Retrievable endoscopic stenting for tuberculous oesophagopleural fistula with empyema

DOI: 10.12809/hkmj154670
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Retrievable endoscopic stenting for tuberculous oesophagopleural fistula with empyema
Brian YO Chan, MBChB; Canon KO Chan, FRCS, FHKAM (Surgery)
Department of Surgery, Queen Elizabeth Hospital, Jordan, Hong Kong
 
Corresponding author: Dr Canon KO Chan (cko296@ha.org.hk)
 
 Full paper in PDF
 
Case report
A 23-year-old female was admitted for fever, cough, and right pleuritic pain in January 2015. Chest X-ray revealed right pleural effusion. Subsequent computed tomography of the thorax demonstrated necrotising pneumonitis in the right lower lobe, with large right empyema and multiple left lung centrilobular nodules suspicious of tuberculosis (Fig 1a). On admission, haemoglobin level was only 84 g/L. Oesophagogastroduodenoscopy (OGD) found a linear deep oesophageal ulceration with suspected fistula opening (Fig 1b), biopsy of which yielded Mycobacterium tuberculosis. Gastrografin swallow confirmed contrast leakage at the lower oesophagus with fistulation to the right hemithorax (Fig 1c), suggesting the occurrence of tuberculous oesophagopleural fistula (OPF) and resulting empyema.
 

Figure 1. Oesophagopleural fistula (arrows)
(a) Computed tomography of the thorax, (b) pretreatment oesophagogastroduodenoscopy, (c) gastrografin swallow, (d) decortication, and (e) complete healing, (f) retrieved fully covered self-expandable metallic stent
 
Prompt chest drainage and systemic antibiotics were initiated, targeting the polymicrobial and smear positive tuberculous tissue samples. Subsequent therapeutic OGD with endoscopic stenting was performed. The patient was placed in the left lateral decubitus position and sedated. The linear ulcer at 24 to 32 cm from incisor, with 5-mm fistula opening at 24 cm was visualised. Submucosal lipiodol injection under fluoroscopy marked the margins of the fistulated ulcer, and the most distal end of the linear ulcer (Fig 2a).
 

Figure 2. Endoscopic insertion of self-expandable metallic stent
(a) Margin marking, (b) guidewire passage, and (c) stent deployment
 
A 12-cm 22-Fr retrievable, fully covered, self-expandable metallic stent (SEMS) with an over-the-wire distal delivery stent deployment system (Taewoong Medical, South Korea) was selected. The shoulders of the stent were placed across the fistula opening, being deployed over the guidewire (Fig 2b and 2c). All positions were confirmed by fluoroscopy and the proximal stent secured with two endoclips at 12 and 6 o’clock position.
 
The patient tolerated the procedure well. She was put on total parenteral nutrition for 2 weeks, then resumed enteral feeding via a nasoduodenal tube inserted during a separate OGD session. Decortication was later performed to clear the empyema cavity (Fig 1d). Follow-up OGD at 8 weeks demonstrated no stent migration and stent was removed uneventfully by pulling on the purse-string suture with endoscopic forceps. Check endoscopy confirmed complete healing of the ulcer by scarring (Fig 1e). The retrieved fully covered SEMS was intact and without tissue ingrowth (Fig 1f).
 
Recovery of the patient was satisfactory. She achieved complete resolution of sepsis and tolerated an oral diet after stent removal. Follow-up computed tomography of the thorax in May 2015 showed minimal thoracic collection and no lung consolidation.
 
Discussion
Oesophageal stenting has significantly matured since its inception. In unresectable malignant obstruction, SEMS has become the standard of care, with high technical success (83%-100%) in positioning and effective dysphagia palliation (80%-95%).1 Emerging roles are also seen in benign conditions like anastomotic leaks or perforations, with promising 81.4% and 86% success in defect closure, respectively.2 Success is nonetheless variable in treating benign strictures and refractory oesophageal variceal bleeding.1 In malignant oesophagorespiratory fistulae (ORF), 80% of cases achieve complete healing with SEMS.3 Little is known about the efficacy in benign ORF, OPF in particular, due to the clinical rarity and inherent heterogeneity.
 
Oesophagorespiratory fistulae is an uncommon entity comprising all pathological connections between the oesophagus and airway. Malignant oesophageal, lung, or mediastinal tumours are the most common causes. Fistulation occurs secondary to tumour invasion or inflammation post-radiotherapy, laser, chemotherapy or stenting. Benign ORF is rare, with major causes being trauma and infection.4 Regarding fistula subtypes, only 3% to 11% represent oesophagopulmonary fistula or OPF that communicate peripherally. The rest are either oesophagotracheal (52%-57%) or oesophagobronchial (37%-40%) in location.5 It is easy to understand why few reports exist of OPF and its treatment.
 
In general, OPF has a similar aetiology to ORF. Malignancies aside, it is a well-recognised complication in 0.2% to 1% of pneumonectomies. Other traumatic causes include endoscopic sclerotherapy, gunshot wound, and foreign body ingestion.5 Infective causes range from tuberculosis to mycotic disease, also candidiasis in immunocompromised individuals. Other reported cases include Crohn’s disease, perforated Barrett’s ulcer, and ruptured diverticulum.6 7 8 Like postsurgical leaks and perforations, OPF is a sinister condition associated with high morbidity and mortality.2 3 Significant mediastinal and pleural contamination, polymicrobial sepsis and abscesses often ensue, warranting multiple drainage procedures and surgery, as well as intensive life support.
 
Oesophagopleural fistula rarely heals spontaneously. Principles of management include drainage of collection, exclusion of fistulation, aggressive antimicrobials, and lastly, intensive nutritional and organ support. Established abscesses persist despite spillage control by stenting, hence necessitating drainage procedures.9 Pleural drainage is possible via tube thoracostomy or image-guided pigtail catheter insertion. Yet if multiloculated collections exist, open or thoracoscopic drainage is preferred since it permits septa breakdown under direct vision, thorough irrigation, and placement of a drain in an ideal position.10 Early use of broad-spectrum intravenous antibiotics with aerobic and anaerobic coverage is equally important. Fistula exclusion may be operative, fluoroscopic, or endoscopic. Traditional surgical approaches involve either primary suturing or segmental oesophagectomy, but are complex and associated with high morbidity (30%-50%) and mortality (10%).11 Bypass and muscle flap buttressing are newer operations possible for the debilitated.12 13 Embolisation with vascular plug and coils under fluoroscopy has been reported in one article. Endoscopic fibrin glue application represents a viable option in small-calibre fistulae. Limited reports also exist for other endoscopic measures like argon plasma or electrocoagulation, suturing, or clipping devices.11
 
Our patient represented a promising candidate for oesophageal stenting. Initially performed with rigid plastic tubes, development has evolved to SEMS with easier insertion and less migration. Most commonly made of nitinol, SEMS exhibits great flexibility and radial force to maintain patency and position. They come uncovered, partially, or fully covered, with a plastic or silicon membrane. Fully covered SEMS is the stent-of-choice in managing fistulae, since the covering is vital for leakage prevention and easy retrievability.1 Most published studies suggest stent placement immediately after leakage confirmation to minimise mediastinal contamination.3 Insertion is via upper endoscopy under sedation, with the patient in a left lateral or prone position to minimise aspiration. Stent size is chosen according to oesophageal diameter and defect size. The proximal and distal ends of the lesion are identified endoscopically, marked by radiopaque dye, then a guidewire advanced over the defect, stent positioned across and deployed over-the-wire, all under endoscopic and fluoroscopic guidance. Potential stent shrinkage or migration is counteracted by allowing 4-6 cm proximal and distal coverage.1 10 A feeding tube is routinely inserted for prompt enteral nutrition. No data are available for optimal timing of when to resume an enteral diet, but in oesophageal leaks, Rajan et al10 demonstrated fitness on day 2 following stent placement. Oral intake is not encouraged though due to potential peristalsis-inducing stent migration and hence leakage. No conclusive timing for stent removal exists, with studies in general reporting intervals of 4 to 6 weeks or 6 to 8 weeks.10 In our case, stent removal at 8 weeks was without difficulty, with no tissue ingrowth or stent disintegration.
 
Only one review of SEMS placement in oesophageal fistulae exists. It is reported that 64.7% clinical success was achieved in defect closure, which is significantly lower than the over 80% rates in malignant ORF, perforations, and post-surgical leaks.2 3 Detailed scrutiny of the seven studies pooled, however, revealed that aortoesophageal and oesophagoatrial fistulae were also included.13 These conditions present with life-threatening torrential haemorrhage, and are undoubtedly different in terms of pathogenesis and survival to the majority of ORF where sepsis is the main issue. Moreover, fistulae subtype or location was mostly not reported, and if present, mostly oesophagotracheal. Significant heterogeneity exists. Only one of 24 fistulae was identified as OPF. It is questionable how applicable the data are.
 
Specific literature is lacking. Our case report aside, Kang et al4 represent the only article reporting endoscopic SEMS for OPF as far as we are aware. Successful technical and clinical outcomes were achieved in both studies. To take this further, considering the similarities in terms of pleural or mediastinal sepsis and treatment goals in minimising further contamination, we believe it is reasonable to extrapolate the success in managing perforations and postsurgical leaks to ORF.
 
Potential SEMS-related complications include retrosternal pain, oesophageal perforation, bronchoesophageal fistulae, stent migration, obstruction, or fracture. Migration of the stent contributes to clinical failure, and appears to be a particularly troubling issue for fully covered SEMS, with 10% to 25% occurrence in covered stents and 2% to 5% in uncovered.1 It is also more frequent in placements for fistulae (33.3%) compared with benign strictures (15.8%).14 Appropriate stent size and length reduce the risk of migration, balancing the larger radial force to oppose migration against the risk of pressure necrosis. To counteract migration, some stents come with flared proximal ends.3 Endoscopic clip application of the proximal stent end to the oesophageal wall has also been reported to be an effective strategy.15 Such technological advances may further improve outcomes.
 
Our case represents the first in local medical literature to report SEMS use in benign OPF. With the global trend towards minimally invasive therapies, we expect a paradigm shift towards effective novel techniques such as endoscopic stenting or repair. In this patient with tuberculous fistulae, we favoured stenting over any endoscopic suturing or clipping to avoid the tension exhibited in inflamed tissue.
 
References
1. Kang HW, Kim SG. Upper gastrointestinal stent insertion in malignant and benign disorders. Clin Endosc 2015;48:187-93. Crossref
2. van Halsema EE, van Hooft JE. Clinical outcomes of self-expandable stent placement for benign esophageal diseases: a pooled analysis of the literature. World J Gastrointest Endosc 2015;7:135-53. Crossref
3. Mangiavillano B, Pagano N, Arena M, et al. Role of stenting in gastrointestinal benign and malignant diseases. World J Gastrointest Endosc 2015;7:460-80.
4. Kang GH, Yoon BY, Kim BH, et al. A case of spontaneous esophagopleural fistula successfully treated by endoscopic stent insertion. Clin Endosc 2013;46:91-4. Crossref
5. Shin JH, Kim JH, Song HY. Interventional management of esophagorespiratory fistula. Korean J Radiol 2010;11:133-40. Crossref
6. Albuquerque A, Ramalho R, Macedo G. Multiple esophagopleural and esophagobronchial fistulas in a patient with Crohn’s disease. Endoscopy 2012;44 Suppl 2:E114-5. Crossref
7. Andersson R, Nilsson S. Perforated Barrett’s ulcer with esophago-pleural fistula. A case report. Acta Chir Scand 1985;151:495-6.
8. Agarwal V, Singh SK, Siddiqi MS, Joshi LM, Tandon S. Esophagopleural fistula following spontaneous rupture of traction diverticulum. Asian Cardiovasc Thorac Ann 2003;11:344-5. Crossref
9. Kim KR, Shin JH, Song HY, et al. Palliative treatment of malignant esophagopulmonary fistulas with covered expandable metallic stents. AJR Am J Roentgenol 2009;193:W278-82. Crossref
10. Rajan PS, Bansal S, Balaji NS, et al. Role of endoscopic stents and selective minimal access drainage in oesophageal leaks: feasibility and outcome. Surg Endosc 2014;28:2368-73. Crossref
11. Koo JH, Park KB, Choo SW, Kim K, Do YS. Embolization of postsurgical esophagopleural fistula with AMPLATZER vascular plug, coils, and Histoacryl glue. J Vasc Interv Radiol 2010;21:1905-10. Crossref
12. Kim JJ, Park JK, Moon SW, Park K. A new surgical technique for spontaneous esophagopleural fistula after pneumonectomy: cervical esophagogastrostomy via presternal and subcutaneous route, using a thoracic esophageal mucosal stripping. Thorac Cardiovasc Surg 2013;61:496-8. Crossref
13. David EA, Kim MP, Blackmon SH. Esophageal salvage with removable covered self-expanding metal stents in the setting of intrathoracic esophageal leakage. Am J Surg 2011;202:796-801. Crossref
14. Buscaglia JM, Ho S, Sethi A, et al. Fully covered self-expandable metal stents for benign esophageal disease: a multicenter retrospective case series of 31 patients. Gastrointest Endosc 2011;74:207-11. Crossref
15. Park SY, Park CH, Cho SB, et al. The usefulness of clip application in preventing migration of self-expandable metal stents in patients with malignant gastrointestinal obstruction [in Korean]. Korean J Gastroenterol 2007;49:4-9.

