In March 2011, a 47-year-old Chinese woman who enjoyed good past health presented to a local general out-patient clinic in Hong Kong with a 2-week history of a mildly painful cord-like structure stretching from the inferior part of the left breast to the umbilicus level (Fig). She had worked as a dishwasher 3 months prior to the appearance of the lesion, a job that required her to carry stacks of heavy dishes. There was no recent trauma or surgery of the breast and no family history of breast cancer. Physical examination revealed a 15-cm long by 0.5-cm wide erythematous subcutaneous cord-like lesion stretching from the inferior part of the left breast down along the anterolateral chest wall to the umbilicus level. The lesion was firm and mildly tender. It was adherent to the skin, but was slightly movable over the deeper tissues. Examination of the breasts showed no asymmetry or skin changes. Palpation of the right breast was normal. There was, however, mild lumpiness over the outer upper quadrant of the left breast although no definite breast lump found. The nipples were normal with no discharge. There were no palpable axillary or regional lymph nodes.

The patient was diagnosed with Mondor’s disease with involvement of the thoracoepigastric vein. The course of the disease was explained and the patient was advised to avoid repetitive strain of the chest wall. Paracetamol was prescribed for symptomatic relief. She was referred to the Surgical Specialist Outpatient Clinic (SOPC) for further evaluation of left breast lumpiness. The cord in this patient disappeared spontaneously after approximately 5 weeks. Clinical assessment at the SOPC in May 2011 did not identify any palpable breast lump. Routine mammogram was later performed in August 2012 and revealed a 2-cm ill-defined high-density speculated lesion in the outer-upper quadrant of the left breast. Supplementary ultrasonography was also performed and revealed an ill-defined irregular hypoechoic lesion measuring 0.7 x 0.6 x 1.65 cm. The patient was followed up in the SOPC 2 weeks later and the lesion was also clinically palpable. Core biopsy confirmed invasive ductal carcinoma. Left modified radical mastectomy was performed with metastatic invasive ductal carcinoma and axillary lymph node involvement confirmed (stage pT1cpN1). The patient was also treated with adjuvant chemotherapy.

Mondor’s disease is an uncommon clinical condition of thrombophlebitis of the subcutaneous veins of the anterolateral thoracoabdominal wall. The most commonly affected vessels are the thoracoepigastric, lateral thoracic, and superior epigastric veins.1 It is characterised by sudden onset of one or more subcutaneous palpable and visible cord(s) over the mammary area, chest wall, or epigastrium.

Mondor’s disease occurs most commonly in middle-aged patients, and is more common in women than in men (ratio 3:1).2 The involved subcutaneous veins will initially turn red and tender and subsequently become a painless and tough fibrous band. Pathologically, the first stage is due to infiltration of inflammatory cells resulting in obliterative thrombophlebitis of the affected veins, causing redness and tenderness. In the second stage, connective tissues proliferate in the vessels with consequent formation of the fibrous band.1 Recanalisation of the veins occurs later and the fibrous band will disappear within several weeks.3

It is thought to be a very uncommon disease although the true incidence is unknown as it is self-limiting and patients may not seek medical attention. The diagnosis can usually be made based on clinical history and typical physical findings. Biopsy is not essential.

The aetiology of Mondor’s disease is still unclear. In many cases it is idiopathic, although it has also been linked with recent breast surgery, local trauma, excessive physical activity with muscle strain, an inflammatory process, infections, and mammary pathology including mastitis or abscess.2 Association with breast cancer has also been reported. Catana et al4 studied 63 cases of Mondor’s disease of whom eight (12.7%) had associated breast cancer. The authors suggested that mammography should be performed in patients with Mondor’s disease even when physical examination was normal. A retrospective review in 2011 identified five cases of Mondor’s disease of the breast; none of which was associated with breast cancer.5 Nonetheless, the authors advised thorough evaluation of the breast to exclude an underlying breast cancer. In our patient, the correlation with an occult carcinoma of the breast could not be confirmed since there was a time delay between the presentation of Mondor’s disease and the diagnosis of breast carcinoma. Moreover, the patient’s recent strenuous job with repetitive straining of the chest wall muscle might have been a predisposing factor.

