression to septic shock and multi-organ failure.1

Common causes of NF include minor trauma, skin infection, intravenous drug use, and surgical complication.1 The abdomen, groin, and extremities are the regions most commonly affected by NF.1 2 3 4 5 Necrotising fasciitis is commonly polymicrobial, caused by virulent toxin-producing bacteria such as Group A haemolytic streptococci and Staphylococcus aureus. Other causative bacteria include Bacteroides, Clostridium, Enterobacteriaceae, Peptostreptococcus, Proteus, Pseudomonas, and Klebsiella.1

The diagnosis of NF is challenging due to its rarity and non-specific presentation. Usually the early manifestations are local inflammatory signs and symptoms such as swelling, erythema, and tenderness, occasionally with fever. However, NF should be suspected when the severity of pain or clinical status are disproportional to local findings.5 Laboratory studies show leucocytosis with predominant neutrophilia,1 but is unfortunately non-specific.5 Presence of soft tissue gas in the absence of penetrating trauma suggests a diagnosis of NF,2 although the absence of soft tissue gas does not exclude the diagnosis, as evidenced by our case.

Plain radiographs are usually unhelpful for initial diagnosis as soft tissue gas is seldom detected until late in the disease process.1 Magnetic resonance imaging is superior in delineating soft tissue pathology but is a suboptimal modality for critically ill patients.2 Computed tomography is the preferred imaging modality, with reported findings including asymmetric fascial thickening with fat stranding and subcutaneous gas tracking along fascial planes.2 It also delineates the extent of tissue involvement well and is useful for monitoring treatment response.

Necrotising fasciitis secondary to perforated appendicitis is rarely reported. We have found only 18 case reports of NF caused by acute appendicitis published in the English literature.1 2 3 4 5 The affected regions included the abdominal wall (most commonly involved), perineum, and thigh. According to Taif and Alrawi,5 there have been only three reported cases of appendicitis complicated by NF predominantly involving the lower limb. All cases involved the right thigh, likely from more direct infective spread along the right femoral neurovascular bundles than the left.

Our case represents a rare but life-threatening consequence of a common disease despite the absence of risk factors. Early clinical changes of NF can be subtle. Early recognition, broad-spectrum antibiotic treatment, and aggressive surgical debridement are the cornerstones of management for this potentially lethal disease.1 A high index of suspicion is needed in diagnosis such that emergent surgical intervention can be initiated to improve clinical outcome.

All authors contributed to the design, acquisition and interpretation of data, drafting of the article, and critical revision for important intellectual content.

We would like to thank the staff radiographers of the Department of Radiology and Imaging, Queen Elizabeth Hospital for their assistance in acquisition of the images.

All authors have disclosed no conflicts of interest. 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.

1. Chen CW, Hsiao CW, Wu CC, Jao SW, Lee TY, Kang JC. Necrotizing fasciitis due to acute perforated appendicitis: case report. J Emerg Med 2010;39:178-80. Crossref

2. Hung YC, Yang FS. Necrotizing fasciitis—a rare but severe complication of perforated appendicitis. Radiol Infect Dis 2015;2:81-3. Crossref

3. Hua J, Yao L, He ZG, Xu B, Song ZS. Necrotizing fasciitis caused by perforated appendicitis: a case report. Int J Clin Exp Pathol 2015;8:3334-8.

4. Wanis M, Nafie S, Mellon JK. A case of Fournier’s gangrene in a young immunocompetent male patient resulting from a delayed diagnosis of appendicitis. J Surg Case Rep 2016;2016:rjw058. Crossref

5. Taif S, Alrawi A. Missed acute appendicitis presenting as necrotising fasciitis of the thigh. BMJ Case Rep 2014;2014:bcr2014204247. Crossref

A 24-year-old Chinese man was referred to the Chest Unit of Grantham Hospital, Hong Kong in June 2016 for management of bronchiectasis. The patient had experienced his first episode of lower respiratory tract infection (LRTI) at age 17 years, which required hospital admission for intravenous antibiotics. He had since developed four to five episodes of LRTI annually and subsequently developed bronchiectasis with daily copious sputum and occasional haemoptysis.

Review of the patient’s records revealed a history of autoimmune hypothyroidism since age 12 years, which was based on thyroid scintigraphy and high titres of antithyroid autoantibodies and required thyroxine replacement. At age 21 years, after an incidental finding of iron deficiency anaemia, the patient underwent upper endoscopy, which revealed oesophageal candidiasis (Fig 1). The patient had recurrent and chronic oral ulcers, and excisional biopsy with Grocott staining displayed fungal spores and pseudohyphae consistent with candidiasis.