A common PRRT2 mutation in familial paroxysmal kinesigenic dyskinesia in Hong Kong: a case series of 16 patients

DOI: 10.12809/hkmj154579
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
A common PRRT2 mutation in familial paroxysmal kinesigenic dyskinesia in Hong Kong: a case series of 16 patients
CY Law, PhD, FHKAM (Pathology)1 #; WL Yeung, FHKAM (Paediatrics)2 #; YF Cheung, MPH, FRCP3 #; HF Chan, FHKAM (Medicine)3; Eva Fung, FHKAM (Paediatrics)4; Joannie Hui, FHKAM (Paediatrics)4; Iris OK Yung, MD5; YP Yuen, MSc, FHKAM (Pathology)6; Angel OK Chan, MD, FHKAM (Pathology)7; CW Lam, PhD, FHKAM (Pathology)1
1 Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong
2 Department of Paediatrics and Adolescent Medicine, Alice Ho Miu Ling Nethersole Hospital, Tai Po, Hong Kong
3 Division of Neurology, Department of Medicine, Queen Elizabeth Hospital, Jordan, Hong Kong
4 Department of Paediatrics, Prince of Wales Hospital, Shatin, Hong Kong
5 Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, Hong Kong
6 Department of Chemical Pathology, Prince of Wales Hospital, Shatin, Hong Kong
7 Division of Clinical Biochemistry, Queen Mary Hospital, Pokfulam, Hong Kong
 
# These authors contributed equally to this work.
 
Corresponding author: Dr CW Lam (ching-wanlam@pathology.hku.hk)
 
 Full paper in PDF
 
Case reports
Family 1
Patient 1 was a 47-year-old woman who presented with paroxysmal abnormal movement since childhood. She was first seen in 2004. The attack was characterised by dystonic painful posture with upward or downward deviation of the eyes, head turning, shoulder abduction and extensions, lower limb dystonia, impaired speech, and occasionally stepping movements, with preserved consciousness. The attacks lasted for 1 to 2 minutes with a frequency of up to 8 times a day. Each attack was precipitated by stress or being startled, for example, being approached by a car unexpectedly when crossing the road, frightened by a cockroach, a sudden phone call, or an abrupt movement. Occasionally, the attack could occur during sleep. There was no incontinence. The patient had normal intelligence. Physical examination, biochemical tests, computed tomography of the brain, and electroencephalography were normal. The attacks were controlled with carbamazepine and frequency of attacks reduced to fewer than 3 times a day and each episode was shortened to 10 to 20 seconds. The patient also had a history of seizure of unknown aetiology in childhood. She had a strong family history; her daughter has presented with seizure on two to three occasions since the age of 10 months and had been taking an anticonvulsant for 2 years. Since then she had experienced no further seizures and by the age of 4 years no antiepileptic drug or follow-up has been required. Two older sisters and a nephew of the proband also had childhood seizures.
 
Family 2
Patient 2 was a 26-year-old woman who presented with paroxysmal kinesigenic dyskinesia (PKD) since the age of 8 years. The patient first presented with episodes of afebrile seizure at 7 months old in 1997. She was prescribed phenobarbitone and required no further medication or follow-up after the age of 3 years. The current involuntary movement affected all limbs with the right side being most affected. Each attack lasted for a few seconds to less than 3 minutes without loss of consciousness. Each episode was triggered by sudden body movement, anxiety, or deprived sleep. Frequency of attacks could reach up to 6 times a day. The patient claimed she could occasionally partially control the symptoms. Physical examination, biochemical tests, and brain imaging were unremarkable. Her brother was also affected by PKD. The attack was controlled by carbamazepine; a missed dose would usually lead to relapse.
 
Family 3
Patient 3 was a 14-year-old boy who presented in 2004 with chorea-like movement of the four limbs since the age of 18 months. Each attack lasted for about 15 to 20 seconds and there was no impaired consciousness. The frequency of attacks could reach up to 10 times a day. The attacks were triggered after running or waking up from sleep. A good clinical response was achieved with carbamazepine. The attacks recurred only after a missed dose. Physical examination, biochemical investigations, and brain imaging were unremarkable and he had normal development and intelligence. Five paternal family members were similarly affected.
 
Family 4
Patient 4 was a 33-year-old man who presented with involuntary movement since the age of 9 years. He was first seen in 2011. The involuntary body movement affected his right facial muscle and right upper and lower limbs. The attack usually lasted for 5 to 10 seconds with no impaired consciousness. No remarkable triggering factor was noted. Physical examination, biochemical tests, and brain imaging were unremarkable. The patient also experienced migraine triggered by increased stress. He had been prescribed carbamazepine since the age of 10 years and a missed dose would lead to relapse. Two of his daughters were affected by seizures. The elder daughter presented at 7 months old with two episodes of generalised seizure, each lasting around 30 seconds. The younger daughter presented at 3 months old with a brief lip smacking, limb twitching, and up-rolling eyeball; the attack lasted about 2 minutes. Both daughters were prescribed phenobarbitone. They achieved normal growth and no further antiepileptic drug was required at 34 months of age for the elder sister while the younger sister continued on low-dose phenobarbitone.
 
Family 5
Patient 5 was a 14-year-old boy who presented with PKD since the age of 9 years. He presented with on-and-off dystonic movement involving the limbs, trunk, and occasionally the face. The attacks lasted for less than 10 seconds and there was no impaired consciousness. Each episode was triggered by sudden body movement, for example, starting to write or going out of an elevator. The frequency of attacks ranged from once every 2 days to twice a day. Physical examination and biochemical investigations were unremarkable. Magnetic resonance imaging of the brain showed an incidental finding of left temporal arachnoid cyst. A trial of carbamazepine achieved a good clinical response.
 
Family 6
Patient 6 was a 29-year-old man who presented with PKD around the age of 3 years in 1988. He presented with jerky variable involuntary movement of all limbs without loss of consciousness. The attacks usually lasted for less than 1 minute and were triggered by sudden body movements. The attacks were not precipitated by alcohol, caffeine, fatigue, stress, or excitement. The frequency of attacks could be daily. Aura was noted before dystonic movement. Physical examination, biochemical tests, and brain imaging were unremarkable. The attacks were effectively controlled by carbamazepine. His father had been similarly affected since his teenage years. Each attack usually lasted for 1 to 2 minutes, precipitated by prolonged sitting or excitement. Aura was noted before dystonic movement. The sister of the proband was mildly affected with sudden tightness and stiffness of limbs without impaired consciousness. Aura was reported before the dystonic movement. The other three siblings of the proband were asymptomatic.
 
Mutational analysis for PRRT2 gene
Exons of PRRT2 were amplified using polymerase chain reaction, of which its conditions and primer sequences for PRRT2 are available upon request. Sequencing results were compared with the National Center for Biotechnology Information reference sequences NM_145239.2 and NP_660282.2. Mutation analysis for PRRT2 gene in families 1 to 5 showed a heterozygous frameshift mutation c.649dupC (p.Arg217Profs*8) [Fig 1]. This is a known pathogenic mutation that can result in premature transcription termination and a truncated PRRT2 protein. For family 1, DNA samples were not available for other affected family members except the proband. For family 6, a novel heterozygous frameshift mutation, c.379delG (p.Glu127Serfs*49), was detected (Fig 2). The mutation will lead to premature transcription termination and a truncated PRRT2 protein.
 

Figure 1. Mutational analysis for patient with paroxysmal kinesigenic dyskinesia for families 1 to 5
Heterozygous NM_145239.2:c.649dupC (NP_660282.2: p.Arg217Profs*8) in exon 2 shown in the forward (sense) direction
 

Figure 2. Mutational analysis for patient with paroxysmal kinesigenic dyskinesia for family 6
Heterozygous NM_145239.2:c.379delG (NP_660282.2: p.Glu127Serfs*49) in exon 2 shown in the forward (sense) direction
 
Discussion
Familial PKD (OMIM#128200) is the most common type of paroxysmal movement disorder. It is defined by the presence of (1) identified kinesigenic triggers, (2) short duration of attacks, usually <1 minute, (3) no loss of consciousness or pain during attacks, (4) absence of known organic causes and normal neurological examination, (5) response to phenytoin or carbamazepine treatment, and (6) age of onset at 1 to 20 years in the absence of a family history of PKD.1 The attack is characterised by the presence of involuntary movement such as dystonia, choreoathetosis, and ballism. The co-existence of PKD and infantile convulsions can occur in a subset of PKD patients and is known as PKD with infantile convulsions (PKD/IC).
 
The disorder PKD is transmitted as an autosomal dominant trait with incomplete penetrance. The disease is caused by mutation of the PRRT2 gene (proline-rich transmembrane protein 2; OMIM*614386).2 3 PRRT2 mutation can also cause PKD/IC, paroxysmal exercise–induced dyskinesia, paroxysmal non-kinesigenic dyskinesia, benign familial infantile epilepsy, episodic ataxia, hemiplegic migraine, intellectual disability, and benign paroxysmal torticollis of infancy.4 5 Patients with PKD can be misdiagnosed with epilepsy or psychogenic illness6; an aetiological diagnosis will require genetic analysis of PRRT2 gene, the most common disease-causing gene for PKD.
 
PRRT2 mutation is the major cause of PKD in Chinese, Koreans, Japanese, and Europeans7 8 9 10 11 and accounts for 33% to 46% of sporadic and 80% to 100% of familial forms of PKD.12 Heterozygous c.649dupC is a mutation hotspot of which the mutation detection rate for Chinese can be as high as 62%.13 Our findings also suggest that the majority (81.3%; 95% confidence interval, 57.0%-93.4%) of PKD patients (13 out of 16) carried the c.649dupC mutation.
 
Most (79%) PKD patients had a distinctive phenotype.1 Atypical features have been reported, for example, long duration of attack,2 attacks triggered by stress/anxiety,3 and painful dystonia.14 This explains the unusual features observed in family 1 (painful dystonia, attacks precipitated by stress) and family 2 (attacks up to 3 minutes). Intriguingly, no obvious triggering factors were identified in family 4, likely because they were too subtle and not recognised by the patient.
 
Co-existence of infantile convulsion can occur in a subset of PKD patients (ie PKD/IC), as with the proband in families 1 and 2. Nevertheless, PKD was not apparent in the affected children of families 1 and 4, likely because the mean age of onset was 11.6 ± 3.5 years,1 and they were too young for PKD manifestation.
 
An aetiological diagnosis for patients with PKD is clinically important. First, the majority of patients show an excellent response to carbamazepine or phenytoin and some show significant improvement with low-dose carbamazepine.15 Second, neurologists, paediatricians, and pathologists can explain to the family the aetiology of PKD. Third, patients can be misdiagnosed with epilepsy or ‘psychogenic illness’. A definitive diagnosis can end the diagnostic uncertainty and relieve patients of the emotional uncertainty and unnecessary investigations.
 
In conclusion, the cases reported here constitute the first genetic-confirmed series of PKD in Hong Kong. We recommend PRRT2 c.649dupC screening for all patients with all forms of PKD.
 