Since Mondor’s disease is self-limiting, symptomatic treatment is suggested. General advice includes rest, local application of heat, and better breast support. Oral non-steroidal anti-inflammatory drugs provide effective symptomatic relief.2

In summary, Mondor’s disease is a condition that is rarely encountered in primary care. Recognising this condition is important as it can avoid unnecessary investigations and referral for diagnosis. Although the association of underlying breast cancer with Mondor’s disease has not been confirmed, family physicians should be aware of the possibility and conduct a thorough evaluation including clinical examination and imaging of the breast to exclude its presence in patients diagnosed with Mondor’s disease.

1. Alvarez-Garrido H, Garrido-Ríos AA, Sanz-Muñoz C, Miranda-Romero A. Mondor’s disease. Clin Exp Dermatol 2009;34:753-6. Crossref

2. Mayor M, Burón I, de Mora JC, et al. Mondor’s disease. Int J Dermatol 2000;39:922-5. Crossref

3. Ichinose A, Fukunaga A, Terashi H, et al. Objective recognition of vascular lesions in Mondor’s disease by immunohistochemistry. J Eur Acad Dermatol Venereol 2008;22:168-73.

4. Catana S, Zurrida S, Veronesi P, Galimberti V, Bono A, Pluchinotta A. Mondor’s disease and breast cancer. Cancer 1992;69:2267-70. Crossref

5. Salemis NS, Merkouris S, Kimpouri K. Mondor’s disease of the breast. A retrospective review. Breast Dis 2011;33:103-7. Crossref

An 18-year-old girl was admitted to the Aga Khan Hospital, Pakistan in April 2014 with progressively worsening shortness of breath, orthopnoea, malaise, and low-grade fever for 3 years, and generalised body swelling for 6 months. She had no significant medical history or trauma.

On physical examination she was a medium-built girl with a heart rate of 120 beats/min, raised jugular venous pressure, and bilateral pedal pitting oedema. Chest auscultation revealed muffled heart sounds with bilateral basilar lung crepitations. The chest X-ray showed wide mediastinum with clear lung markings.

The computed tomographic (CT) scan showed a conglomerate undefined mass in the anterior, middle, and posterior mediastinum encasing the entire heart and great vessels with most marked extension in the retrocardiac area (Fig 1). The echo showed a large echo-dense mass compressing the heart with invasion into the left atrium (LA), obliterating most of the LA cavity.

Video-assisted thoracoscopic surgery was performed and the mass biopsied for histopathological examination. The histopathology showed fibrosis and chronic granulomatous inflammation with fungal hyphae on periodic acid–Schiff staining (Fig 2). The fungal cultures grew Aspergillus flavus.

A diagnosis of invasive mediastinal aspergillosis was made and the patient was started on oral itraconazole 100 mg twice a day. She showed a remarkable recovery in her symptomatology in the first 6 weeks of follow-up.

Aspergillosis refers to a variety of diseases caused by several species of Aspergillus organisms that are abundant in the environment and recognition of which has increased over recent years. There are three main categories in general: saprophytic aspergilloma, allergic bronchopulmonary aspergillosis, and invasive aspergillosis. The term ‘invasive aspergillosis’ is generally used to imply a histopathologically demonstrated invasion of tissues by these spores. It represents an important cause of morbidity and mortality, particularly among immunocompromised patients, occurring mostly in those with haematological malignancies who are undergoing chemotherapy and organ transplantation with concomitant immunosuppressive therapy. Extension of invasive pulmonary aspergillosis to the mediastinum has been reported only rarely.1 Our case is an immunocompetent patient with extensive mediastinal aspergillosis who presented with dyspnoea and symptoms of cardiac tamponade.