Further questioning of the patient revealed frequent tinea infections and orogenital candidiasis since early childhood. The patient had had childhood chickenpox with two further episodes of zoster reactivation during his teens. There were no features suggestive of atopy nor any history of recurrent abscesses. The patient had difficulty attending his frequent medical appointments and often required sick leave from his work as a technician. He was a never smoker and social drinker. The patient was born and raised in Hong Kong, and had received all routine vaccinations without problems. The family history was unremarkable with no history of consanguinity. The patient lived with his parents and younger brother, none of whom had candidiasis.

High-resolution computed tomography revealed bilateral lower lobe bronchiectasis (Fig 2) and bronchoscopy again showed extensive candidiasis with no airway abnormalities. Pulmonary function test results and serum alpha-1-antitrypsin level were normal. Sputum cultures were negative for acid-fast bacilli and yeasts, and aerobic culture yielded commensals only. The patient’s complete blood counts were grossly normal apart from a persistently low absolute lymphocyte count (0.5-0.7 × 109 /L). Immunoglobulin (Ig) levels (IgG/IgM/IgA/IgE) were all within normal limits. Screening for diabetes mellitus and testing for human immunodeficiency virus (HIV) was negative. Complement levels and the dihydrorhodamine assay were normal. A serology panel also found positive anti-nuclear antibodies with a titre of 1:320, in addition to previously documented thyroid autoantibodies. Repeated lymphocyte subsets showed persistent panlymphocytopenia (CD19:43/μL[n:91-452], CD3:491/μL[n:938-2311], CD4:206/μL[n:437-1226], CD8:263/μL[n:322-1104] and CD16/56:115/μL[n:177-1059]), with impaired lymphocyte proliferation after phytohaemagglutinin and pokeweed mitogen stimulation.

In view of his chronic mucocutaneous candidiasis (CMC), autoimmunity and combined immunodeficiency, the patient was referred to us for further evaluation. An interleukin (IL)-17–related defect was suspected and sequencing of the signal transducer and activator of transcription (STAT) 1 gene was performed. A previously reported gain-of-function (GOF) mutation of p.G384D in the DNA-binding domain was identified.1 The patient was counselled and long-term itraconazole and co-trimoxazole prophylaxis treatment was started. Measurement of pneumococcal antibody responses were scheduled. The patient continues to receive multidisciplinary care between immunology, pulmonology, and internal medicine after a unifying diagnosis for his wide spectrum of disease manifestations was made.

That primary immunodeficiencies (PIDs) only affect children is a common misconception. Diagnoses are also made in adulthood due to genuine adult-onset types, as in our case, or delayed disease recognition. We describe the first reported adult case of STAT1-GOF mutation in our locality. The patient had a typical history of CMC, complicated by recurrent infections, bronchiectasis, and autoimmune hypothyroidism. The patient also had panlymphocytopenia, which is reported in 20% to 30% of STAT1-GOF patients and associated with LRTIs.2 The first possible indication of STAT1-GOF mutation was the autoimmune hypothyroidism in the context of CMC.

Typically, CMC is characterised by persistent/recurrent non-invasive Candida infections of the skin, nails, and mucous membranes. Candidiasis is usually an opportunistic infection and associated with immunosuppression acquired through diabetes mellitus or HIV, or use of chemotherapy, glucocorticoids, or antibiotics. Candidiasis is also associated with a variety of PIDs, usually with an underlying IL-17 pathway defect. Examples include hyper-IgE syndromes, autoimmune polyendocrinopathy syndrome type 1, CARD9 deficiency, in addition to IL-17F and IL-17RA deficiencies.3

Since 2011, STAT1-GOF mutations have been discovered that cause autosomal dominant familial CMC. These mutations are now established as the most common genetic cause of inherited CMC. Such STAT1-GOF mutations have also been reported in paediatric patients in Hong Kong with CMC and penicilliosis.4 These mutations impair STAT1 dephosphorylation and enhance the production of STAT1-dependent cytokines (interferon-α/β, interferon-γ and IL-27). In turn, this likely represses STAT3-dependent gene transcription and impairs the development of IL-17–producing T cells, although the exact mechanisms remain unclear.5

A recent analysis of the clinical manifestations in 274 individuals with 76 different STAT1-GOF mutations revealed an extremely broad disease phenotype.2 In addition to CMC, patients were also prone to other fungal, bacterial (usually LRTIs), and viral infections. Results of immunological investigations were variable, but abnormalities were significantly associated with increased infections. More than a third of patients had autoimmune/inflammatory disorders, most commonly hypothyroidism, and 21% of patients had bronchiectasis.2 Most patients with autoimmunity had positive autoantibodies. Alarmingly, these patients are more likely to develop other autoimmune disorders, cerebral/abdominal aneurysms, and squamous cell carcinomas (likely secondary to chronic mucocutaneous inflammation).

