Click here to watch a video of showing the treatment outcome of a patient with refractory tardive dystonia by pallidal deep brain stimulation

Tardive dystonia (TD) is an iatrogenic extrapyramidal movement disorder caused by the use of dopamine receptor antagonists (DRAs). Antipsychotic medications, especially belonging to the first-generation class, are typically responsible for the condition.1 The reported prevalence of this adverse drug reaction among adults varies from 1% to 2% and only 10% of patients recover after medication termination.2 The latency of onset could range from several days to 20 years.3

Initial management strategies include withdrawal of the offending antipsychotic, switching to a second-generation antipsychotic such as clozapine, and suppressive therapies such as benzodiazepines or tetrabenazine, but none has demonstrable efficacy.3 In recent years deep brain stimulation (DBS) of the globus pallidus interna (GPi) has proven to be effective for secondary dystonias such as TD.4 5 6 7 We report our experience with using DBS for treating three young ethnic Chinese patients with severe TD refractory to pharmacological management.

Three paranoid schizophrenia patients were referred by psychiatrists for TD satisfying the proposed diagnostic criteria by Adityanjee et al.2 All three patients were managed by the Movement Disorder Group, Division of Neurosurgery, Department of Surgery and Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong. Despite withdrawal of the antipsychotic responsible for the condition, and switching to second-generation medication, they all experienced progressive TD with severe disability. Their clinical details are outlined in Table 1. Investigations excluding other movement disorders included serum levels of ceruloplasmin, copper, thyroid-stimulating hormone, thyroxine as well as syphilis, and antinuclear antibody titres were either undetected or within normal limits. Magnetic resonance imaging of the brain was also unremarkable. For objective clinical evaluation video filming, the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Global Dystonia Rating Scale (GDS) scores were documented before the procedure, at 1 week and 3 months postoperatively.8 9 Quality of life (QoL) assessments were performed for two of the patients, preoperatively and 3 months postoperatively, using the Chinese-version validated EuroQoL-5 dimensions (EQ-5D) instrument.10 This instrument serves as a basis for comparing health outcomes using a basic ‘common core’ of health-related QoL characteristics. The dimensions covered were mobility, self-care, usual activities, pain/discomfort, and anxiety or depression.11 After targeted questioning of these five domains, the patient was required to report on a visual analogue scale (VAS) from a score of zero (worst imaginable health state) to 100 (best imaginable health state).

We performed frame-based stereotaxy using the Leksell coordinate frame and multipurpose stereotactic arc system (Elekta AB, Stockholm, Sweden). The target was set at the ventroposterior part of GPi. The target coordinates were 19 mm lateral to the inter-commissural line (from the anterior commissure to the posterior commissure [AC-PC line]), 2 mm anterior to the mid-commissural point, and 4 mm inferior to the AC-PC line. The trajectory on the coronal view was 0 degree from the mid-sagittal plane. On sagittal view, it was 60 degrees from the AC-PC line.

The operation was performed under local anaesthesia for patients 1 and 2 in December 2004 and March 2009, respectively. Patient 3 was operated on under total intravenous general anaesthesia in April 2011 because of uncontrolled and vigorous trunk and limb movement. For patient 3, propofol was stopped 10 minutes before commencing microelectrode recording (MER). In all patients, MER was successfully performed and bilateral pallidal discharges were recorded.

For patients 1 and 2, visual-evoked MERs were registered at the target point by shining a light source in their eyes. If no capsular responses were evoked during macrostimulation below a threshold of 4 mA (0.1 ms PW, 130 Hz), a permanent quadripolar electrode (Medtronic 3387; Medtronic, Minneapolis [MN], US) was implanted bilaterally. During the same operative sitting, a pulse generator (Kinetra; Medtronic, Minneapolis [MN], US) was connected and implanted subcutaneously in the left infraclavicular region. A postoperative computed tomographic scan verified the final DBS electrode positions.