References
1. Bruno MK, Hallett M, Gwinn-Hardy K, et al. Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria. Neurology 2004;63:2280-7. Crossref
2. Chen WJ, Lin Y, Xiong ZQ, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011;43:1252-5. Crossref
3. Wang JL, Cao L, Li XH, et al. Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain 2011;134:3493-501. Crossref
4. Liu Q, Qi Z, Wan XH, et al. Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression. J Med Genet 2012;49:79-82. Crossref
5. Gardiner AR, Bhatia KP, Stamelou M, et al. PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine. Neurology 2012;79:2115-21. Crossref
6. Matsumoto N, Takahashi S, Okayama A, Araki A, Azuma H. Benign infantile convulsion as a diagnostic clue of paroxysmal kinesigenic dyskinesia: a case series. J Med Case Rep 2014;8:174. Crossref
7. Chen YP, Song W, Yang J, et al. PRRT2 mutation screening in patients with paroxysmal kinesigenic dyskinesia from Southwest China. Eur J Neurol 2014;21:174-6. Crossref
8. Youn J, Kim JS, Lee M, et al. Clinical manifestations in paroxysmal kinesigenic dyskinesia patients with proline-rich transmembrane protein 2 gene mutation. J Clin Neurol 2014;10:50-4. Crossref
9. Okumura A, Shimojima K, Kubota T, et al. PRRT2 mutation in Japanese children with benign infantile epilepsy. Brain Dev 2013;35:641-6. Crossref
10. Méneret A, Grabli D, Depienne C, et al. PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 2012;79:170-4. Crossref
11. Becker F, Schubert J, Striano P, et al. PRRT2-related disorders: further PKD and ICCA cases and review of the literature. J Neurol 2013;260:1234-44. Crossref
12. Labate A, Tarantino P, Viri M, et al. Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation, episodic ataxia, and absences. Epilepsia 2012;53:e196-9. Crossref
13. Cao L, Huang XJ, Zheng L, Xiao Q, Wang XJ, Chen SD. Identification of a novel PRRT2 mutation in patients with paroxysmal kinesigenic dyskinesias and c.649dupC as a mutation hot-spot. Parkinsonism Relat Disord 2012;18:704-6. Crossref
14. Ebrahimi-Fakhari D, Kang KS, Kotzaeridou U, Kohlhase J, Klein C, Assmann BE. Child Neurology: PRRT2-associated movement disorders and differential diagnoses. Neurology 2014;83:1680-3. Crossref
15. Chou IC, Lin SS, Lin WD, et al. Successful control with carbamazepine of family with paroxysmal kinesigenic dyskinesia of PRRT2 mutation. Biomedicine (Taipei) 2014;4:15. Crossref

Neurocysticercosis: diagnostic dilemma

DOI: 10.12809/hkmj154524
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Neurocysticercosis: diagnostic dilemma
Joyce HM Cheng, MB, ChB; Eric MW Man, MB, ChB, FRCR; SY Luk, MB, BS, FRCR; Wendy WC Wong, MB, BS, FRCR
Department of Radiology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
 
Corresponding author: Dr Joyce HM Cheng (chm915@ha.org.hk)
 
 Full paper in PDF
 
Case report
A 7-year-old Nepalese boy with unremarkable past health was admitted in July 2013 with a 2-week history of headache, dizziness, and vomiting that subsided spontaneously. On admission, he was afebrile with unremarkable neurological and fundal examination.
 
He had been living in Nepal until the age of 5 years and then immigrated to Hong Kong. He recently travelled to Nepal but had otherwise no contact history with pigs or febrile persons.
 
Blood tests were unremarkable except mildly elevated erythrocyte sedimentation rate of 26 mm/h. Lumbar puncture yielded normal cerebrospinal fluid (CSF) white cell count, and protein and glucose level. Culture of blood and CSF was negative.
 
Initial contrast computed tomographic brain showed two subcentimetre (7 mm and 9 mm) left parieto-occipital adjacent rim-enhancing lesions (Fig a) with T1-weighted hypointense and T2-weighted/fluid-attenuated inversion recovery hyperintense signal on contrast magnetic resonance imaging (MRI) [Fig b]. Significant perifocal oedema and mass effect with compression on the left occipital horn was noted. Magnetic resonance spectroscopy showed a significant lipid-lactate peak (Fig c), decreased N-acetylaspartate, and no elevated choline. No amino acid peak was identified. Perfusion imaging with arterial spine labelling showed no elevated regional cerebral blood flow (Fig d). Contrast MRI of the spine showed no leptomeningeal enhancement, intradural nor extradural spinal mass lesions.
 

Figure. (a) (i) Axial and (ii) coronal reformatted contrast computed tomography showing two rim-enhancing lesions over left parieto-occipital region (arrows). (b) (i) Magnetic resonance (MR) axial images showing T1-weighted (T1W) hypointense and T2-weighted (T2W) hyperintense lesions over left parieto-occipital region with perifocal oedema (arrows); (ii) post-gadolinium T1W MR axial and coronal images showing rim enhancement of the lesions (arrows). (c) Single-voxel MR spectroscopy of left parieto-occipital lobe lesion of (i) short (TE 30), (ii) intermediate (TE 135), and (iii) long (TE 270) echo showing significantly elevated lipid-lactate (1.3 ppm), with a peak doublet centred at 1.3 ppm in TE 30 and TE 270, and inverts in TE 135; N-acetylaspartate peak (2.0 ppm) is decreased; and choline (3.2 ppm) is not elevated. (d) Perfusion imaging in arterial spine labelling showing no significantly elevated regional cerebral blood flow over the left parieto-occipital lesions. (e) T2W and post-gadolinium T1W MR axial images at (i) 2-month and (ii) 5-month intervals showing gradual reduction in the size of the two rim-enhancing lesions over parieto-occipital region (arrows)
 
Subsequent extensive investigations of blood (including anti-Taenia solium immunoglobulin G), CSF, urine and stool for tuberculosis and T solium were performed, and all results were negative.
 
Overall review of the clinical presentation, travel history, laboratory and imaging findings, and the two cerebral rim-enhancing lesions were suggestive of an infective process, in particular, neurocysticercosis or tuberculosis.
 
After thorough investigations and interdepartmental discussions, it was decided to treat the patient as a probable case of neurocysticercosis and a course of empirical albendazole and prednisolone was prescribed.
 
The patient remained asymptomatic after treatment. Follow-up MRI performed after 2 and 5 months (Fig e) showed reduction in size of the two cerebral rim-enhancing lesions (3 mm and 1 mm), as well as the extent of perifocal oedema.
 
Discussion
Neurocysticercosis is a parasitic infection of the central nervous system by T solium (ie pork tapeworm) usually through accidental ingestion of contaminated food containing its eggs. It has been a diagnostic challenge in developed areas owing to its infrequent occurrence, low sensitivity of serological tests, and highly variable and non-specific manifestations, both clinically and radiologically. It is further complicated by clinical and radiological features that overlap considerably with tuberculosis infection, particularly in tuberculosis-endemic areas.
 
A few international diagnostic criteria for neurocysticercosis have been proposed, and aim to stratify the diagnostic strength based on the interpretation of clinical, radiological, serological, and epidemiological information. One of the most widely accepted revised criteria was proposed by Del Brutto et al in 2001,1 and classifies patients into two degrees of diagnostic certainty—definitive or probable. Definitive diagnosis requires the presence of one absolute criterion or two major plus one minor epidemiological criteria. Probable diagnosis can be made if there are one major plus two minor criteria; one major plus one minor and one epidemiological criteria; or presence of three minor plus one epidemiological criteria. Four categories of criteria based on their diagnostic strength are shown in Table a.1
 

Table (a). Four categories of criteria based on their diagnostic strength1
 
The diagnostic dilemma in our index case was the lack of characteristic imaging features and positive serological proof, hence difficult differentiation from tuberculosis infection, i.e. tuberculomas. Other common differential diagnoses of cystic lesions include pyogenic abscesses and metastases. Both were unlikely in our patient given the aseptic clinical presentation, normal blood and CSF profiles, absence of a known primary and lack of associated radiological findings (eg cerebritis, ventriculitis or meningeal enhancement). Biopsy or excision of the cerebral cystic lesions might offer a straightforward histopathological diagnosis, however, it is an invasive investigation and imposes potential risks.
 
Attempts have been made in the literature to distinguish cysticercosis and tuberculosis neurological infection by combined interpretation of the clinical, radiological, and serological features.2 3 4
 
Clinically, tuberculomas are more often associated with increased intracranial pressure and focal neurological deficits, whereas patients with neurocysticercosis are usually less symptomatic or present with seizures.2
 
Radiologically, the imaging findings of neurocysticercosis are variable, depending on the stage and location of infestation. A diagnostic dilemma lies in those who present with intracranial cystic lesions without presence of scolex, and that may be present in both neurocysticercosis and tuberculosis. Table b shows some MRI imaging features that may help distinguish the two diagnoses.2 3 4 5
 

Table (b). MR imaging features which may help in distinguishing neurocysticercosis from tuberculosis2 3 4 5
 
Based on the neuroimaging features and the revised diagnostic criteria, a probable diagnosis of neurocysticercosis was made: presence of lesions compatible with neurocysticercosis that resolved after treatment with albendazole, and a history of travelling to an endemic area.
 
Neurocysticercosis is an uncommon parasitic infection of the central nervous system in Hong Kong and requires a high degree of clinical suspicion for diagnosis. Despite the advances in neuroimaging, accurate diagnosis is still sometimes difficult, which is related to the pleomorphic disease nature and significant overlapping features with tuberculosis. A combination of proper interpretation of diagnostic criteria and imaging findings is helpful in making the diagnosis without invasive and potentially harmful investigations.
 
References
1. Del Brutto OH, Rajshekhar V, White AC Jr, et al. Proposed diagnostic criteria for neurocysticercosis. Neurology 2001;57:177-83. Crossref
2. Rajshekhar V, Haran RP, Prakash GS, Chandy MJ. Differentiating solitary small cysticercus granulomas and tuberculomas in patients with epilepsy. Clinical and computerized tomographic criteria. J Neurosurg 1993;78:402-7. Crossref
3. Garg RK, Kar AM, Kumar T. Neurocysticercosis like presentation in a case of CNS tuberculosis. Neurol India 2000;48:260-2.
4. Garg RK. Diagnosis of intracranial tuberculoma. Indian J Tuberc 1996;43:35-9.
5. Pretell EJ, Martinot C Jr, Garcia HH, Alvarado M, Bustos JA, Martinot C; Cysticercosis Working Group in Peru. Differential diagnosis between cerebral tuberculosis and neurocysticercosis by magnetic resonance spectroscopy. J Comput Assist Tomogr 2005;29:112-4. Crossref

A case of refractory seizure with cognitive impairment due to anti-GABA encephalitis

DOI: 10.12809/hkmj154604
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
A case of refractory seizure with cognitive impairment due to anti-GABA encephalitis
Adrian TH Hui, MB BS, MRCP (UK); YO Lam, MB, BS, MRCP (UK); CK Chan, MB, BS, FHKAM (Medicine); KY Cheung, MB, ChB, FHKAM (Medicine); BH Fung, MB, BS, FHKAM (Medicine); PW Ng, MB, BS, FHKAM (Medicine)
Department of Medicine and Geriatrics, United Christian Hospital, Kwun Tong, Hong Kong
 
Corresponding author: Dr Adrian TH Hui (hth077@ha.org.hk)
 
 
Case report
A 57-year-old man presented with first episode of loss of consciousness at work in February 2014. He experienced no symptoms prior to this syncope event. He was witnessed by his colleagues to have tonic rigidity over his upper limbs, with a bite mark evident over the lateral aspect of his tongue. He had experienced a right-sided temporal headache characterised as dull and persistent for 3 weeks prior to this incident without any precipitating factors or aura identified.
 
He enjoyed good past health and had been educated to high school level. He was currently working as an accountant. He did not smoke or drink, had no recent travel history, and was not on any long-term medication or taking herbs. He could not recall any febrile convulsion during childhood or significant family history of neurological diseases.
 
He was fully oriented and remained afebrile on admission. Routine blood tests (electrolytes, glucose, and inflammatory markers), physical examination, and initial computed tomographic (CT) brain were unremarkable. The patient refused lumbar puncture and was discharged against medical advice.
 
Three days after discharge, he was admitted to a private hospital with generalised tonic-clonic convulsion. Electroencephalography was normal and magnetic resonance imaging (MRI)/magnetic resonance angiography brain showed no mass lesion or infarct. He was discharged with a prescription of levetiracetam in view of the second episode of seizure.
 
He was again admitted to us in early March 2014 with breakthrough seizure and post-ictal drowsiness, despite good drug compliance and no identifiable precipitating factors. His seizure was initially controlled with levetiracetam with the addition of phenytoin, but he remained disoriented with confused speech. His Mini-Mental State Examination (MMSE) score was 14/30: his main deficit was delayed recall with failure to perform serial sevens and to copy a polygon. He developed a low-grade fever of 37.8°C with negative septic workup. Lumbar puncture did not reveal any evidence of central nervous system infection (white cell count, <1/mm3, protein level not elevated, and negative culture result). Electroencephalography showed right temporal spikes only. He was prescribed empirical Augmentin (Sandoz, Australia) 1.2 g every 8 hours intravenously and his fever settled.
 
One week after admission, he experienced multiple episodes of generalised tonic-clonic seizure without progression to status epilepticus. Doses of both phenytoin and levetiracetam were increased along with the addition of valproic acid. His seizures abated but cognition was not improved. Electroencephalography was repeated and demonstrated left temporal polyspikes over F7/T3/T5 in addition to bitemporal sharp waves (Fig 1). Brain MRI was also repeated and showed no abnormality (Fig 2). Blood tests were unremarkable with normal electrolytes, negative tumour markers (alpha-fetoprotein/carcinoembryonic antigen/prostate-specific antigen), negative autoimmune markers (antinuclear antibodies/rheumatoid factor), normal thyroid function and lactate level, and human immunodeficiency virus–negative status. Lumbar puncture was repeated, and this time showed mild lymphocytic pleocytosis with white cell count of 9/mm3 (98% lymphocyte count), protein level again not elevated, cerebrospinal fluid (CSF)–serum glucose ratio of 0.53 (4.1/7.8). Both serum and CSF oligoclonal bands were present, and immunoglobulin G index was also elevated.
 