The outcome for patients with STAT1-GOF mutations remains poor, with most deaths resulting from infection, aneurysms, or malignancies. Long-term (as opposed to intermittent) systemic antifungal therapy remains the mainstay of treatment, aiming to reduce the development of antifungal resistance and malignancy. Additional antibiotic prophylaxis and intravenous Ig should be considered for patients with recurrent infections. In our patient, intravenous Ig would have been indicated if his response to pneumococcal vaccination was suboptimal in the context of bronchiectasis. Furthermore, autoimmune hypothyroidism is associated with cerebral aneurysms and baseline magnetic resonance angiography may be indicated. Lastly, any ear, nose, and throat or gastrointestinal symptoms should alert the physician to a need for regular monitoring of such malignancies with biopsy. Experimental therapies such as colony-stimulating factors and ruxolitinib, a Janus kinase 1/2 inhibitor, have been reported to successfully improve CMC and will merit a trial if his CMC worsens with time.6

For other PIDs, the main goals are to reduce the incidence of infections and to prevent development of complications; with the ultimate aim of cure. Improved awareness and further development of adult clinical immunology in Hong Kong is required, so that adult patients with PID receive more timely and comprehensive care.

All authors have made substantial contributions to the concept; acquisition of data; interpretation of data; drafting of the article; and critical revision for important intellectual content.

All authors have disclosed no conflicts of interest. 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.

1. Yamazaki Y, Yamada M, Kawai T, et al. Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody. J Immunol 2014;193:4880-7. Crossref

2. Toubiana J, Okada S, Hiller J, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood 2016;127:3154-64. Crossref

3. Puel A, Cypowyj S, Maródi L, Abel L, Picard C, Casanova JL. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr Opin Allergy Clin Immunol 2012;12:616-22. Crossref

4. Lee PP, Mao H, Yang W, et al. Penicillium marneffei infection and impaired IFN-γ immunity in humans with autosomal-dominant gain-of-phosphorylation STAT1 mutations. J Allergy Clin Immunol 2014;133:894-6.e5. Crossref

5. Zheng J, van de Veerdonk FL, Crossland KL, et al. Gain-of- function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC). Eur J Immunol 2015;45:2834-46. Crossref

6. van de Veerdonk FL, Netea MG. Treatment options for chronic mucocutaneous candidiasis. J Infect 2016;72 Suppl:S56-60. Crossref

Despite the advances in neuroscience and medical therapy for epilepsy, status epilepticus, especially when refractory or super-refractory (defined as seizure that continues or recurs ≥24 hours after onset of anaesthetic therapy, including cases that recur on reduction or withdrawal of anaesthesia),1 remains an enormous challenge. Multiple and high-dose drug loading is usually prescribed but may be futile. New modalities of treatment including hypothermia and ketogenic diets have been tried with some success in reported case series.2 We report a case of new-onset super-refractory status epilepticus treated successfully with electroconvulsive therapy (ECT).

A 31-year-old male with a history of childhood asthma presented to Tuen Mun Hospital in November 2012 following onset of generalised tonic-clonic seizure at home. He had upper respiratory symptoms with fever, myalgia, and cough for a week previously. There was no history of recent travel or drug abuse.

Physical examination revealed no focal neurological abnormalities. Investigations showed a normal routine blood picture and renal function except mild liver impairment with alanine aminotransferase level of 72 U/L. General autoimmune (antinuclear antibodies, anti–early nuclear antigen antibodies, C3/C4 and antithyroid antibodies) and toxicology screening were negative. Dried blood spot test for neurometabolic screening was also negative. Examination of cerebrospinal fluid showed white blood cell count 9 per mm3, red blood cell 2 per mm3, protein 0.54 g/dL, and glucose 5.4 g/dL. Microbiological investigations (herpes simplex virus, human immunodeficiency virus, Japanese encephalitis virus, varicella zoster virus, and enteroviruses) were negative. Serology for neurosyphilis and leptospirosis was also negative. Serum anti-CASPR2 Ab, anti-LGI1 Ab, anti-VGKC Ab, and anti-NMDAR Ab (serum and cerebrospinal fluid) were all negative.

He was initially treated with intravenous acyclovir and ceftriaxone for presumed acute infectious meningoencephalitis. Routine electroencephalogram (EEG) showed a generalised slow background of 4 to 6 Hz without epileptiform discharges. He developed a clustering of generalised tonic-clonic seizures 2 days later and was admitted to the intensive care unit. He underwent mechanical ventilation and aggressive treatment with medication at the maximal tolerable dosage including intravenous phenytoin (300 mg/d), valproate (1200 mg/d), midazolam (~60 mg/h), propofol (up to 110 mg/h), phenobarbitone (300 mg/d), and levetiracetam (3000 mg/d). Despite treatment he remained convulsive with seizures evident on EEG. Intravenous immunoglobulin was first given 8 days following admission for possible autoimmune encephalitis but was unsuccessful. Electroencephalogram showed generalised epilepti-form discharges and runs of EEG seizure activity over the bitemporal and bifrontocentral regions. His condition was later complicated by rhabdomyolysis and renal failure (creatine phosphokinase up to 47 000 U/L) that was controlled by aggressive intravenous fluid administration.