Patients’ mean age was 41 years, ranging from 28 to 49 years with a mean duration of antipsychotic exposure of 3.7 years. Patients 2 and 3 received first-generation antipsychotics and patient 1 was administered second-generation medication. Preoperatively, all patients required either assisted living or was homebound. The craniospinal regions were the most seriously affected regions and all demonstrated opisthotonus and retrocollis. Chronic rhythmic neck hyperextension movements resulted in premature cervical spondylosis, and patients 1 and 3 required nasogastric tube feeding. At the time of surgery, all were unable to walk independently. The mean preoperative BFMDRS score was 61, ranging from 44 to 80, and mean GDS score was 47, ranging from 40 to 52. There were no treatment-related complications and the procedure was well tolerated. As expected, there was no minimal response before stimulation but after pulse generator activation, marked amelioration of dystonic symptoms was observed. The stimulation settings were set at monopolar mode (anodal case and cathodal target contact) and are presented in Table 2. Notable improvement was found in patients 2 and 3 within the first week. In that week, the mean BFMDRS score decreased by over 30%. By 3 months, all patients reached a stable state with a mean of 77% and 66% improvement in the BFMDRS and the GDS scores, respectively. Patients 1 and 3 overcame dysphagia to resume oral dietary intake and all patients were able to perform basic activities of daily living without assistance. No psychiatric side-effects were detected. Patients 2 and 3 experienced an improvement in QoL as reflected by a mean increase in the EQ-5D VAS score by 86% (Table 2).

Tardive dystonia is an iatrogenic complication belonging to a group of DRA-induced movement disorders known as the tardive syndromes. Although it may co-exist with tardive dyskinesia, TD is a distinct condition with different epidemiology, clinical features, prognosis, and treatment outcome.3 Literature shows a higher prevalence of TD in men than in women, with a male-to-female ratio of 2.4:1, and a mean age of onset of 36 years.2 The first-generation antipsychotics such as chlorpromazine, flupenthixol, and haloperidol are the strongest aetiological factors although second-generation medications and antiemetics such as metoclopramide have also been implicated.1 2 Although the mean duration of medication exposure varies from 3.3 to 6.6 years, there does not appear to be a minimal ‘safe’ period and symptom onset can occur as early as within days or weeks.1

In this report, all patients fulfilled Adityanjee et al’s diagnostic criteria2 for TD, namely, (1) chronic dystonia characterised by sustained, stereotypical involuntary muscle contractions or posture; (2) dystonia developing during or within 2 months’ discontinuation of treatment with DRAs; (3) other secondary dystonias adequately ruled out, and (4) a negative family history for dystonia. The onset of symptoms is insidious initially, involving one body region and, typically, progressing to segmental, ie craniocervical, or generalised dystonia. Torticollis or retrocollis is characteristic of TD and chronic repetitive movements could result in spondylotic myelopathy or even fractures.12 Truncal involvement manifests as opisthotonus and, in the severest of cases, patients could become bed-bound, reduced to a state of dependency.2 In contrast to classic orobuccolingual tardive dyskinesia, TD is largely irreversible with 90% of patients failing to achieve remission at a mean follow-up of 6.6 years.13

The limitations of medical treatment reflect incomplete understanding of the complex pathophysiology of TD. Multiple theories have been proposed of which the most prominent describe postsynaptic dopamine receptor hypersensitivity, degeneration of striatal cholinergic neurons, and gamma-amino-butyric acid–containing neurons.13 In contrast, the success of pallidal DBS in the treatment of primary dystonias led to its adoption for secondary dystonias such as TD.5 6 7 14 15 In this series we demonstrate a significant beneficial effect for medically refractory TD where rapid remarkable improvements in motor symptoms were observed within days without exacerbation of psychiatric symptoms. Our results are in agreement with other DBS outcome trials for TD. A systematic review of 17 studies involving 50 TD patients concluded that pallidal stimulation led to a mean improvement in BFMDRS scores by 77.5% (95% confidence interval, 71.4%-83.3%).4 The motor benefits are sustainable with a documented duration of 41 months (range, 18-80 months).5 7 16 Long-term responses for 8 to 10 years have also been reported.6 17 Although most data were from case studies or small trials, our experience supports DBS as an effective and safe surgical treatment modality that can considerably improve QoL.