Figure 1. Electroencephalography demonstrates left temporal polyspikes over F7/T3/T5 in addition to bitemporal sharp waves
 

Figure 2. Magnetic resonance imaging of the brain showing no hyperintense mesio-temporal lobe signal change on T2 and fluid-attenuated inversion recovery
 
Both autoimmune encephalitis and post-ictal pleocytosis are important differential diagnoses to be considered. Serum and CSF were saved for the detection of auto-antibodies, although anti–N-methyl D-aspartate (anti-NMDA), anti–voltage-gated potassium channel (anti-VGKC), and antineuronal (anti-Hu/anti-Ri/anti-Yo) antibodies were all negative, anti-GABAB antibodies were detected in both serum and CSF of this patient.
 
Discussion
Autoimmune encephalitis, previously labelled limbic encephalitis, was first described in the 1960s when patients with lung cancer also suffered from temporal lobe epilepsy, memory loss, and dementia features.1 It was once thought that limbic encephalitis was always associated with malignancy. In 1985, the first onconeuronal antibody, anti-Hu antibody, was discovered in small-cell lung carcinoma patients.1 More antibodies were identified in subsequent years, namely CV2/CRMP5-Ab and Ma2-Ab, that target intracellular peptides being expressed on the cell membrane.1 At the turn of the 21st century, patients who had features of limbic encephalitis did not necessarily develop malignancy, and those affected were usually young individuals who responded well to immunotherapy. Researchers later found antibodies in these patients that targeted cell membrane antigens that are receptors involved in synaptic transmission, plasticity, and neuronal excitability. The first such antibody discovered was VGKC.1
 
The pathophysiological mechanism involves both humeral and cellular immunity mediated by antibody production and cytotoxic T cells, respectively.1 The hippocampus and hypothalamus are most vulnerable during the active disease stage as the permeability of the blood-brain barrier is increased more than other regions of the brain, and is thereby more susceptible to autoimmune attack.2
 
Treatment modalities include removal of the underlying tumour and the antibodies. Thus far, no randomised controlled trials have analysed the efficacy of such treatment. Clinical experience would suggest that the first-line immunotherapy would be steroid as anti-inflammatory agent and intravenous immunoglobulin (IVIG)/plasma exchange for antibody removal.3 If first-line treatment becomes ineffective, second-line treatment including rituximab as a B-cell depleting agent and cyclophosphamide as an anti-inflammatory agent would be considered.2
 
As clinicians, it is important to recognise classic features that alert us to the possibility of autoimmune encephalitis. These features include subacute onset of confusion, short-term memory loss, behaviour change (depression, apathy, irritability), and seizures (usual temporal complex partial type).4 These features can precede the development of cancer for paraneoplastic encephalitis.5 It is important to obtain the history of smoking and family history of malignancy. The occurrence of refractory seizure despite prescription of multiple antiepileptics should prompt the clinician to consider this diagnosis as well. As part of the workup to exclude other differential diagnoses, lumbar puncture, electroencephalogram, and brain MRI should be performed, although these are non-specific tests for confirming autoimmune encephalitis.4 A CSF picture of lymphocytosis with mildly elevated protein and presence of oligoclonal bands will be present.4 Electroencephalography will show temporal lobe abnormalities, while brain MRI will reveal a unilateral or bilateral hyperintense medial temporal lobe signal change on T2 and fluid-attenuated inversion recovery without contrast enhancement that can progress to hippocampal and temporal lobe atrophy.4 6
 
A condition that mimics autoimmune encephalitis is infectious encephalitis, particularly herpes encephalitis. To differentiate the two, several clinical clues might be useful. Fever is almost always present in infectious encephalitis; it is present in about 50% of autoimmune encephalitis cases.6 Skin lesions can be found in varicella-zoster infection.6 Lymphocytic pleocytosis is milder in autoimmune encephalitis than in viral illnesses.6 Periodic lateral epileptic discharge over the temporal region can be found in herpes encephalitis, and typical brain MRI findings in this aetiology would be asymmetric medial temporal lobe necrosis along with cingulate and insular region involvement.6 Herpes simplex virus–polymerase chain reaction in CSF would be essential as part of the workup as well. Ultimately, for definitive diagnosis of autoimmune encephalitis, paired serum and CSF antibodies should be obtained.
 
In GABAB encephalitis, antibodies target both GABAB1 and B2 subunits located mainly in the hippocampus, thalamus, and cerebellum.7 Patients usually have early prominent seizures (temporal lobe epilepsy), memory deficits, increased anxiety, and mood dysregulation. Novel symptoms such as ataxia or opsoclonus-myoclonus have also been recently reported.7 8 Small-cell lung carcinoma is often present.7 Concurrent antibodies such as VGKC-Ab, GAD-Ab (glutamic acid decarboxylase) have also been documented.7 9 The outcome is driven by the adequacy of tumour removal if found and the presence of other auto-antibodies, particularly onconeural antibodies (amphiphysin and SOX1) that are associated with a poorer prognosis.8
 
In a recent literature review, the discovery of anti-GABAA antibody as a target of autoimmunity has received much attention as a cause of refractory seizures or status epilepticus.10 In contrast to GABAB encephalitis, extensive cortical-subcortical brain MRI abnormalities and the co-existence with other antibodies particularly GAD65 or TPO (thyroid peroxidase) were shown in a recent case series report.10
 
To monitor disease activity, both serum and CSF antibodies should be collected as some are more readily detectable in one compartment than another: NMDA antibodies are readily obtained from CSF and VGKC from serum.2 In general, treatment such as long-term immunosuppression should be guided by clinical judgement and not necessarily on antibody level.
 
In our patient, after a 5-day course of IVIG there was no recurrence of seizure. Oral prednisolone (1 mg/kg/day) was then prescribed and slowly tapered. His cognition was assessed 1 week after IVIG. Although MMSE remained low with a score of 15/30, improvement in abstract thinking, calculation, and proverb interpretation was noted upon discharge.
 
Positron emission tomography/CT was performed in late March 2014 to screen for malignancy. There was abnormal fluorodeoxyglucose uptake over the medial aspect of the left temporal lobe. Brain MRI was repeated 2 months after discharge and showed resolved signal/swelling in the medial aspect of the left temporal lobe. His cognition was again assessed in November 2014 and showed improvement in orientation and judgement, but still moderately to severely impaired memory.
 
Declaration
No conflict of interests was declared by the authors.
 
Acknowledgement
I would like to thank Dr Josep Dalmau, Service of Neurology, Hospital Clinic, University of Barcelona, Spain, for his assistance in processing our sample.
 
References
1. Didelot A, Honnorat J. Autoimmune limbic encephalitis. Future Neurol 2011;6:97-111. Crossref
2. Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 2011;10:759-72. Crossref
3. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157-65. Crossref
4. Derry CP, Wilkie MD, Al-Shahi Salman R, Davenport RJ. Autoimmune limbic encephalitis. Clin Med (Lond) 2011;11:476-8. Crossref
5. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008;7:327-40. Crossref
6. Armangue T, Leypoldt F, Dalmau J. Autoimmune encephalitis as differential diagnosis of infectious encephalitis. Curr Opin Neurol 2014;27:361-8. Crossref
7. Lancaster E, Lai M, Peng X, et al. Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010;9:67-76. Crossref
8. Höftberger R, Titulaer MJ, Sabater L, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 2013;81:1500-6. Crossref
9. Boronat A, Sabater L, Saiz A, Dalmau J, Graus F. GABAB receptor antibodies in limbic encephalitis and anti-GAD–associated neurologic disorders. Neurology 2011;76:795-800. Crossref
10. Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014;13:276-86. Crossref

One too many: intellectual disability secondary to undiagnosed phenylketonuria

DOI: 10.12809/hkmj144500
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
One too many: intellectual disability secondary to undiagnosed phenylketonuria
Joannie Hui, FRCP (Edin), FRACP1; SC Chong, FHKCPaed, FHKAM (Paediatrics)1; LK Law, PhD, FRCPath2; LK Lee, FHKCPaed, MPH (HK)1; Sandy Chang, RD, BSc (Hons) Nutrition/Dietetics3; Phyllis Yau, RD, PgDip Dietetics3; YP Yuen, FHKCPath, FHKAM (Pathology)2
1 Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong
2 Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong
3 Dietetics Department, Prince of Wales Hospital, Shatin, Hong Kong
 
Corresponding author: Dr Joannie Hui (joanniehui@cuhk.edu.hk)
 
 
Case report
Hyperphenylalaninaemia refers to the clinical condition characterised by increased amounts of phenylalanine in blood and other tissues. It can result from either a deficiency of phenylalanine hydroxylase (PAH) or defects in synthesis or regeneration of tetrahydrobiopterin (BH4), a cofactor for PAH (Fig 1).
 

Figure 1. Metabolic pathways related to phenylketonuria
Five enzymes are involved in the tetrahydrobiopterin (BH4) synthesis or regeneration cycle: (1) GTP cyclohydrolase I (GTPCH), 6-pyruvoyl tetrahydropterin synthase (PTPS), sepiapterin reductase (SR), dihydropteridine reductase (DHPR), and pterin-4acarbinolamine dehydratase (PCD). Deficiencies of all except SR result in hyperphenylalaninaemia. BH4 is an essential cofactor for PAH, TH, and TPH
 
We describe a 2-year-old boy who was referred by the Maternity Child Health Clinic to the Department of Paediatrics in June 2014 for assessment of developmental delay. He was the second child in his family, born at term and following an uneventful pregnancy to non-consanguineous Chinese parents. His birth weight was 3475 g. He was formula-fed from birth, then gradually weaned to a normal toddler diet. Family history was unremarkable. The mother was from Hubei, a province in Central China, and father was from Shenzhen, a major city in Southern China. The 5-year-old brother was well and there were no developmental concerns.
 
The boy’s early developmental milestones were unremarkable. He developed social smile at 1 month of age, sat unsupported at 8 months, and walked independently at 1 year and 8 months. He started saying single words at 15 months but at the age of 2 years was still saying only a few single words and no phrases. Also he was noted to be hyperactive with behaviour that was at times difficult to control. His physical growth was satisfactory. His head circumference was 48.5 cm (50th centile), weight 14.1 kg (90th centile), and height 87 cm (50th centile). There were no dysmorphic features and no abnormalities were detected on physical examination. His hair was slightly brownish.
 
Initial baseline investigations revealed normal blood count and liver, renal, and thyroid function. Urine organic acid analysis showed markedly elevated phenylalanine metabolites including phenyllactic, 3-phenylpyruvic, and phenylacetic acids. Plasma phenylalanine level was markedly elevated at 1948 µmol/L (reference range [RR], 26-91 µmol/L) and tyrosine was 47 µmol/L (RR, 24-115 µmol/L). Urine biopterin was mildly elevated at 5.0 µmol/mmol creatinine (RR, 0.5-3.0) while neopterin was normal at 1.7 µmol/mmol creatinine (RR, 1.1-4.0). Erythrocyte dihydropteridine reductase activity was normal. A BH4 loading test was performed to check for BH4 responsiveness according to standard protocol.1 Blood for phenylalanine and tyrosine was checked serially at 8, 16, and 24 hours after each administration of 20 mg/kg BH4 (Kuvan) orally on day 1 and day 2 of the loading test. No appreciable drop in blood phenylalanine level was observed confirming BH4 non-responsiveness.
 
All coding exons and flanking introns of the PAH gene (reference sequence NM_000277.1) were sequenced using the standard Sanger method. A heterozygous missense mutation c.860T>C was detected in exon 8 of the PAH gene. This mutation changes the highly conserved leucine at position 287 to proline (p.Leu287Pro) [Fig 2]. Another mutation affecting the same amino acid p.Leu287Gly has been reported previously in patients with phenylketonuria (PKU).2 In-silico analyses by four prediction software (PolyPhen-2, SIFT, Mutation Taster, PON-P2) also consistently predicted that the mutation is pathogenic. Therefore, PAH c.860T>C (p.Leu287Pro) is highly likely to be a pathogenic mutation. The mother was a carrier of this missense mutation. PAH gene dosage analysis by multiplex ligation probe amplification (SALSA MLPA probemix P055-C1 PAH) did not detect any PAH gross deletion or duplication. Therefore, the second PAH mutation of this patient remained unidentified.
 

Figure 2. Electropherogram of the PAH mutation NM_000277.1:c.860T>C (p.Leu287Pro)
The arrow indicates the position of mutation
 
The patient was started on a phenylalaninere-stricted diet after diagnosis. Special formula XP-2 powder from SHS was used as the phenylalanine-free and tyrosine supplement source. With dietary advice and close supervision, his phenylalanine levels gradually came down to 300 to 500 µmol/L while tyrosine levels were maintained at 50 to 80 µmol/L over the following 6 months. It is too early to report on his progress in terms of development and behaviour consequent to better control of the blood phenylalanine level.
 