Magnetic resonance imaging of the brain (Fig 1) showed multiple patchy areas of cortical T2 hyperintensity bilaterally that were more indicative of epileptic changes with the possibility of encephalitis. Electroencephalogram finally reached burst suppression and seizure suppression following infusion of thiopentone (300 mg/h) and ketamine (220 mg/h). The former was withdrawn because of sepsis that was treated with ticarcillin/sulbactam and meropenem/ertapenem. The generalised epileptiform discharges and seizures returned 8 days later despite such aggressive treatment.

Hypothermia by external cooling (18 days after admission) with body temperature reduced to 32°C with a ketogenic diet (81% lipid, 4.7% Chinese hamster ovary and 13.9% protein) and urine ketosis had no effect. Plasmapheresis was attempted on day 22 but also failed.

Finally, ECT was attempted using the spECTrum 5000Q (Techsan, Czech Republic) and followed the standard psychiatric protocol for treatment of refractory major depression. Ketamine and propofol continued throughout the procedure. The first course of ECT commenced 30 days after admission, and was administered 3 times per day for 3 days:

• Day 1: pulse width at 0.5 ms, frequency 40 Hz × 1 and 60 Hz × 2, duration of 8 seconds, current 800 mA, 200 J
• Day 2: pulse width at 0.5 ms, frequency 60 Hz × 2 and 80 Hz × 1, duration of 8 seconds, current 800 mA, 200 J (tonic seizure, EEG seizure, and R arm clonus-induced)
• Day 3: pulse width at 0.5 ms, frequency 80 Hz × 3, duration of 8 seconds, current 800 mA, 200 J (tonic seizure–induced and EEG showed spindle coma)

Attenuation and abolition of continuous lateralised epileptiform discharges and seizures were achieved with interictal focal epileptiform discharge over the right frontal region only. The EEG seizure induced by stimulation comprised generalised fast beta activities different to the patient’s own seizure activities.

The EEG from the first day of the first course stimulation is shown in FIgure 2.3 4 The second course was given 8 days later (again thrice per day for 3 days) as there was no sustainable improvement. In this course, all therapies were given with pulse width 0.5 ms, frequency 80 Hz, duration of 8 seconds, and current 800 mA, 200 J after referencing the EEG response of the last stimulation. Arm clonus, with one arm paralysed with muscle relaxants and the other for observing EEG-induced seizure and threshold titration, was observed in 10 of the 15 stimulations.

Electroencephalogram 1 week after completion of the second course showed a triphasic wave pattern rather than the previous generalised periodic discharges with EEG seizures over the right frontocentral and right hemisphere. The patient had hyperammonaemia, likely secondary to hepatotoxicity due to the prolonged use of multiple antiepileptics and anaesthetics, and was treated with sodium benzoate.

Oxcarbazepine and lacosamide were added for focal electrographic seizures. Electroencephalogram 10 days after ECT continued to show generalised continuous slow waves with intermittent rhythmic slowing of 1 Hz. There was some eye blinking but no ictal EEG changes.

Electroencephalogram 1 month after ECT showed an improved background of 6 to 8 Hz and occasional EEG seizures over the right frontocentral region, as well as clinically automotor seizures.

The patient was transferred back to the general ward 1 month later and commenced active rehabilitation. He was discharged home 3 months later, although he continued to require a frame for walking and experienced short duration of breakthrough seizures. His positron emission tomography scan later showed no evidence of malignancy. One year later, the patient remained ambulatory with aids but with cognitive decline and personality changes. He was able to self-care, but his seizures remained pharmacoresistant.

This is the first case of super-refractory status epilepticus, defined as status epilepticus that continues or recur ≥24 hours after the onset of anaesthetic therapy including those cases that recur on reduction or withdrawal of anaesthesia,1 that has been treated with ECT successfully in our locality.

There are only individual reports describing the use of ECT for status epilepticus over the last 30 years,5 6 although its use was first described in the 1940s. It was not until the introduction of super-refractory status epilepticus7 that the role of multiple exploratory therapies (those without support from systemic investigations or clinical trials including use of ketamine, hypothermia, ketogenic diet, and ECT) were added to the management protocol.8 The most promising news for this specific seizure status nonetheless comes from the recent discovery of the treatable autoimmune encephalitic nature of many such cases with specific identifiable antibodies such as anti-NMDAR Ab, anti-LGI1 Ab, and anti-VGKC Ab.