Involuntary dystonic movement imposes unique technical difficulties not only for obtaining preoperative brain scans of acceptable quality, but also for performing the actual surgery. Sedation or general anaesthesia may be needed for such procedures as was needed in our patient 3. Furthermore, correct choice of anaesthetic drug is critical for successful MER. For example, propofol was found to affect the recording quality of the subthalamic nucleus of Parkinson’s disease patients.18 To overcome this interference, lower doses of propofol were used; these proved to be equally feasible to perform MER under general anaesthesia.19 20 Due to the relatively rapid offset action of intravenous propofol, after 10 minutes of cessation, we were able to observe the characteristic mean discharge frequencies of 20 to 40 Hz at the GPi target. The discharge pattern qualities were similar to those of the other two patients for whom the procedure was performed under local anaesthesia. Our experience demonstrates that in severely dystonic patients, total intravenous general anaesthesia with propofol can produce comparable clinical outcomes.

In 2014, patient 1 has received DBS for 10 years. In that period, she was capable of performing daily activities at home without assistance and was considered to have dystonia remission. However, when the pulse generator battery approached its end-of-life state, 2 years after implantation, segmental dystonia reappeared over the neck and hand regions. Her BFMDRS score rapidly rose from 0 to 23 within a week. The symptoms were relieved after battery replacement. The high voltage and pulse width requirements in GPi stimulation for TD can considerably shorten battery longevity (Kinetra; Medtronic) to an average of 2 years. The introduction of a non-invasive transcutaneous rechargeable battery system (Activa; Medtronic, Minneapolis [MN], US) with a 9-year life span is an improved solution to frequent replacements. Not only is it more cost-effective in terms of overall battery costs, but also reduces the number of surgical procedures. All three patients are currently implanted with this new device. The daily recharging process was convenient and non-disruptive, and the pulse generator performance was as effective as the non-rechargeable counterparts. With these encouraging results, we have continued to provide DBS as treatment for patients with refractory TD. Two more cases were treated in 2013 and 2014, respectively, with results as good as those in the three cases reported here.

Medically refractory TD is a disabling and essentially irreversible condition that can be successfully managed by pallidal DBS. There is a need to conduct multicentre trials to reliably assess and define appropriate selection criteria for DBS as a new therapeutic option. In our series, response to stimulation can be observed as soon as within 1 week. Our patients experienced remarkable alleviation of dystonia symptoms at 3 months enabling them to return to performing daily activities without assistance, with no additional psychiatric side-effects. On clinical follow-up, the effect was well maintained for a period of 3 to 10 years.

The Oriental Daily News Charitable Fund, Oriental Press Group Limited subsidised the purchase of the implantable hardware devices.

No conflicts of interests were declared by authors.

1. Burke RE, Fahn S, Jankovic J, et al. Tardive dystonia and inappropriate use of neuroleptic drugs. Lancet 1982;1:1299. CrossRef

2. Adityanjee, Aderibigbe YA, Jampala VC, Mathews T. The current status of tardive dystonia. Biol Psychiatry 1999;45:715-30. CrossRef

3. Kiriakakis V, Bhatia KP, Quinn NP, Marsden CD. The natural history of tardive dystonia. A long-term follow-up study of 107 cases. Brain 1998;121:2053-66. CrossRef

4. Mentzel CL, Tenback DE, Tijssen MA, Visser-Vandewalle VE, van Harten PN. Efficacy and safety of deep brain stimulation in patients with medication-induced tardive dyskinesia and/or dystonia: a systematic review. J Clin Psychiatry 2012;73:1434-8. CrossRef

5. Trottenberg T, Volkmann J, Deuschl G, et al. Treatment of severe tardive dystonia with pallidal deep brain stimulation. Neurology 2005;64:344-6. CrossRef

6. Chang EF, Schrock LE, Starr PA, Ostrem JL. Long-term benefit sustained after bilateral pallidal deep brain stimulation in patients with refractory tardive dystonia. Stereotact Funct Neurosurg 2010;88:304-10. CrossRef

7. Gruber D, Trottenberg T, Kivi A, et al. Long-term effects of pallidal deep brain stimulation in tardive dystonia. Neurology 2009;73:53-8. CrossRef

8. Burke RE, Fahn S, Marsden CD, Bressman SB, Moskowitz C, Friedman J. Validity and reliability of a rating scale for the primary torsion dystonias. Neurology 1985;35:73-7. CrossRef