Invasive aspergillosis varies in severity and clinical course, depending upon the affected organ and the host. It is caused by many Aspergillus groups; however the most common is the Aspergillus fumigatus group. These groups live in soil, and derive nutrients from dead plants and animal matter. It has been further subdivided in recent years to angioinvasive and airway-invasive aspergillosis. Invasive aspergillosis is a major cause of morbidity and mortality in immunosuppressed patients.2

The form that Aspergillus lung disease takes is heavily dependent on the immune response of the patient.3 Indolent forms of locally invasive aspergillosis in the form of chronic necrotising or semi-invasive aspergillosis in apparently immunocompetent individuals are now recognised.

Invasive aspergillosis is a result of three factors: (1) suppression of the immune response due to debilitating disease or therapy; (2) glucocorticoid therapy with consequent diminished inflammatory response and disruption of the normal flora by antimicrobial agents4; and (3) local implantation of the fungus. The disease is well known in immunocompromised individuals but has also been described in healthy individuals. Patients with a compromised immune system, specifically with neutropenia, are susceptible to acute airway-invasive and angioinvasive aspergillosis in the absence of pre-existing lung pathology.

There have been a few cases described in which patients were immunocompetent. Orr et al5 documented two patients with normal host defences in whom postmortem examination revealed death due to disseminated aspergillosis (one patient had a history of coronary heart disease, the other acute renal failure following gangrenous appendicitis). Our patient was otherwise healthy as confirmed by the normal haematological studies.

The usual pathogenesis of invasive aspergillosis is by dissemination from a primary site, such as the lungs or the paranasal sinuses, or by contiguous spread.6 In this particular patient, the chest X-ray and CT scan of the chest were clear without a primary lesion. It was therefore postulated that inhalation of the fungal spores with immediate mediastinal invasion resulted in the implantation of a high concentration of aspergillus spores around the heart. This was followed by chronic infiltration around the pericardium and extension into the heart.

This idea was supported by the histopathology report of granulomatous tissue fibrosis, indicating a long-standing process, and in keeping with the history of worsening shortness of breath for 3 years. Our case showed an undefined mass in the anterior, middle, and posterior mediastinum extending into the LA. The effects of the mass could explain all of the patient’s symptoms, namely worsening dyspnoea and cardiac tamponade symptoms.

In conclusion, this case highlights that there is usually a long dormant period before the clinical manifestation of aspergillosis, clinically and radiologically the disease may be suggestive of a malignant process, and contamination with aspergillus should be considered from all possible aspects, particularly in healthy individuals.

1. Shakoor MT, Ayub S, Ayub Z, Mahmood F. Fulminant invasive aspergillosis of the mediastinum in an immunocompetent host: a case report. J Med Case Rep 2012;6:311. Crossref

2. Al-Alawi A, Ryan CF, Flint JD, Müller NL. Aspergillus-related lung disease. Can Respir J 2005;12:377-87. Crossref

3. Gefter WB. The spectrum of pulmonary aspergillosis. J Thorac Imaging 1992;7:56-74. Crossref

4. Mashimoto H, Suyama N, Araki J, et al. A case of mediastinitis and bilateral pyothorax, following acute epiglottitis with concurrent Aspergillus infection [in Japanese]. Kansenshogaku Zasshi 1992;66:648-52. Crossref

5. Orr DP, Myerowitz RL, Dubois PJ. Patho-radiologic correlation of invasive pulmonary aspergillosis in the compromised host. Cancer 1978;41:2028-39. Crossref

6. Hendrix WC, Arruda LK, Platts-Mills TA, Haworth CS, Jabour R, Ward GW Jr. Aspergillus epidural abscess and cord compression in a patient with aspergilloma and empyema. Survival and response to high dose systemic amphotericin therapy. Am Rev Respir Dis 1992;145:1483-6. Crossref

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.

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).

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.

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.

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 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.

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.

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

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

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.

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

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).

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.

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.

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.

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