The term NORSE (new-onset refractory status epilepticus) was introduced in 20059 for patients with refractory status epilepticus and no history of seizures and no identifiable aetiology. Reviewing the limited literature, these cases reported usually have features suggestive of an infectious or inflammatory nature with febrile episodes or abnormal cerebrospinal fluid pleocytosis.10 These cases are most likely to be autoimmune encephalitis, but the antibodies are not available or have not yet been identified. Our patient was likely true NORSE, although the possibility of a postinfectious or autoimmune mechanism cannot be excluded as the panel of testing has not been exhausted.

Electroconvulsive therapy in status epilepticus was first described by Carrasco González et al in 1997 and Viparelli and Viparelli in 1992.5 11 Since then, there have been other case reports or series reporting success of this therapy, both in adult and paediatric patients.12 13 It is usually applied with the withdrawal of anticonvulsants or anaesthetics. Mechanisms suggested include enhanced gamma-aminobutyric acid inhibition, the effect of paradoxical stimulation of status epilepticus and electrical modulation.14 In our patient, anticonvulsants or anaesthetic agents were given without an end date and we applied ECT in addition to, not instead of, such drug therapy. The EEG epileptiform discharges showed immediate attenuation following electrical stimulation, and supports the possibility of enhancing the seizure threshold or an inhibitory mechanism. The later EEG changes were related to significant metabolic encephalopathy (hyperammonaemia) rather than previous runs of epileptiform discharges, also suggested the modulatory effect of ECT when a course was given rather than just a few shots. Of course, one would also argue that the improvement could be the late effect of previous intravenous immunoglobulin or plasmapheresis although these had no immediate effect on the EEG or clinical seizures or epileptiform discharges.

Despite the apparent successful outcome for our patient following the addition of ECT, we require more cases, both adult and paediatric, with such treatment applied as well as a clear definition of the status epilepticus stages (early, refractory or super-refractory) and specific categorisation of the syndrome and aetiology (autoimmune or cryptogenic to be NORSE) before we can confidently support the role and effectiveness of this physical therapy.

The authors have no conflicts of interest to disclose.

1. Shorvon S, Trinka E. The London-Innsbruck Status Epilepticus Colloquia 2007-2011, and the main advances in the topic of status epilepticus over this period. Epilepsia 2013;54(Suppl 6):11-3. Crossref

2. Cervenka MC, Hocker S, Koenig M, et al. Phase I/II multicenter ketogenic diet study for adult superrefractory status epilepticus. Neurology 2017;88:938-43. Crossref

3. Hirsch LJ, LaRoche SM, Gaspard N, et al. American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology: 2012 version. J Clin Neurophysiol 2013;30:1-27. Crossref

4. Beniczky S, Hirsch LJ, Kaplan PW, et al. Unified EEG terminology and criteria for nonconvulsive status epilepticus. Epilepsia 2013;54(Suppl. 6):28-9. Crossref

5. Carrasco González MD, Palomar M, Rovira R. Electroconvulsive therapy for status epilepticus. Ann Intern Med 1997;127:247-8. Crossref

6. Griesemer DA, Kellner CH, Beale MD, Smith GM. Electroconvulsive therapy for treatment of intractable seizures. Initial findings in two children. Neurology 1997;49:1389-92. Crossref

7. Shorvon S. Super-refractory status epilepticus: an approach to therapy in this difficult clinical situation. Epilepsia 2011;52(Suppl 8):53-6. Crossref

8. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802-18. Crossref

9. Wilder-Smith EP, Lim EC, Teoh HL, et al. The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity. Ann Acad Med Singapore 2005;34:417-20.

10. Gall CR, Jumma O, Mohanraj R. Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy. Seizure 2013;22:217-20. Crossref

11. Viparelli U, Viparelli G. ECT and grand mal epilepsy. Convuls Ther 1992;8:39-42.

12. Kamel H, Cornes SB, Hegde M, Hall SE, Josephson SA. Electroconvulsive therapy for refractory status epilepticus: a case series. Neurocrit Care 2010;12:204-10. Crossref

13. Lambrecq V, Villéga F, Marchal C, et al. Refractory status epilepticus: electroconvulsive therapy as a possible therapeutic strategy. Seizure 2012;21:661-4. Crossref

14. Walker MC. The potential of brain stimulation in status epilepticus. Epilepsia 2011;52(Suppl 8):61-3. Crossref

A 56-year-old man underwent laparoscopic cholecystectomy for acute cholecystitis at another hospital in December 2013. The cholecystectomy was uneventful and the patient was discharged home 3 days later. However, after hospital discharge, the patient presented with recurring upper abdominal pain, tarry stool, and fever. He was admitted to another hospital 4 weeks after the cholecystectomy because of fever, right upper quadrant pain, and haematemesis. Emergency oesophagogastroduodenoscopy and colonoscopy were performed. No bleeding source was identified. Computed tomography (CT) revealed subhepatic fluid collection; old-blood–stained fluid was drained by image-guided catheter drainage. The patient was transferred to the Department of Surgery, Pamela Youde Nethersole Eastern Hospital, Hong Kong, for further treatment.