9. Comella CL, Leurgans S, Wuu J, Stebbins GT, Chmura T; Dystonia Study Group. Rating scales for dystonia: a multicenter assessment. Mov Disord 2003;18:303-12. CrossRef

10. Luo N, Chew LH, Fong KY, et al. Do English and Chinese EQ-5D versions demonstrate measurement equivalence? An exploratory study. Health Qual Life Outcomes 2003;1:7. CrossRef

11. Pinto Prades JL. A European measure of health: the EuroQol [in Spanish]. Rev Enferm 1993;16:13-6.

12. Konrad C, Vollmer-Haase J, Gaubitz M, Nabavi DG, Reilmann R, Knecht S. Fracture of the odontoid process complicating tardive dystonia. Mov Disord 2004;19:983-5. CrossRef

13. Margolese HC, Chouinard G, Kolivakis TT, Beauclair L, Miller R. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 1: pathophysiology and mechanisms of induction. Can J Psychiatry 2005;50:541-7.

14. Kupsch A, Benecke R, Müller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006;355:1978-90. CrossRef

15. Vidailhet M, Jutras MF, Roze E, Grabli D. Deep brain stimulation for dystonia. Handb Clin Neurol 2013;116:167-87. CrossRef

16. Sako W, Goto S, Shimazu H, et al. Bilateral deep brain stimulation of the globus pallidus internus in tardive dystonia. Mov Disord 2008;23:1929-31. CrossRef

17. Boulogne S, Danaila T, Polo G, Broussolle E, Thobois S. Relapse of tardive dystonia after globus pallidus deep-brain stimulation discontinuation. J Neurol 2014;261:1636-7. CrossRef

18. Raz A, Eimerl D, Zaidel A, Bergman H, Israel Z. Propofol decreases neuronal population spiking activity in the subthalamic nucleus of Parkinsonian patients. Anesth Analg 2010;111:1285-9. CrossRef

19. Pinsker MO, Volkmann J, Falk D, et al. Deep brain stimulation of the internal globus pallidus in dystonia: target localisation under general anaesthesia. Acta Neurochir (Wien) 2009;151:751-8. CrossRef

20. Hertel F, Züchner M, Weimar I, et al. Implantation of electrodes for deep brain stimulation of the subthalamic nucleus in advanced Parkinson’s disease with the aid of intraoperative microrecording under general anesthesia. Neurosurgery 2006;59:E1138; discussion E1138.

A new outbreak of influenza caused by a new strain of H1N1, also known as ‘human swine influenza’ was first described in April 2009 in Mexico. This strain was different from the rest, in that it had a propensity to infect very healthy and young subjects, and also caused severe manifestations, such as acute respiratory distress, pneumonia, and even death. Approximately 80% of affected patients were younger than the age of 25 years.1

Since April 2009, there have been few reports of the neurological complications of human swine influenza.2 3 4 We report a case of severe human swine influenza causing acute demyelinating encephalomyelitis of the tumefactive form.

A 21-year-old woman with a history of diplegic cerebral palsy and epilepsy was hospitalised for breathlessness, cough, and fever for 3 days in January 2011. The initial chest X-ray was unremarkable, the white cell count (WCC) was elevated (13 x 10⁹ /L; reference range [RR], 3.4-9.6 x 10⁹ /L) and showed neutrophil predominance (8.9 x 10⁹ /L; RR, 1.27-6.2 x 10⁹ /L). An initial nasopharyngeal swab for influenza A and influenza B was negative. She was treated empirically with amoxicillin and clavulanic acid. She developed generalised tonic-clonic convulsion and desaturation 2 days later, for which she was intubated and received intensive care. Computed tomography of the brain showed multiple patchy hypodensities at the grey/white junction and white matter of frontal, parietal and temporal lobes on both sides, suspicious of underlying white matter disease.

Bedside bronchoscopy showed an inflamed mucosa, a small-sized airway with a distorted right bronchus, and purulent sputum. Bronchoalveolar lavage was positive for human swine influenza. The patient was given a course of oseltamivir, and later she received treatment with piperacillin and tazobactam.