Discussion
We believe this is the first reported case of a locally born child with classic PKU in Hong Kong. Although a low phenylalanine diet was commenced promptly upon diagnosis, the cognitive impairment that has occurred as a result of the unrecognised long-standing hyperphenylalaninaemia is likely irreversible. Other than this patient reported here, two other classic PKU patients are being followed up at the authors’ metabolic clinic. Both patients were born in Guangzhou, the capital city of Guangdong province in South China. They were diagnosed through the newborn screening programme in Guangdong province. With good dietary compliance, both children have achieved normal growth and development.
 
This year marked the 56th anniversary of PKU newborn screening. Effective newborn screening programmes worldwide including those in China have identified thousands of infants with PKU and prevented intellectual disability through early diagnosis and treatment. Yet in Hong Kong the need for PKU screening has never been seriously addressed. Over the last 30 years, newborn screening in Hong Kong has remained unchanged with cord blood screening for G6PD (glucose-6-phosphate dehydrogenase) deficiency and congenital hypothyroidism. The current practice of newborn screening lags behind the rest of the world, and has never been challenged because for years there have been only scant cases of 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency and no classic PKU cases reported locally. In the absence of newborn screening, why has only PTPS deficiency and no classic PKU patients been identified in Hong Kong? One reason could be that individuals with PTPS deficiency often present with more complex neurological manifestations and are more likely to undergo extensive investigations. On the contrary, those with classic PKU present with variable degrees of intellectual disability and behavioural problems and no overt neurological signs, and may not have been as extensively investigated. In addition, there is a general misconception among practising clinicians in Hong Kong that PKU is a disease of the Caucasian population. Even if it does affect the Chinese population, only the Northern Chinese are affected. As such, plasma amino acid or urine organic acid profile may not have been routinely requested for investigation in children with unexplained developmental delay, intellectual disability, behavioural problems, or autistic spectrum disorders. Further, these investigations may not be as widely available in non–hospital-based private laboratories.
 
Without a territory-wide newborn screening programme, it is impossible to ascertain the true incidence of PKU in Hong Kong. Irrespective of whether Hong Kong does have a different PKU incidence compared with the rest of China, the presence of confirmed cases locally provides a strong argument for diagnosis and treatment of affected individuals at the earliest instance rather than after symptomatic presentation. Hong Kong cannot afford to have more intellectual disability as a result of the unavailability of PKU screening. Until this programme becomes universally available, we advocate plasma amino acid and urine organic acid analysis to be incorporated into the diagnostic workup for all children with unexplained developmental delay, intellectual disability, behavioural problems, and autistic spectrum disorders.
 
References
1. Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab 2011;104 Suppl:S2-9. Crossref
2. Bardelli T, Donati MA, Gasperini S, et al. Two novel genetic lesions and a common BH4-responsive mutation of the PAH gene in Italian patients with hyperphenylalaninemia. Mol Genet Metab 2002;77:260-6. Crossref

Babesiosis acquired from a pet dog: a second reported case in Hong Kong

DOI: 10.12809/hkmj144390
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Babesiosis acquired from a pet dog: a second reported case in Hong Kong
Jacky MC Chan, FHKCP, FHKAM (Medicine); KY Tsang, FHKAM (Medicine), FRCP (Glasg & Edin); Thomas SH Chik, MB, ChB, MRCP(UK); WS Leung, FHKCP, FHKAM (Medicine); Owen TY Tsang, FHKAM (Medicine), FRCP (Edin)
Department of Medicine and Geriatrics, Princess Margaret Hospital, Laichikok, Hong Kong
 
Corresponding author: Dr Jacky MC Chan (cmc061@ha.org.hk)
 
 Full paper in PDF
 
A 61-year-old Chinese man was admitted to our hospital in June 2012 with a 2-week history of fever and chills. After admission, he developed hypotension and respiratory distress and was transferred to the intensive care unit (ICU) for further management.
 
He frequently commuted between New York, Hong Kong, and Shanghai for business. He lived in his own house in New York and had a dog. Three weeks before onset of his symptoms, he swept his basement where his dog spent most of its time. He was not aware of any tick bite.
 
He was a chronic smoker but enjoyed good past health. His symptoms began with fever and chills while in China. He also experienced malaise and a mild dry cough. He had no skin rash, or abdominal or urinary symptoms. A diagnosis of upper respiratory tract infection was made and he was given a course of piperacillin-tazobactam during hospitalisation in China. Symptoms persisted, however, and he presented to a public hospital in Hong Kong. Initial blood tests revealed a normochromic normocytic anaemia (haemoglobin, 81 g/L) with reticulocytosis, marked thrombocytopenia, and moderate renal impairment. Blood smear revealed the presence of intra-erythrocytic ring-form parasites, suggestive of Plasmodium falciparum infection (Fig 1). Chest X-ray showed bilateral extensive abnormal lung infiltrates. He was transferred to our hospital for further management.
 

Figure 1. Intra-erythrocytic ring-form trophozoite in thin blood smear (Giemsa stain; original magnification, x 100)
 
He soon developed shock and was transferred to the ICU. Further blood tests revealed hyperbilirubinaemia and evidence of haemolysis. Peripheral blood smear for malaria was repeated and revealed 3.8% parasitised red cells. Pleomorphic ring forms were noted, with occasional arrangement in a cross-like pattern (Fig 2). Rapid antigen test for P falciparum was negative and this raised the suspicion of babesiosis. A subsequent blood Babesia microti polymerase chain reaction (PCR) test was positive and a diagnosis of babesiosis was confirmed.
 

Figure 2. Babesia microti in thin blood smear (Giemsa stain; original magnification, x 100). Tetrads of merozoites are arranged in a cross-like pattern (Maltese cross)
 
Quinine and clindamycin were initiated. The patient experienced severe tinnitus after 5 days of treatment and quinine was stopped. Doxycycline was added for treatment due to persistent fever and because it is known that Lyme’s disease can be a concurrent infection. He stayed in the ICU for 6 days and his condition was stabilised with resolution of fever. Blood smear for Babesia turned negative on day 14 of treatment. Supportive blood transfusion was given for anaemia and the patient was discharged after 21 days.
 
He attended regular follow-ups in our clinic. Repeated blood smear for babesiosis and Babesia PCR test (in September 2012, 3 months after treatment) were negative. He had the basement of his New York apartment professionally cleaned and had his dog treated for ticks.
 
Discussion
This is the second imported case of human babesiosis in Hong Kong since 2007.1 Babesiosis is a tick-borne disease in which patients are infected with intra-erythrocytic parasites of the genus Babesia. The common species affecting humans are B microti and Babesia divergens, mostly found in the United States and Europe, respectively. White-footed mice are the primary reservoir host, but other small rodents may also carry B microti. The Babesia parasites are transmitted to humans accidentally by Ixodid tick bites. In the United States, Ixodes scapularis is the most common vector. The ticks become infected with B microti when they feed on vertebrate reservoir hosts such as infected white-footed mice and white-tailed deer. Humans are usually accidental hosts.2
 
The diagnosis of human babesiosis is made by microscopic examination of Giemsa-stained thick and thin blood smears. Microscopically, Babesia species may appear as round or oval-shaped forms, with blue cytoplasm and red chromatin. Multiple parasites may be present in a single-infected red blood cell. Differentiation of the ring-form of Babesia species and P falciparum may be difficult. Some distinguishing features of babesiosis include the presence of extra-erythrocytic forms in severe cases and the absence of pigment deposits typically seen in older ring stages of P falciparum. The Maltese cross pattern in which tetrads of merozoites are arranged is pathognomonic of babesiosis, but they are not commonly seen.3 Nonetheless, the different species of babesiosis cannot be distinguished by microscopic examination. Real-time PCR performed on DNA targeting the 18S rRNA gene of B microti is therefore a more specific and accurate method to detect B microti.4
 
Our patient was a case of possible pet-associated human Babesia infection. Babesiosis is a zoonotic protozoan disease of medical, veterinary, and economic importance. A case of human babesiosis acquired from a pet dog has been reported where the dog was heavily infested with ticks.5 In a Brazilian evaluation of ectoparasites in dogs kept in apartments, Ixodid nymphs were found in 2%. In houses with grassy yards, 18% of pet dogs were found to carry Ixodid nymphs.6 Different species of Ixodid ticks have been identified in dogs, with the head being the most common site of attachment. The activity of tick attachment peaks in spring and in autumn. Canine babesiosis is diagnosed by veterinarians in approximately 20% of tick-infested dogs.7 In one study in New York state, I scapularis ticks were collected from recreational lands to determine the prevalence and distribution of tick-borne pathogens. The overall prevalence of B microti was approximately 3% among both nymphs and adult ticks.8
 
In Hong Kong, around 250 000 households are estimated to keep dogs or cats, representing 10.6% of all households.9 There has been no single reported case of human babesiosis in Hong Kong although the disease is common in the cat and dog population. Recently a new Babesia species, Babesia hongkongensis has been identified in the feline population.10 The prevalence of this new local species is low among free-roaming cats in Hong Kong and the pathogenicity in pet cats is unknown.
 
The clinical presentation of human babesiosis varies. Infected patients may present with a mild-to-moderate viral-like illness, with gradual onset of chills, sweats, headache, arthralgia, and anorexia. Some patients present with a prolonged course of pyrexia of unknown origin. Physical examination may reveal mild splenomegaly or hepatomegaly. Severe infection generally occurs in those with an underlying immunosuppressed condition, particularly patients with previous splenectomy. Complications of babesiosis include acute respiratory failure, disseminated intravascular coagulation, and multi-organ failure.3
 
Combination therapy with atovaquone and azithromycin is the treatment of choice for mild-to-moderate Babesia infection. In severe cases, the use of clindamycin and quinine is recommended. In general, the combination of atovaquone and azithromycin is better tolerated with fewer adverse effects.11 All doses of antimicrobial therapy are administered for 7 to 10 days. For severely immunocompromised patients with persistent relapsing infection, a longer duration of at least 6 weeks’ treatment is recommended, continuing for 2 weeks after blood smears become negative for Babesia. For fulminant cases, exchange transfusion may be required.2 12
 
References
1. Wong WS, Chung JY, Wong KF. Images in haematology. Human babesiosis. Br J Haematol 2008;140:364. Crossref
2. Vannier E, Krause PJ. Human babesiosis. N Engl J Med 2012;66:2397-407. Crossref
3. Vannier E, Gewurz BE, Krause PJ. Human babesiosis. Infect Dis Clin North Am 2008;22:469-88, viii-ix. Crossref
4. Teal AE, Habura A, Ennis J, Keithly JS, Madison-Antenucci S. A new real-time PCR assay for improved detection of the parasite Babesia microti. J Clin Microbiol 2012;50:903-8. Crossref
5. EL-Bahnasawy MM, Khalil HH, Morsy TA. Babesiosis in an Egyptian boy acquired from pet dog, and a general review. J Egypt Soc Parasitol 2011;41:99-108.
6. Soares AO, Souza AD, Feliciano EA, Rodrigues AF, D’Agosto M, Daemon E. Evaluation of ectoparasites and hemoparasites in dogs kept in apartments and houses with yards in the city of Juiz de Fora, Minas Gerais, Brazil [in Portuguese]. Rev Bras Parasitol Vet 2006;15:13-6.
7. Földvári G, Farkas R. Ixodid tick species attaching to dogs in Hungary. Vet Parasitol 2005;129:125-31. Crossref
8. Prusinski MA, Kokas JE, Hukey KT, Kogut SJ, Lee J, Backenson PB. Prevalence of Borrelia burgdorferi (Spirochaetales: Spirochaetaceae), Anaplasma phagocytophilum (Rickettsiales: Anaplasmataceae), and Babesia microti (Piroplasmida: Babesiidae) in Ixodes scapularis (Acari: Ixodidae) collected from recreational lands in the Hudson Valley Region, New York State. J Med Entomol 2014;51:226-36. Crossref
9. Thematic Household Survey Report No. 48. Census and Statistics Department, Hong Kong SAR Government 2011. Available from: http://www.statistics.gov.hk/pub/B11302482011XXXXB0100.pdf. Accessed Feb 2016.
10. Wong SS, Poon RW, Hui JJ, Yuen KY. Detection of Babesia hongkongensis sp. nov. in a free-roaming Felis catus cat in Hong Kong. J Clin Microbiol 2012;50:2799-803. Crossref
11. Krause PJ, Lepore T, Sikand VK, et al. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med 2000;343:1454-8. Crossref
12. Dorman SE, Cannon ME, Telford SR 3rd, Frank KM, Churchill WH. Fulminant babesiosis treated with clindamycin, quinine, and whole-blood exchange transfusion. Transfusion 2000;40:375-80. Crossref

Intracoronary thrombus in an 18-year-old teenager. Why?