When the patient arrived at hospital, his blood pressure was approximately 90/60 mm Hg and his pulse rate was 110 beats per minute. Laboratory studies revealed the following values: haemoglobin level, 72 g/L; white blood cell count, 20.3 × 10⁹ /L; platelet count, 388 × 10⁹ /L; total bilirubin, 164 μmol/L; alanine aminotransferase, 187 IU/L; and alkaline phosphatase, 337 IU/L. The patient was treated with intravenous fluid hydration and was transfused with three units of packed red blood cells. He was also given a course of antibiotics. Abdominal CT showed a cystic artery pseudoaneurysm of 1.22 × 1.96 × 1.38 cm (anterior-posterior × transverse × longitudinal dimensions). Two subhepatic collections with haematoma were also visible, over the gallbladder fossa and below hepatic segment 6. Selective right hepatic artery angiography revealed a pseudoaneurysm at the cystic artery. This aneurysm was embolised with stainless steel coils (Fig 1). The catheter for subhepatic collection drainage was then replaced with one with better positioning. Endoscopic retrograde cholangiopancreatography was performed the next day. The cholangiogram showed a dilated biliary tree with haemobilia; most of the blood clots were extracted using a balloon. A cystic duct stump leak was observed after blood clot removal, and a 10-cm-long 11.5-F biliary stent was inserted for biliary drainage (Fig 2). Liver function improved gradually. The patient was discharged from hospital 2 weeks after admission.

Follow-up CT no longer showed pseudoaneurysm and instead showed a resolving collection. Endoscopic retrograde cholangiopancreatography with stent removal was performed 3 months later. The cholangiogram showed a normal biliary tree. The patient recovered and liver function test results were normal.

Hepatic artery or cystic artery pseudoaneurysms are rare complications of laparoscopic cholecystectomy, with cystic artery involvement being reported much less frequently in the literature. Pseudoaneurysm formation is a consequence of vascular injury; important causes include arterial access procedures, accident trauma, and surgical trauma.1 Two-thirds of cases are iatrogenic.1 With the advent of laparoscopic cholecystectomy, iatrogenic hepatobiliary injury is now another cause. Concomitant formation of cystic artery pseudoaneurysm and cystic duct stump leak is a rare complication of laparoscopic cholecystectomy. The majority of pseudoaneurysms present within 6 weeks after the operation.2 3

We have reported a case of laparoscopic cholecystectomy that was complicated by a cystic artery pseudo-aneurysm and a cystic duct stump bile leak, which were managed with angiographic coil embolisation and endoscopic biliary drainage, respectively. The patient presented with the classic Quincke’s triad of haemobilia, namely upper gastrointestinal bleeding, right upper quadrant pain, and obstructive jaundice. The aetiology most likely originated from the infected fluid collection after cholecystectomy, which caused a series of events, including cystic duct stump leak, cystic artery pseudoaneurysm, and haemobilia, in that order. First, bile leakage is a potential complication of cholecystectomy and the cystic duct stump is the most common site of leakage.4 The contributing factor of cystic duct stump leak in the current case was likely cystic duct stump necrosis secondary to mechanical or thermal injury during cholecystectomy, as well as adjacent infection. Second, haemobilia can occur secondary to a cystic artery pseudoaneurysm, although extremely rarely. Artery pseudoaneurysm is a continuous inflammatory process that leads to erosion in the elastic and muscular components of the arterial wall, ultimately resulting in pseudoaneurysm formation. The likely precipitating factors in the current case include initial clip encroachment of the vasculature, mechanical or thermal injury, and continuous inflammation due to the adjacent infected bile or collection.

Pseudoaneurysm can present with bleeding in the form of haemobilia, haematemesis, or melaena. In the current case, upper gastrointestinal bleeding from haemobilia resulted from the cystic artery pseudoaneurysm’s communication with the cystic duct. The resulting symptoms were typical of Quincke’s triad of upper abdominal pain, upper gastrointestinal haemorrhage, and jaundice.5 However, these symptoms are present collectively only in a minority (32%-40%) of patients.5 Thus, detection relies heavily on both clinical reasoning and imaging techniques. If intra-abdominal collection or haemorrhage is suspected clinically, arterial-phase CT is appropriate to detect any pseudoaneurysm. Since gastrointestinal haemorrhage is one of the presentations, urgent oesophagogastroduodenoscopy may be arranged first to rule out any suspected upper gastrointestinal pathology. However, as in the current case, if that procedure fails to show any bleeding source, urgent CT should be considered. Close observation and timely arrangement of appropriate procedures are essential.