One week later, the patient remained comatosed despite discontinuing sedation. Physical examination showed an absent deep pain response, wandering eyes with bilateral tonic pupils, and sluggish response to light. The doll’s eye reflex was absent, and the limbs were hypotonic and areflexic.

Autoimmune blood testing revealed nil abnormal. Her erythrocyte sedimentation rate and C-reactive protein level were elevated at 71 mm/h (RR, 5-15 mm/h) and 92 mg/L (RR, 0-10 mg/L), respectively. The serum antibody titre for influenza type A showed a significant increase from 10 to 640 over 10 days. Other virus and atypical pneumonia titres were also negative.

Electroencephalogram showed alpha coma pattern, and intermittent generalised slow waves at 1-2 Hz, 50-100 µV. Periodic lateralised epileptiform discharges at 1 Hz, 40-60 µV were evident over the right frontocentral region lasting for 4 to 5 seconds. Overall, the features were supportive of severe encephalopathy and cerebral dysfunction.

Lumbar puncture yielded a high opening pressure, and cerebrospinal fluid (CSF) protein was elevated at 4.26 g/L (RR, 0.1-0.4 g/L), glucose 2.2 mmol/L (RR, 2.2-3.9 mmol/L), WCC 0.3 x 10⁶ /L, red cell count 0.6 x 10⁶ /L, oligoclonal bands and Gram stain were negative. Three serial CSF specimens were sent for influenza A viral titres and showed an upward trend. Herpes simplex virus polymerase chain reaction (PCR), tuberculosis PCR, and Cryptococcus were negative.

Magnetic resonance imaging (MRI) of the brain, cervical and thoracic spines showed multiple T1-weighted hypointense, and T2-weighted hyperintense lesions up to 3 cm in diameter in the cerebral white matter bilaterally, the genu and splenium of the corpus callosum, external and internal capsules, midbrain, dorsal pons, and medulla oblongata. These lesions were contrast non-enhancing. The lesions involving the cerebral white matter and corpus callosum showed ring-like peripheral restricted diffusion.

Long segments of T1-weighted hypointense and T2-weighted hyperintense lesions were detected along the whole spinal cord, with the cervical cord being the most severely involved. The lesions at the cervical cord were continuous with that at the medulla oblongata (Fig). Overall, the features were in favour of acute disseminated encephalomyelitis (ADEM) with tumefactive demyelination.

This patient was treated with pulsed methylprednisolone, and later given two courses of intravenous immunoglobulin. However, there was no neurological improvement and the patient finally succumbed.

Since the first appearance of human swine influenza in April 2009 until now, there have been reports of neurological complications that mostly occurred in the paediatric population. A few were also reported in adults,2 3 4 but in them the presentations were not as florid and radiologically severe. We report this case of a 21-year-old, ambulatory and independent woman, with a history of cerebral palsy and epilepsy. She is one of the few adults to have ADEM as a complication of human swine influenza, and the first reported to have the tumefactive form.

Acute disseminated encephalomyelitis is an inflammatory demyelinating disorder of the central nervous system (CNS), which is thought to be due to a T-cell hypersensitivity reaction.5 6 It is one of the many syndromes that can develop after vaccination or a microbial infection, and has a 2- to 30-day latency period.3 7

The typical MRI appearance is of demyelinating lesions preferentially affecting white matter tracts in a periventricular distribution. Diagnostic difficulty occurs whenever these demyelinating lesions appear to be solitary, large, or tumefactive. Tumefactive lesions are usually defined as solitary lesions, typically greater than 2 cm in diameter and imaging characteristics resembling a tumour. They tend to be circumscribed and have little in the way of mass effect or vasogenic oedema, typically involving the supratentorium, and are centred within the white matter, although they may extend to involve the cortical grey matter. The exact pathogenesis is unknown. Approximately half of tumefactive demyelinating lesions show pathological contrast enhancement, usually in the form of rings. Commonly they occur in the form of an open ring, with the incomplete portions on the grey matter side of the lesion. The enhancing portion of the ring is believed to represent the leading edge of demyelination and thus favours the white matter side of the lesion. The central non-enhancing core represents a more chronic phase of the inflammatory process.8