DOI: 10.12809/hkmj144439
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Intracoronary thrombus in an 18-year-old teenager. Why?
Mert I Hayiroglu, MD; Adnan Kaya, MD; Sahin Avsar, MD; Nijat Bakishaliev, MD; Emrah Bozbeyoglu, MD
Department of Cardiology, Dr Siyami Ersek Cardiovascular and Thoracic Surgery Hospital, Istanbul, Turkey
 
Corresponding author: Dr Adnan Kaya (adnankaya@ymail.com)
 
 Full paper in PDF
 
Case report
In August 2014, an 18-year-old boy with no prior history of coronary or cardiac disease presented to our tertiary cardiovascular and thoracic surgery hospital in Turkey with crushing substernal chest pain, nausea, and vomiting that had persisted for 1 hour. He had started work as a barman at a beach club 3 months earlier and denied any use of off-label drugs. His first electrocardiography (ECG) was normal with sinus rhythm (heart rate, 90 beats/min; Fig 1a). The patient, however, was tachypnoeic and reported a heavy squeezing chest discomfort. On physical examination, the pain was not relieved by position change and increased continuously. Blood pressure was 142/75 mm Hg and pulse oximetry showed oxygen saturation to be 94%. Chest auscultation was normal, as was chest X-ray. Cardiomegaly and pneumothorax were absent and the mediastinum was not widened.
 

Figure 1. (a) First electrocardiography shows normal sinus rhythm. (b) Control electrocardiography shows widened QRS complexes consistent with right bundle branch block pattern, interpreted as idioventricular rhythm
 
Smoking was the only risk factor for developing coronary artery disease in this young patient. Hypertension, diabetes mellitus, hyperlipidaemia, family history of heart disease, and obesity were absent as risk factors for coronary artery disease.
 
The patient was thought to have myocarditis and ibuprofen was prescribed for symptom relief. The pain worsened, however, and ECG showed widened QRS complexes (right bundle branch block pattern in precordial derivations) with a rate of 112 beats/min (Fig 1b). The ECG was interpreted as idioventricular rhythm. Bedside transthoracic echocardiography was performed and left ventricular anterior wall hypokinesis with 40% ejection fraction was observed. Clopidogrel and acetylsalicylic acid were started and immediate coronary angiography (CAG) was performed to identify the cause. A significant stenosis of the mid-segment of the left anterior descending (LAD) artery with a fresh thrombus image was present with distal TIMI-3 flow (Thrombolysis In Myocardial Infarction grade 3, which implies normal flow that fills the distal coronary bed completely) [Fig 2a]. Right coronary artery and left circumflex artery were normal. Since the patient’s haemodynamic parameters were stable with TIMI-3 distal blood flow in the LAD, conservative treatment with intravenous glycoprotein 2b/3a (GP-2b3a) inhibitor was prescribed. After successful infusion of GP-2b3a without any complications, control CAG was performed (Fig 2b). Complete dissolution of thrombus was observed and left ventricular anterior hypokinesis was reversed.
 

Figure 2. (a) A significant stenosis of mid-segment of left anterior descending artery with a fresh thrombus image is present with distal Thrombolysis In Myocardial Infarction grade 3 flow (arrow). (b) After successful infusion of glycoprotein 2b/3a without any complications, control coronary angiography was performed and dissolution of thrombus is observed
 
The patient’s laboratory findings were all within normal range except markers of myocardial damage. Troponin I level was 24 µg/L. Platelet count and liver function tests were normal, as was clotting panel. The patient’s blood was screened for factor V Leiden mutation, prothrombin gene mutation, MTHFR gene mutation, protein C activity, protein S activity, plasminogen activator inhibitor–1 activity, homocysteine levels, and anti-cardiolipin antibodies. No secondary aetiology was evident that could account for such thrombus formation in an 18-year-old boy so he was further questioned about drug use. This time he admitted the use of marijuana 1 hour prior to the onset of intense chest pain.
 
Discussion
Acute myocardial infarction (AMI) is the leading cause of death in North America and Europe.1 Despite this, AMI in an 18-year-old teenage boy is very rare. In our case the possible causes of thrombophilia were excluded and smoking of cannabis was thought to be the main cause of AMI.
 
Recent cannabis use is associated with acute coronary syndrome and can lead to severe cardiovascular problems and sudden death, not only in people at increased cardiovascular risk but also in young people without any medical history or risk factors.2 The effects of cannabinoids are primarily mediated by the activation of cannabinoid receptors that are present in a variety of tissues including the brain (basal ganglia, pars reticulata of the substantia nigra, entopeduncular nucleus, globus pallidus, putamen, cerebellum, hippocampus, and cerebral cortex) and cells of the immune system, spleen, blood vessels, and the heart.3
 
The pharmacological effects of marijuana, based on stimulation of cannabinoid receptors CB1 and CB2 that are widely distributed in the cardiovascular system, have been well described. A dose-dependent increase in heart rate up to 100% of basal rate occurs 10 to 30 minutes after beginning to smoke.4 Most users experience an increase in blood pressure especially while supine4 although postural hypotension after smoking marijuana is common. Tolerance to this drug can occur with frequent repeated use.5 Another harmful effect of smoked marijuana is associated with an increase in carboxyhaemoglobin, resulting in decreased oxygen-carrying capacity6 and subsequent demand-supply mismatch by decreasing oxygen transportation to the heart. This mechanism is suggested to underlie atherosclerotic stable coronary disease and concomitant cannabinoid use. Nonetheless in our case, the patient was too young and the lesion appearance on CAG was suggestive of a small plaque rupture with superimposed thrombus formation rather than stable atherosclerotic disease. Acute myocardial infarction associated with cannabinoid use and with normal coronary artery has been reported in the literature. Ours is an interesting case report associated with cannabinoid inhalation and superimposed thrombus formation detected by CAG. In our patient, implantation of a stent in the LAD artery was not an option because the lesion was thought to be thrombotic. Dissolution of the thrombus was achieved with GP-2b3a infusion.
 
Clinicians are reminded of this very rare aetiology of acute coronary syndrome and its management among young patients. Bearing in mind the increasing use of drugs such as marijuana and other synthetic cannabinoids among young people, management of associated cardiac problems is vital. A CAG should be performed whenever drug abuse is suspected in any patient who presents with chest pain. If a thrombotic lesion is detected on CAG, infusion of GP-2b3a may dissolve the thrombus.
 
References
1. Griffin BP, editor. Manual of cardiovascular medicine. 3rd ed. Philadelphia: Lippincott Williams and Wilkins; 2009: 1.
2. Casier I, Vanduynhoven P, Haine S, Vrints C, Jorens PG. Is recent cannabis use associated with acute coronary syndromes? An illustrative case series. Acta Cardiol 2014;69:131-6.
3. Járai Z, Wagner JA, Varga K, et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci USA 1999;96:14136-41. Crossref
4. Johnson S, Domino EF. Some cardiovascular effects of marihuana smoking in normal volunteers. Clin Pharmacol Ther 1971;12:762-8. Crossref
5. Benowitz NL, Jones RT. Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. Clin Pharmacol Ther 1975;18:287-97. Crossref
6. Aronow WS, Cassidy J. Effect of marihuana and placebo-marihuana smoking on angina pectoris. N Engl J Med 1974;291:65-7. Crossref

Preimplantation genetic diagnosis for hereditary cancer syndrome: local experience

DOI: 10.12809/hkmj144499
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Preimplantation genetic diagnosis for hereditary cancer syndrome: local experience
Vivian CY Lee, FHKAM (Obstetrics and Gynaecology)1; Judy FC Chow, MPhil2; Estella YL Lau, PhD1; Ava Kwong, FRCS, FHKAM (Surgery)3; SY Leung, FRCPath, FHKAM (Pathology)4; William SB Yeung, PhD2; PC Ho, MD2; Ernest HY Ng, MD2
1 Department of Obstetrics and Gynaecology, Queen Mary Hospital, Pokfulam, Hong Kong
2 Department of Obstetrics and Gynaecology, The University of Hong Kong, Pokfulam, Hong Kong
3 Hong Kong Hereditary Breast Cancer Family Registry; Division of Breast Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
4 Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
 
Corresponding author: Dr Vivian CY Lee (v200lee@hku.hk)
 
 Full paper in PDF
 
Case reports
We present three cases of preimplantation genetic diagnosis (PGD) performed for hereditary cancer syndromes at the Centre of Assisted Reproduction and Embryology, The University of Hong Kong, Queen Mary Hospital in Hong Kong.
 
Case 1
A 33-year-old woman was referred for consideration of PGD because she was a BRCA2 gene mutation carrier. She had cancer of the right breast at the age of 24 years and underwent modified radical mastectomy with axillary dissection and immediate latissimus dorsi flap reconstruction. Adjuvant chemoradiotherapy was given and she was prescribed tamoxifen for 5 years after the operation. Her paternal grandmother had breast cancer diagnosed at the age of 60 years. Genetic screening was performed and confirmed the patient to be a BRCA2 mutation carrier. Her elder brother and her father underwent the spot test and were found to carry a BRCA2 mutation but her younger sister was not affected. Laparoscopic ovarian cystectomy was performed for a hyperechoic cyst noted over the right ovary, which was confirmed to be an endometriotic cyst. After a multidisciplinary meeting of clinical geneticists, breast surgeons, oncologists, gynaecologists, psychologists, nurses, and academics in the ethics department, followed by psychological assessment and also counselling, she was offered in-vitro fertilisation (IVF) and PGD. Her IVF and PGD cycle was performed in 2011, using an antagonist protocol with letrozole co-treatment. Fifteen oocytes were retrieved and 12 were fertilised following intracytoplasmic sperm injection (ICSI). Blastomere biopsy was performed on eight good-quality cleaving embryos and five were confirmed to be free of the BRCA2 mutation. Two unaffected blastocysts were transferred, resulting in a singleton pregnancy and one unaffected blastocyst was cryopreserved. She delivered a baby boy at term by caesarean section. Postnatal cord blood confirmed that the baby boy did not carry the BRCA2 mutation.
 
Case 2
A 33-year-old woman was referred for PGD because she was a carrier of FAP truncating germline mutation APC c.532-8G>A (NG_008481:g93262G>A) with a strong family history of colonic cancer. She underwent colonoscopy surveillance and more than 100 small colonic polyps were found. She was advised to have a prophylactic colectomy but was firm in her request to get pregnant with PGD treatment before the definitive treatment while fully understanding the risks of malignancy because of the delay in definitive treatment. She underwent an IVF cycle in 2012. Of 19 oocytes retrieved, 16 underwent ICSI. Fifteen were fertilised and 15 embryos were available for blastomere biopsy on day 3. Five embryos were found without the FAP mutation and four good-quality blastocysts were cryopreserved due to the risk of ovarian hyperstimulation syndrome. She failed to conceive in two frozen embryo transfer (FET) cycles with one blastocyst replaced in each cycle. She subsequently underwent the last FET cycle with two blastocysts transferred, and a consequent singleton pregnancy. The pregnancy is 26 weeks’ gestation at the time of writing. The couple refused an invasive prenatal test and requested postnatal cord blood confirmation.
 
Case 3
A 37-year-old patient was referred from a clinical geneticist for PGD as her husband was diagnosed to have neurofibromatosis type I and was a carrier of c.4495 C to T (p.Gln1499X) mutation in NF1 gene. The mutation is a nonsense mutation that changes the codon to a STOP codon. This mutation has not been reported to be associated with NF1, but such mutation is expected to result in a truncated protein product and is therefore very likely to be pathogenic. The couple were counselled accordingly and were very keen for PGD treatment. The woman underwent the first IVF cycle but only four oocytes were retrieved. Two mature oocytes were injected but only one was fertilised. The couple requested cryopreservation of the only embryo on day 2. She underwent a second IVF cycle with five oocytes retrieved: four mature oocytes underwent ICSI and three were fertilised. The cryopreserved day-2 embryo from the first cycle was thawed and cultured for 24 hours. A total of four embryos were available for embryo biopsy on day 3 and three were found to lack the NF1 mutation. Two blastocysts were transferred with a resulting singleton pregnancy. One surplus blastocyst was cryopreserved. After detailed counselling, the couple requested amniocentesis to confirm the PGD diagnosis and amniocentesis will be arranged at 16 to 18 weeks’ gestation (at the time of writing the pregnancy is 14 weeks’ gestation).
 