Prompt recognition with adequate management was very important in the current case. The treatment of our patient included five objectives: achieving haemostasis, controlling the cystic duct stump leak, relieving obstructive jaundice, controlling the infection with antibiotics, and draining the intra-abdominal collection. Untreated haemobilia poses an immediate threat to life. It can lead to acute haemodynamic instability, necessitating detection, access, and control of the pseudoaneurysm. Arterial-phase CT is a good initial non-invasive mode of detection of laparoscopic cholecystectomy complications. It can be used to evaluate intra-abdominal collection, biliary tree dilatation, and possible bile duct injury, and to visualise pseudoaneurysms or haemorrhage. Arterial-phase CT also allows a three-dimensional assessment of the bile duct and vasculature. Selective arterial angiography can provide a real-time evaluation of pseudoaneurysms and bleeding. At the same time, it can provide the chance of immediate therapeutic intervention. Transarterial embolisation is the treatment of choice for haemostasis, and a high success rate, of 75% to 100%, has been reported.2 3 5 When bleeding control by embolisation fails, repeated sessions of transarterial embolisation for haemostasis or surgical intervention to repair or ligate the artery is necessary. Endoscopic retrograde cholangiopancreatography with stent placement or sphincterotomy is highly effective in diagnosing haemobilia, controlling cystic duct stump leakage, and relieving obstructive jaundice. We favoured stenting over sphincterotomy because of a presumed lower risk of immediate complications.

The lessons to be learnt from this case include the importance of (1) meticulous surgical techniques (such as good haemostasis, careful use of powered devices, proper use of endoclips, and adequate drainage of the operative field), and (2) early recognition and prompt management.

In conclusion, cystic artery pseudoaneurysm is a rare, potentially life-threatening complication of laparoscopic cholecystectomy, and prompt recognition and treatment are essential. Haemobilia may be present many weeks after the initial injury.

The authors have no conflicts of interest to disclose.

1. Green MH, Duell RM, Johnson CD, et al. Haemobilia. Br J Surg 2001;88:773-86.

2. Senthilkumar MP, Battula N, Perera M, et al. Management of a pseudo-aneurysm in the hepatic artery after a laparoscopic cholecystectomy. Ann R Coll Surg Engl 2016;98:456-60. Crossref

3. Nicholson T, Travis S, Ettles D, et al. Hepatic artery angiography and embolization for hemobilia following laparoscopic cholecystectomy. Cardiovasc Intervent Radiol 1999;22:20-4. Crossref

4. Lau WY, Lai EC, Lau SH. Management of bile duct injury after laparoscopic cholecystectomy: a review. ANZ J Surg 2010;80:75-81. Crossref

5. Merrell SW, Schneider PD. Hemobilia—evolution of current diagnosis and treatment. West J Med 1991;155:621- 5.

A 78-year-old woman was diagnosed with atrial fibrillation in September 2015. An echocardiogram showed no evidence of valvular heart disease. She was prescribed dabigatran 110 mg twice a day. In December 2016, she was admitted to our hospital for acute ischaemic stroke, presenting with a sudden onset of decreased level of consciousness. Apart from atrial fibrillation, she also had hypertension, diabetes mellitus, hyperlipidaemia, and a history of hip fracture with bilateral hip implants, requiring a rollator for walking.

On the day of admission, she was reported by her carer to be poorly responsive, with no verbal response and no spontaneous limb movement. She was last seen well 30 minutes previously. Physical examination revealed bilateral pinpoint pupils and no verbal response. She had slight flexion of her four limbs to pain and her National Institutes of Health Stroke Scale (NIHSS) score was 34. The blood pressure was 142/64 mm Hg. There was no hypoglycaemia. Naloxone was given with no improvement. Cerebral computed tomography (CT) showed no early infarct changes but bilateral subcortical white matter hypodensities, compatible with small vessel disease (Fig a). A clinical diagnosis was made of acute ischaemic brainstem stroke. The family confirmed that the patient had been taking dabigatran regularly as prescribed, with the last dose taken about 2 hours before symptom onset. She had taken no sedative medications.