One must distinguish between infectious and post-infectious encephalitis, as all causes of the former should be excluded before concluding to the latter diagnosis. This involves systemic screening for herpes CNS infections, viruses endemic to specific regions, and other common causes of infective encephalitis. Other mimickers of ADEM include CNS lymphomas, systemic diseases like systemic lupus erythematosus, CNS vasculitis, and vascular, toxic or infectious leukoencephalopathies.5 The time course of ADEM, however, is usually hyperacute or acute, whereas the others are usually more chronic. Multiple sclerosis (MS) is also a differential diagnosis, but less likely as in the CSF oligoclonal bands were not present and protein was elevated, and radiologically there were no plaques or lesions disseminated in time. Although in most cases, ADEM is seemingly diagnosed clinically by exclusion, the definitive diagnosis of ADEM is histopathological. Lesions are usually bilateral, although not symmetrical, and mainly they involve the cerebral white matter and brainstem. Occasionally the cerebellum and spinal cord are involved. Small veins and venules in the white matter are surrounded by lymphocytes, macrophages and occasional plasma cells, whereas arteries and arterioles are relatively free of inflammation. Perivascular haemorrhages, axonal fragmentation, inflammatory cells within the leptomeninges, and subpial demyelination in the brainstem and spinal cord may be present.7

For our patient, the diagnosis of tumefactive ADEM was mainly made on clinical grounds and typical radiological features. However, postmortem brain biopsy was not performed. We undertook reverse-transcription (RT) PCR analysis for swine flu on CSF samples, but all results came back negative. However, paired CSF and serum samples for influenza A viral titres showed an increasing trend. For patients with suspected neurological complications of swine flu, the sensitivity and specificity of RT PCR and viral titres specifically on CSF samples have not been studied in detail and warrant further investigation. Previous reports of children with influenza A encephalitis in the US showed that CSF PCR were all negative in the three cases.9

The treatment of ADEM is borrowed from that of MS. First-line treatment mainly involves corticosteroids, which have been found to shorten the duration of symptoms and halt disease progression. Patients are given 6-methylprednisolone 6 to 8 g over 6 to 8 days, followed by oral prednisolone at tapering doses, but the prognosis remains variable. Approximately 80% of patients have a full recovery and ADEM is classically a monophasic disease. However, relapses have been reported in 5% to 10% of cases. If relapses occur on more than one occasion, a diagnosis of MS rather than multiphasic disseminated encephalomyelitis is probably more likely. Around 30% of patients are non-responders to steroids. Half of these non-responders benefit from treatment with intravenous immunoglobulin. Some authors recommend the use of cyclophosphamide in patients at high risk for relapse, either during the first attack or when relapse occurs. However, overall results have been disappointing.10

Herein we report one of the few adult cases of severe tumefactive demyelinating ADEM complicating human swine influenza infection. As different strains of influenza continue to spread throughout the world and in different populations, it is expected that more neurological complications will be reported. As it seems that neurological complications are more common in young age-groups with existing neurological diseases, prophylactic vaccination should be considered for such patients. In addition, resorting to early antiviral and immunomodulating therapy should also be emphasised for this patient group.

1. Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team, Dawood FS, Jain S, Finelli L, et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;360:2605-15. CrossRef

2. Kimura E, Okamoto S, Uchida Y, et al. A reversible lesion of the corpus callosum splenium with adult influenza-associated encephalitis/encephalopathy: a case report. J Med Case Rep 2008;2:220. CrossRef

3. Athauda D, Andrews TC, Holmes PA, Howard RS. Multiphasic acute disseminated encephalomyelitis (ADEM) following influenza type A (swine specific H1N1). J Neurol 2012;259:775-8. CrossRef

4. Wang J, Duan S, Zhao J, Zhang L. Acute disseminated encephalomyelitis associated with Influenza A H1N1 infection. Neurol Sci 2011;32:907-9. CrossRef

5. Gupte G, Stonehouse M, Wassmer E, Coad NA, Whitehouse WP. Acute disseminated encephalomyelitis: a review of 18 cases in childhood. J Paediatr Child Health 2003;39:336-42. CrossRef