Pre-preimplantation genetic diagnosis workup and preimplantation genetic diagnosis cycle
Case 1
The exact genomic deletion breakpoints on the BRCA2 gene were unknown when the patient first presented to us (the breakpoint was subsequently studied—c.7436_7805del [GeneBank U43746])1 and the DNA of the patient’s parents was unavailable. Therefore we tried to establish the haplotype around the BRCA2 gene with the sibling DNA of the non-carrier sister and carrier brother. Nonetheless, the patient shared no common haplotype with her non-carrier sister and had exactly the same haplotype as her carrier brother around the BRCA2 gene. Finally, the high-risk haplotype was delineated by haplotype analysis of single sperms from her carrier brother. A PGD protocol was established that involved whole-genome amplification,2 linkage analysis with intragenic single-nucleotide polymorphism markers (rs1801406 and rs1799955) and flanking micro-satellite markers D13S289, D13S1698, D13S1701 and D13S171, located within 2 Mb region flanking BRCA2 gene.
 
Case 2
Case 2 was a carrier of APC c.532-8G>A (NG_008481:g93262G>A). The mutation was directly determined by minisequencing with SNaPshot Multiplex Kit (Applied Biosystems, Foster City, US). Linkage analysis was performed by the haplotyping method3 on a panel of 8 to 10 informative/partially informative microsatellite markers located within a 2 Mb region flanking the APC gene. During the pre-PGD workup, neither sibling DNA nor offspring DNA was available to establish the high-risk haplotype, therefore high-risk haplotype was deduced from the genotype of embryos during PGD treatment cycles, by correlating the result of minisequencing and linkage analysis.
 
Case 3
The husband of case 3 was a carrier of mutation NF1c.4495C>T (NM_000267). Mutation was directly determined by minisequencing and linkage analysis was performed on six informative/partially informative markers located within 2 Mb region flanking NF1 gene. The high-risk haplotype was established by single-sperm haplotype analysis in the husband.
 
All PGD protocols were extensively validated against 40 single lymphocytes (20 maternal and 20 paternal) of the corresponding couples. During the PGD treatment cycle, all biopsied embryos resulted in a definitive diagnosis.
 
Discussion
The British Society of Gastroenterology recommends that all families with familial adenomatous polyposis (FAP) and Lynch syndrome should be screened in the context of a registry. A systematic review revealed that registration and screening resulted in a significant reduction in colorectal cancer incidence and mortality.4 With earlier detection of these cancer syndromes and a better surveillance system, patient survival is improved.5 As prenatal diagnosis is not a widely acceptable reproductive option, PGD to reduce the chance of having offspring with the same genetic predisposition to cancer is probably an attractive option after detailed counselling regarding the procedures and ethical concerns. It also avoids the need for termination. One recent study from the Netherlands showed that PGD is an acceptable choice for couples with hereditary breast and ovarian cancer (HBOC).6
 
In the first decade after the first published paper on PGD, the technique was used as an alternative to prenatal diagnosis for severe lethal inherited diseases.7 Indications for PGD have since been extended to adult-onset diseases such as Huntington chorea and spinocerebellar ataxia as well as diseases with incomplete penetrance such as hereditary cancer syndromes. It has been challenged ethically and the use of PGD in these indications was controversial,8 although both ESHRE (European Society of Human Reproduction and Embryology9) and HFEA (Human Fertilisation & Embryology Authority; www.hfea.gov.uk) accepted these adult-onset and multifactorial diseases as indications for PGD.
 
Ovarian stimulation used for IVF treatment may trigger a high oestradiol concentration that may theoretically increase the risk of recurrence of hormone receptor–positive breast cancer. The use of letrozole to suppress the oestradiol concentration during IVF has been successful; some large case series have reported a comparable breast cancer recurrence rate in those who did and did not undergo IVF.10 11 A case-control study also revealed that even without letrozole, IVF treatment does not appear to increase the chance of breast cancer in BRCA gene mutation carriers.12
 
The use of prenatal invasive tests, such as chorionic villus sampling and amniocentesis, to confirm PGD results is controversial in adult-onset diseases with incomplete penetrance with the need for termination of pregnancy if the fetus is affected.13 In our case series, only one couple out of three accepted the use of invasive prenatal tests and the possibility of termination. A recent study revealed that a proportion of couples with HBOC refused prenatal testing even following natural conception.6 In view of the growing number of requests for postnatal cord blood confirmation for these adult-onset multifactorial diseases, its use in FAP families was discussed in our PGD ethics committee. This committee comprised reproductive medicine subspecialists, a clinical geneticist, maternal fetal medicine subspecialists, and laboratory in-charge. The pros and cons of postnatal testing were discussed. Since the risk of extra-colonic malignancies, such as hepatoblastoma, in FAP families is about 500 to 750 times that of the general population and the diagnosis is usually made before the age of 3 years,14 early diagnosis with postnatal confirmation of possible incorrect PGD diagnosis in order to have appropriate surveillance for these lethal malignancies would be considered worthwhile. A large case series also showed the importance of surveillance in paediatric FAP carriers of whom a considerable proportion with malignancies required treatment.15 The choice of using invasive prenatal procedures or postnatal cord blood testing to confirm a PGD diagnosis depends on discussion between the couple and the multidisciplinary team about the variable presentation of different syndromes.
 
Although PGD can be a practical and sound reproductive option for couples with hereditary cancer syndromes, awareness and knowledge of this technique is lacking even in prosperous developed countries such as the United States where PGD treatment is readily available.16 17 More information about PGD should be available to the general population, so that those who need this technique have access to this option and appropriate counselling.
 
Conclusion
The use of PGD is an alternative reproductive option for hereditary cancer syndromes. With good case selection, a multidisciplinary approach and support for the patient and family, this can be an acceptable option that takes account of the ethical concerns. More information about this technique should be provided to the general population and families with hereditary cancer syndromes.
 
References
1. Wang Q, Chow JF, Yeung WS, et al. Preimplantation genetic diagnosis using combined strategies on a breast cancer patient with a novel genomic deletion in BRCA2. J Assist Reprod Genet 2014;31:1719-26. Crossref
2. Chow JF, Yeung WS, Lau EY, et al. Singleton birth after preimplantation genetic diagnosis for Huntington disease using whole genome amplification. Fertil Steril 2009;92:828.e7-10.
3. Renwick P, Trussler J, Lashwood A, Braude P, Ogilvie CM. Preimplantation genetic haplotyping: 127 diagnostic cycles demonstrating a robust, efficient alternative to direct mutation testing on single cells. Reprod Biomed Online 2010;20:470-6. Crossref
4. Barrow P, Khan M, Lalloo F, Evans DG, Hill J. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br J Surg 2013;100:1719-31. Crossref
5. Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008;57:704-13. Crossref
6. Derks-Smeets IA, Gietel-Habets JJ, Tibben A, et al. Decision-making on preimplantation genetic diagnosis and prenatal diagnosis: a challenge for couples with hereditary breast and ovarian cancer. Hum Reprod 2014;29:1103-12. Crossref
7. Handyside AH, Kontogianni EH, Hardy K, Winston R. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature 1990;344:768-70. Crossref
8. De Wert G, Dondorp W, Shenfield F, et al. ESHRE task force on ethics and Law22: preimplantation genetic diagnosis. Hum Reprod 2014;29:1610-7. Crossref
9. Shenfield F, Pennings G, Devroey P, Sureau C, Tarlatzis B, Cohen J; ESHRE Ethics Task Force. Taskforce 5: preimplantation genetic diagnosis. Hum Reprod 2003;18:649-51. Crossref
10. Azim AA, Costantini-Ferrando M, Oktay K. Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study. J Clin Oncol 2008;26:2630-5. Crossref
11. Reddy J, Oktay K. Ovarian stimulation and fertility preservation with the use of aromatase inhibitors in women with breast cancer. Fertil Steril 2012;98:1363-9. Crossref
12. Kotsopoulos J, Librach CL, Lubinski J, et al. Infertility, treatment of infertility, and the risk of breast cancer among women with BRCA1 and BRCA2 mutations: a case-control study. Cancer Causes Control 2008;19:1111-9. Crossref
13. Moutou C, Gardes N, Nicod JC, Viville S. Strategies and outcomes of PGD of familial adenomatous polyposis. Mol Hum Reprod 2007;13:95-101. Crossref
14. Galiatsatos P, Foulkes WD. Familial adenomatous polyposis. Am J Gastroenterol 2006;101:385-98. Crossref
15. Munck A, Gargouri L, Alberti C, et al. Evaluation of guidelines for management of familial adenomatous polyposis in a multicenter pediatric cohort. J Pediatr Gastroenterol Nutr 2011;53:296-302. Crossref
16. Quinn GP, Vadaparampil ST, King LM, Miree CA, Friedman S. Conflict between values and technology: perceptions of preimplantation genetic diagnosis among women at increased risk for hereditary breast and ovarian cancer. Fam Cancer 2009;8:441-9. Crossref
17. Quinn GP, Vadaparampil ST, Miree CA, et al. High risk men’s perceptions of pre-implantation genetic diagnosis for hereditary breast and ovarian cancer. Hum Reprod 2010;25:2543-50. Crossref

A rare but serious complication of continuous ambulatory peritoneal dialysis: delayed perforation of the colon by the Tenckhoff catheter

DOI: 10.12809/hkmj144419
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
A rare but serious complication of continuous ambulatory peritoneal dialysis: delayed perforation of the colon by the Tenckhoff catheter
PY Chu, FRCR; KL Siu, FRCR
Department of Diagnostic Radiology, Tuen Mun Hospital, Tuen Mun, Hong Kong
 
Corresponding author: Dr PY Chu (idleadam@hotmail.com)
 
 Full paper in PDF
 
Case report
A 68-year-old male had end-stage renal failure due to diabetes mellitus. He underwent Tenckhoff catheter insertion in 2013 for continuous ambulatory peritoneal dialysis (CAPD). The catheter was flushed regularly once a week and was functional in the first 2 months following insertion.
 
The catheter became blocked 2 months following insertion after an episode of CAPD peritonitis. Peritoneal dialysate showed scanty growth of Stenotrophomonas (Xanthomonas) maltophilia. Kidney, ureter, and bladder X-ray (KUB) was ordered to identify catheter tip position that was subsequently revealed to be in the central part of the pelvic cavity (Fig 1a). The cause of blockage was suspected to be omental wrap. Omentectomy was planned and the Tenckhoff catheter was left in situ; CAPD peritonitis was successfully treated with antibiotics and the patient was discharged. The peritoneal membrane was rested for 2 weeks and the patient maintained on temporary twice-weekly haemodialysis.
 

Figure 1. (a) Initial kidney, ureter, bladder X-ray showing the Tenckhoff catheter in the central pelvic cavity (arrow), with coiling of catheter tip; (b) abdominal X-ray 5 months after insertion demonstrating inferior migration of the catheter tip with loss of tip coiling (arrow); (c) pelvic X-ray a few days after (b) showing the Tenckhoff catheter passing out through anus (arrow); (d) contrast-enhanced computed tomography of abdomen and pelvis showing Tenckhoff catheter perforation through the sigmoid colon (arrow)
 
The patient was admitted to Tuen Mun Hospital again in early 2014 because of fall. Computed tomographic (CT) brain revealed a significant left acute subdural haemorrhage. Urgent craniotomy with clot evacuation was performed. At that time, abdominal X-ray demonstrated inferior migration of the catheter tip with loss of coiling of the distal tip (Fig 1b). A few days later, the tip of Tenckhoff catheter was noticed in the anus of the patient. Follow-up KUB confirmed the clinical finding (Fig 1c).
 
The patient had no symptoms or signs of acute peritonitis. Contrast-enhanced CT abdomen and pelvis confirmed perforation of the Tenckhoff catheter through the sigmoid colon with the tip in the anus (Fig 1d).
 
The contrast-enhanced CT demonstrated Tenckhoff catheter perforation through the sigmoid colon (Fig 2a) with soft-tissue fibrosis around the catheter at the site of the perforation (Fig 2b). There was no ascites or inflammatory fluid collection. Contrast enema showed no evidence of contrast extravasation.
 

Figure 2. Contrast-enhanced computed tomographic abdomen and pelvis
(a) Tenckhoff catheter perforation through the sigmoid colon (arrow), and (b) soft-tissue fibrosis (arrow) around the catheter at the site of the perforation are shown
 
The patient became chair-bound after the head injury. It was decided not to remove or reposition the Tenckhoff catheter or perform omentectomy. The rectal side of the catheter was cut short.
 
Discussion
The pathogenesis of late perforation of the bowel has been proposed to involve intimate contact between the peritoneal catheter and the intestinal wall. The continuous pressure causes local ischaemia, eventually leading to erosion, laceration, and frank perforation.1 Lack of fluid in the peritoneal space after cessation of CAPD predisposes to pressure-induced necrosis because of loss of the fluid cushion.2 3 In our patient, perforation was unlikely when the catheter was in daily use because it did not come into continuous close contact with the bowel for any long period of time.4
 
In most previous studies, delayed perforation of the bowel was associated with acute peritonitis.1 3 5 6 Kagan and Bar-Khayim1 reviewed the publications from 1980 to 1995 and identified 24 cases of bowel perforation during the study period. All cases were associated with acute peritonitis, with 29% mortality and significant morbidity. The age of patients ranged from 22 to 80 years, with no gender predominance. The time to bowel perforation also ranged broadly from 0.5 to 96 months after initiation of dialysis. Sigmoid was the most common site of perforation, accounting for 14 of the 24 cases. Asymptomatic delayed perforation of the bowel by Tenckhoff catheter was rarely reported.7 8
 
Our patient had acute peritonitis in late 2013. The KUB showed normal position of Tenckhoff catheter (Fig 1a) . Since the Tenckhoff catheter was not functioning, omental wrap was suspected.
 