After obtaining informed consent, an intravenous bolus of 5 g idarucizumab was given. Blood for clotting profile, including thrombin time, was taken before treatment and 5 minutes afterwards. Intravenous recombinant tissue plasminogen activator (r-tPA) was then given at 0.6 mg/kg body weight 10 minutes after the start of idarucizumab injection, 2 hours from symptom onset. The prolonged activated partial thromboplastin time (APTT) and thrombin time (TT) normalised after administration of idarucizumab. The Table shows the clotting variables before and after idarucizumab. By the next morning, the patient had regained her speech although her response was slow with dysarthria and dysphagia. She could raise her four limbs against gravity, power being grade 3. Follow-up CT at 24 hours post r-tPA showed no significant infarct and no bleeding (Fig b). Transcranial Doppler ultrasonography showed no evidence of significant vertebrobasilar occlusive disease. By day 2, she had recovered further neurologically, with improvement in alertness, dysarthria and dysphagia, and could tolerate oral feeding. Limb power was grade 4+ over four limbs. Pupils were no longer pinpoint. She was recommenced on dabigatran 150 mg twice a day on day 2 based on her age and creatinine clearance. The patient was discharged on day 7 with her neurological function returned to baseline.

This is the first report in Hong Kong of the successful use of idarucizumab to reverse the anticoagulant effect of dabigatran, followed by intravenous thrombolysis with r-tPA for the treatment of ischaemic stroke. Novel oral anticoagulants (NOACs) are now increasingly used for the prevention of cardioembolic stroke in patients with non-valvular atrial fibrillation. Dabigatran, which acts as a thrombin inhibitor, is one such NOAC. Idarucizumab is a monoclonal antibody that has a high affinity for binding to the immunoglobulin G fragment of dabigatran. A 5-g dose was shown to be able to reverse the anticoagulant effect of dabigatran within minutes and had a good safety profile in the study of Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD trial).1

Patients who develop an acute ischaemic stroke while taking dabigatran are often excluded from treatment with intravenous thrombolysis owing to their bleeding risk. For patients who are not candidates for mechanical thrombectomy or who are in institutions where an endovascular thrombectomy service is not routinely available, giving intravenous thrombolysis after reversal of the anticoagulant effect is a treatment option. There is no pro-anticoagulant effect from idarucizumab itself, and an in-vitro study demonstrated no interaction between idarucizumab and r-tPA–induced thrombolysis.2 As far as we know, there have been five case reports at the time of writing of this article, all from German centres, that have reported the successful use of idarucizumab for this indication; none had any haemorrhagic complications.2 3 Four of these studies reported successful thrombolysis with good neurological recovery, whereas one study reported failed clinical improvement in a patient with infarcts in multiple territories.3 Diener et al4 have published an expert opinion on the management of these ischaemic strokes based on their experience in Germany. They proposed that for patients who have taken dabigatran in the preceding 24 hours from the time of assessment (or 96 hours if the creatinine clearance is <30 mL/min), or for patients in whom time of last dabigatran dose is unknown and who have a prolonged APTT or TT, idarucizumab should be given if the patient is not a candidate for mechanical thrombectomy. In our institution, we do not have point-of-care devices to test clotting function, the turnaround time for APTT and TT results may be hours, and dabigatran concentrations cannot be measured in our laboratory. We therefore propose that for patients in whom time of last dabigatran dose is unknown, idarucizumab can still be considered with the family’s consent to enable early intravenous thrombolysis. For the same reason, we did not wait for the results of APTT or TT to confirm reversal of dabigatran’s effect before initiating intravenous thrombolysis. Idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in 88% to 98% of patients in the RE-VERSE AD trial.1

Safety (avoidance of symptomatic intracranial haemorrhages) was our top concern for this patient. As she had multiple risk factors for intracranial haemorrhage (old age, high NIHSS score, cerebral white matter disease and on anticoagulant therapy), we gave r-tPA at a dose of 0.6 mg/kg body weight. This dose was associated with significantly fewer symptomatic intracranial haemorrhages in the recent ENCHANTED trial.5

Following reversal of effect, dabigatran can be resumed as early as 24 hours afterwards. Although our patient had improved by the next day, she still had significant dysphagia and could not tolerate oral feeding. By the second day, she had improved further so dabigatran was resumed at a higher dose based on her age and renal function.

In conclusion, idarucizumab can be considered to reverse the anticoagulant effect of dabigatran in patients with ischaemic stroke within a therapeutic window, so that they may benefit from intravenous thrombolytic therapy.

All authors have disclosed no conflicts of interest.

1. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-20. Crossref

2. Berrouschot J, Stoll A, Hogh T, Eschenfelder CC. Intravenous thrombolysis with recombinant tissue-type plasminogen activator in a stroke patient receiving dabigatran anticoagulant after antagonization with idarucizumab. Stroke 2016;47:1936-8. Crossref

3. Kafke W, Kraft P. Intravenous thrombolysis after reversal of dabigatran by idarucizumab: a case report. Case Rep Neurol 2016;8:140-4. Crossref

4. Diener HC, Bernstein R, Butcher K, et al. Thrombolysis and thrombectomy in patients treated with dabigatran with acute ischemic stroke: Expert opinion. Int J Stroke 2017;12:9-12. Crossref

5. Anderson CS, Robinson T, Lindley RI, et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N Engl J Med 2016;374:2313-23. Crossref