6. Ozkale Y, Erol I, Ozkale M, Demir S, Alehan F. Acute disseminated encephalomyelitis associated with influenza A H1N1 infection. Pediatr Neurol 2012;47:62-4. CrossRef

7. Love S. Demyelinating diseases. J Clin Pathol 2006;59:1151-9. CrossRef

8. Given CA 2nd, Stevens BS, Lee C. The MRI appearance of tumefactive demyelinating lesions. AJR Am J Roentgenol 2004;182:195-9. CrossRef

9. Centers for Disease Control and Prevention (CDC). Neurologic complications associated with novel influenza A (H1N1) virus infection in children—Dallas, Texas, May 2009. MMWR Morb Mortal Wkly Rep 2009;58:773-8.

10. Marchioni E, Tavazzi E, Minoli L, et al. Acute disseminated encephalomyelitis. Neurol Sci 2008;29 Suppl 2:S286-8. CrossRef

Chinese talisman is a religious handwriting or calligraphy which is believed to possess magical powers for expelling evils and avoiding misfortune. It is usually obtained from Daoism religious practitioners.1 Some people believe that consuming burnt Chinese talisman ashes dissolved in water is useful in curing diseases. Here we report a case of lead exposure after prolonged intake of ashes from burnt Chinese talismans.

The patient was a 41-year-old woman. She presented with progressive weakness of four limbs with signs of upper motor neuron disease (MND) since March 2012. Electromyogram findings were compatible with diffuse anterior horn cell disorder. Motor neuron disease was clinically diagnosed by the treating neurologist. Knowing that no curative option exists for MND, she started using Chinese talismans obtained from a religious practitioner in China (Fig). She was instructed to burn the Chinese talismans to ashes and ingest the ashes dissolved in water 3 times daily. She continued this practice for about 1 month, until she believed that it was not useful for her illness. She was then found to have elevated blood lead level (BLL) of 1.83 µmol/L or 38 µg/dL (reference level, <0.48 µmol/L or <10 µg/dL) during routine screening for treatable causes of neuropathy. Her blood mercury level was normal. Blood lead level rechecked 2 weeks later was 2.61 µmol/L (54 µg/dL). Other than the neurological symptoms, the patient had no other clinical features of lead poisoning such as elevated blood pressure, anaemia with basophilic stippling, or gastro-intestinal symptoms. She was subsequently referred to the poison centre for assessment of lead exposure.

Detailed enquiry did not point to any well-known source of lead exposure. She had been working as a cleansing worker in a food-processing factory until she became sick. She had never worked in any mining industry, metal refinery, glass factory, or battery factory. She did not have a history of gunshot wound, nor did she have exposure to lead paint or ceramic craft. Her husband had normal BLL. Abdominal X-ray did not reveal lead-containing foreign materials in the gastro-intestinal tract. She had used several health supplements including vitamin preparations and ginkgo biloba extract. The lead levels of these health supplements were found to be undetectable. Our suspicions were aroused when the patient reported that the Chinese talismans were supposed to be written with cinnabar (硃砂), a red mercuric sulfide containing ore. Substitution of cinnabar with another red mineral, minium (鉛丹, lead tetroxide), when used as Chinese medicine, has been reported.2 3 Analysis of the Chinese talisman by inductively coupled plasma mass spectrometry revealed a very high lead concentration of 17 342 µg/g, thus confirming the source of lead exposure.

Her BLL was 2.82 µmol/L (59 µg/dL) about 2 months after stopping the use of the Chinese talismans. Although her neurological presentation was not typical of lead neurotoxicity,4 there have been case reports of lead poisoning mimicking MND.5 6 Moreover, an animal study showed that anterior horn cells were sensitive to lead toxicity.7 Chelation therapy with succimer (dimercaptosuccinic acid [DMSA]) was started in view of these possibilities. A standard course of DMSA 10 mg/kg 3 times daily for 5 days, followed by 2 times daily for 14 days was given.8 Her BLL taken at 6 weeks after completion of DMSA course was 0.7 µmol/L (14 µg/dL). No improvement of limb weakness was observed in the patient 8 weeks after completion of DMSA course. Further courses of DMSA were judged unnecessary. The patient continued to have medical follow-up for MND.