Later X-rays revealed progressive inferior migration of the catheter and loss of coiling of the catheter tip, suggesting perforation of the bowel (Figs 1b and 1c). The CT abdomen and pelvis confirmed perforation of the sigmoid by the Tenckhoff catheter in addition to soft-tissue fibrosis around the catheter tip (Figs 1d and 2).
 
In our case, in addition to the lack of peritoneal dialysis fluid, there were probably peritoneal adhesions arising from previous peritonitis that resulted in decreased bowel mobility. This in turn created a predisposition to impingement of bowel loops by the Tenckhoff catheter that subsequently led to pressure erosion and perforation.
 
The patient had no clinical or radiological evidence of peritonitis, possibly due to plugging of the bowel perforation site by the catheter and later sealed off by inflammatory adhesion and fibrosis. Thus, there was no leakage of faecal material from the sigmoid into the peritoneal cavity to incite inflammation and consequent faecal peritonitis. Occasionally the omentum can also surround and wall off focal inflammation to prevent extension of the inflammation to involve the rest of the peritoneal cavity, as may be seen in the formation of phlegmon or an abscess in ruptured acute peritonitis.
 
We present a rare but clinically important case of delayed perforation of the bowel by Tenckhoff catheter. According to this case report and several reported cases, regular flushing of the dialysis catheter and early removal if not in use (dysfunctional or not required) may help prevent this complication.
 
Declaration
No conflicts of interest were declared by the authors.
 
References
1. Kagan A, Bar-Khayim Y. Delayed decubitus perforation of the bowel is a sword of damocles in patients on peritoneal dialysis [Letter]. Nephron 1996;74:232-3. Crossref
2. Brady HR, Abraham G, Oreopoulos DG, et al. Bowel erosion due to a dormant peritoneal catheter in immunosuppressed renal transplant recipients. Perit Dial Int 1988;8:163-5.
3. Rambausek M, Zeier M, Weinreich T, Ritz E, Rau J, Pomer S. Bowel perforation with unused Tenckhoff catheters. Perit Dial Int 1989;9:82.
4. Parvin SD, Beaman M. Ileal erosion by the Tenckhoff catheter. Perit Dial Bull 1985;5:82.
5. Valles M, Cantarell C, Vila J, et al. Delayed perforation of the colon by a Tenckhoff catheter. Perit Dial Bull 1982;2:190.
6. Thibodeaux LC. Bowel perforation associated with continuous ambulatory peritoneal dialysis. Nephron 1995;70:265. Crossref
7. Saweirs WW, Casey J. Asymptomatic bowel perforation by a Tenckhoff catheter. Perit Dial Int 2005;25:195-6.
8. Balaji V, Digard N, Wise MH. Delayed bowel erosion due to functioning chronic ambulatory peritoneal dialysis catheter. Nephrol Dial Transplant 1996;11:368-9. Crossref

Primary gestational choriocarcinoma of the vagina: magnetic resonance imaging findings

Untitled Document
DOI: 10.12809/hkmj144362
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Primary gestational choriocarcinoma of the vagina: magnetic resonance imaging findings
T Wong, FRCR; Eliza PY Fung, FHKCR, FHKAM (Radiology); Alfred WT Yung, FHKCR, FHKAM (Radiology)
Department of Radiology, Princess Margaret Hospital, Laichikok, Hong Kong
 
Corresponding author: Dr T Wong (gloria_wong@live.com)
 
 Full paper in PDF
 
Case report
A 33-year-old nulligravid Filipino woman was admitted to the gynaecology ward of Princess Margaret Hospital in April 2014, with lower abdominal pain and recurrent retention of urine. Her pregnancy test was positive. Per-vaginal examination revealed a 4-cm firm, fixed, and wide-based vaginal mass with smooth wall over the upper anterior vagina. Bedside transabdominal ultrasonography confirmed a 4.5-cm solid mass in the anterior vagina and a 3.5-cm intramural fibroid over the left side of the uterus. No adnexal mass or free fluid was seen. Beta human chorionic gonadotropin (β-hCG) level was elevated to 270 743 IU/L (reference level, <5.0 IU/L for non-pregnant women), and repeated checking 3 days later was 253 957 IU/L. Alpha-fetoprotein, carcinoembryonic antigen, and Ca-125 were negative. A urologist was consulted and the patient underwent flexible cystoscopy that revealed indentation of the urinary bladder by an external mass. Mild erythematous changes were visualised at the right urinary bladder base. Biopsy revealed inflammation but no malignant cells.
 
Magnetic resonance imaging (MRI) of the pelvis revealed a 4.8 cm x 5.2 cm x 4 cm (craniocaudal x anteroposterior x transverse) mass located at the anterior aspect of the vagina. It was hypointense with a faint hyperintense rim on T1-weighted images (Fig 1a) and heterogeneously hyperintense with hypointense rim on T2-weighted images (Fig 1b). Peripheral enhancement was observed while the central part remained non-enhanced (Figs 1c and 1d). Part of the mass closely abutted the cervix and urinary bladder, where intervening fat planes could not be well-delineated. The urinary bladder wall was trabeculated. Dilated enhancing tortuous tubular structures were seen at the left adnexal region and numerous signal void foci were observed at the uterine wall. These were due to the presence of high-flow vasculatures related to tumour hypervascularity (Figs 1e to 1h). There was also an incidental finding of a predominantly T2 hypointense non-enhancing intramural fibroid at the posterior uterine fundus (Figs 1b and 1d). No ovarian mass was detected and no intra-uterine gestational sac or ectopic pregnancy.
 

Figure 1. Magnetic resonance imaging (MRI) scans
(a) A T1-weighted axial image showing approximately 4-cm hypointense mass with a slightly hyperintense rim in anterior aspect of the vagina (white arrow). (b) The mass (white arrow) is heterogeneously hyperintense with hypointense rim on T2-weighted images on sagittal plane. Note the incidental finding of a predominantly T2 hypointense fibroid at posterior uterine fundus (black arrow). (c) Axial and (d) sagittal post gadolinium contrast T1-weighted images showing enhancement of the peripheral zone and non-enhancing central zone (white arrows). The fibroid at posterior uterine fundus is again seen on sagittal image (black arrow). (e) Coronal, (f) sagittal, and (g) axial T2-weighted images showing dilated tortuous tubular structures at left adnexal region (white arrows) and numerous signal void foci at uterine wall (open arrows). These were suggestive of hypervascularity of the tumour with the presence of high-flow vasculatures. (h) A sagittal post gadolinium contrast T1-weighted image showing avid enhancement of the high-flow vasculatures (black arrows)
 
Later examination under anaesthesia revealed that the lower part of the vaginal lesion had ruptured. Excision of part of the vaginal lesion was performed. Tissue frozen section confirmed it to be choriocarcinoma with no other germ cell component. DNA polymorphism analysis was performed in a microsatellite analysis using six markers by extracting DNA from the microdissected tumour cells, then comparing it with normal DNA extracted from a peripheral blood sample. The result favoured gestational choriocarcinoma. In addition, chest X-ray revealed multiple ill-defined opacities in both lungs, measuring about 0.8 to 1.2 cm in size (Fig 2a).
 

Figure 2. Frontal chest radiographs of the patient
(a) Before treatment multiple ill-defined small opacities in both lungs (arrows) are shown, representing pulmonary metastases, and (b) radiograph after initiation of chemotherapy showing interval regression of the lesions
 
The patient was diagnosed with primary gestational choriocarcinoma of the vagina with lung metastases, and suspicious infiltration of the urinary bladder and cervix. She was further managed at the gynae-oncology specialist centre and given chemotherapy (etoposide, methotrexate, actinomycin, and cisplatinum). The β-hCG level dropped to 5604 IU/L with interval regression of the pulmonary nodules after initiation of chemotherapy (Fig 2b).
 
Discussion
Gestational trophoblastic disease comprises a wide spectrum of benign/premalignant to malignant conditions and includes hydatidiform mole (complete or partial), invasive mole, choriocarcinoma, and placental-site trophoblastic tumour. The incidence varies in different countries with the highest rate noted in South-East Asia. The cause of such variation is not well understood.1 Choriocarcinoma is a malignant form of gestational trophoblastic neoplasia, and generally arises in the uterine corpus of women of reproductive age with coincident or antecedent pregnancy. Primary extrauterine choriocarcinoma is rare and most reported cases have occurred in the uterine cervix.2 It is thought to arise along the path of migration of germ cells to gonads, or de-differentiated from another histological type.3 Our case was very unusual as it occurred in the vagina. The most common site of metastasis for choriocarcinoma is lung,1 and this also occurred in our patient.
 
The clinical diagnosis of extrauterine choriocarcinoma is extremely difficult as symptoms are often non-specific. Vaginal bleeding is the most common presenting symptom,2 but as such often mimics other more common disease entities. Primary extrauterine choriocarcinoma has been misdiagnosed as ectopic pregnancy,2 4 dysfunctional uterine haemorrhage,5 and cervical polyp.6 This can often lead to a delay in proper management. Since trophoblastic neoplasm such as choriocarcinoma produces an excessive amount of β-hCG, serial monitoring of its trend is very helpful for diagnosis and follow-up of treatment response. The mainstay of treatment is chemotherapy, as choriocarcinoma is highly chemosensitive.2 For a nulligravid woman as in this case, differentiation between gestational or non-gestational origin merely from a clinical history can be confusing. Differentiation by DNA polymorphism analysis is useful to guide the management as non-gestational choriocarcinoma is known to have a worse prognosis and to be resistant to single-agent chemotherapy.7
 
To the best of our knowledge, the imaging findings of primary extrauterine choriocarcinoma are rarely described in the literature, particularly that of vaginal origin. In the present case, MRI showed a hypointense vaginal tumour with hyperintense rim on T1-weighted images and heterogeneously hyperintense with hypointense rim on T2-weighted images. Rim enhancement was observed on T1-weight images after gadolinium contrast injection. The non-enhancing centre of the tumour could be due to tumour necrosis, commonly seen in choriocarcinoma. Poor delineation of fat planes with cervix and urinary bladder raised the suspicion of tumour involvement. Features of chronic bladder outlet obstruction were present as suggested by the trabeculated bladder outline. The signal void foci over the uterine wall and the high-flow vasculatures at the left adnexal region signified angiogenesis and neovascularisation, thus the hypervascular nature of the tumour.1 This is in accordance with the characteristic hypervascularity of choriocarcinoma.5 6 The multiple nodular opacities on chest X-ray most likely represented lung metastases, although histological confirmation was not performed. Interval shrinkage of these nodules was observed on chest X-ray following initiation of treatment.
 
In summary, imaging findings of a hypervascular tumour and exceedingly high levels of β-hCG are useful in making the diagnosis of extrauterine choriocarcinoma, and MRI is valuable in assessing extrauterine extension, tumour vascularity, and overall staging of the tumour.
 
References
1. Allen SD, Lim AK, Seckl MJ, Blunt DM, Mitchell AW. Radiology of gestational trophoblastic neoplasia. Clin Radiol 2006;61:301-13. Crossref
2. Kairi-Vassilatou E, Papakonstantinou K, Grapsa D, Kondi-Paphiti A, Hasiakos D. Primary gestational choriocarcinoma of the uterine cervix. Report of a case and review of the literature. Int J Gynecol Cancer 2007;17:921-5. Crossref
3. Dilek S, Pata O, Tok E, Polat A. Extraovarian nongestational choriocarcinoma in a postmenopausal woman. Int J Gynecol Cancer 2004;14:1033-5. Crossref
4. Gerson RF, Lee EY, Gorman E. Primary extrauterine ovarian choriocarcinoma mistaken for ectopic pregnancy: sonographic imaging findings. AJR Am J Roentgenol 2007;189:W280-3. Crossref
5. Maestá I, Michelin OC, Traiman P, Hokama P, Rudge MV. Primary non-gestational choriocarcinoma of the uterine cervix: a case report. Gynecol Oncol 2005;98:146-50. Crossref
6. Yahata T, Kodama S, Kase H, et al. Primary choriocarcinoma of the uterine cervix: clinical, MRI, and color Doppler ultrasonographic study. Gynecol Oncol 1997;64:274-8. Crossref
7. Koo HL, Choi J, Kim KR, Kim JH. Pure non-gestational choriocarcinoma of the ovary diagnosed by DNA polymorphism analysis. Pathol Int 2006;56:613-6. Crossref

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