This case illustrates a rare source of lead exposure related to the religious practice of consuming burnt Chinese talisman ashes dissolved in water to cure a disease. The list of common sources of lead exposure such as occupational, environmental and recreational ones, can be found in general medicine and toxicology textbooks.4 Uncommon and exotic sources reported in the literature usually involve traditional medicines, cosmetics, and ingestion of lead-containing foreign bodies (eg bullet, necklace, fishing sinker).9 10 11

The use of cinnabar has been described in Daoism alchemy and traditional Chinese medicine.12 13 Both lead tetroxide and cinnabar are red in colour with similar appearance, and substitution of cinnabar with lead tetroxide in Chinese medicine has been reported.3 The reason for the substitution is uncertain but it could be due to mixing up or related to the higher cost of cinnabar.2 The toxicity of lead tetroxide is known since ancient times in China. Lead poisoning related to the topical use of lead tetroxide in Chinese medicine for chronic ulcer has been reported.12

Before the era of molecular genetics, lead poisoning was believed to be one of the possible causes of MND.14 15 Nowadays, with the identification of different genes implicated in MND, it is believed that genetic causes account for a significant proportion of the cases.16 Neurological presentation of mild lead poisoning includes tiredness, headache, insomnia, memory loss, and lessened interest in leisure activities. In severe cases, coma, seizures, and peripheral neuropathy are possible.4 Lead-induced peripheral neuropathy is typically a pure motor disorder with features including footdrop and wristdrop.4 Severe form of lead-induced peripheral neuropathy has been reported in causing generalised weakness mimicking MND.5 6 Unlike MND, lead-induced peripheral neuropathy is associated with increased body burden of lead, a temporal sequence between lead exposure and progression of muscle weakness, clinical stabilisation or remission after removal from exposure, and systemic involvement with other features of lead poisoning such as anaemia and gastro-intestinal disturbance.17

Chelation therapy is usually not indicated in asymptomatic adults with BLL of <3.36 µmol/L (70 µg/dL).4 18 Nevertheless, there is no established action level in the presence of underlying MND. As lead-induced peripheral neuropathy is a possible reversible cause in this patient, chelation therapy was offered despite only a moderate increase in BLL. The lack of clinical improvement after cessation of exposure and normalisation of BLL made the diagnosis of lead-induced peripheral neuropathy unlikely in this patient.

Ingestion of burnt Chinese talisman is a possible source of lead exposure. This rare source of lead poisoning should be considered in a specific group of patients believing in this religious practice.

1. Wu YM. Talismans and spells. Available from: http://taiwanpedia.culture.tw/en/content?ID=2073. Accessed 18 Sep 2013.

2. Ban of cinnabar in Chinese medicine use in Taiwan [in Chinese]. Available from: http://www.twtcm.com.tw/law-content.php?id=9. Accessed 26 Jun 2014.

3. Lead and mercury content of proprietary Chinese medicine Babao powder [in Chinese]. Available from: http://www.consumers.org.tw/unit412.aspx?id=459. Accessed 11 Dec 2013.

4. Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE. Goldfrank’s toxicological emergencies, 9th ed. New York, NY: McGraw-Hill Medical; 2011: 1266-83.

5. Boothby JA, DeJesus PV, Rowland LP. Reversible forms of motor neuron disease. Lead “neuritis”. Arch Neurol 1974;31:18-23. CrossRef

6. Rubens O, Logina I, Kravale I, Eglîte M, Donaghy M. Peripheral neuropathy in chronic occupational inorganic lead exposure: a clinical and electrophysiological study. J Neurol Neurosurg Psychiatry 2001;71:200-4. CrossRef

7. Yokoyama K, Araki S, Akabayashi A, Kato T, Sakai T, Sato H. Alternation of glucose metabolism in the spinal cord of experimental lead poisoning rats: microdetermination of glucose utilization rate and distribution volume. Ind Health 2000;38:221-3. CrossRef

8. Rogan WJ, Dietrich KN, Ware JH, et al. The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead. N Engl J Med 2001;344:1421-6. CrossRef

9. Karri SK, Saper RB, Kales SN. Lead encephalopathy due to traditional medicines. Curr Drug Saf 2008;3:54-9. CrossRef

10. Levin R, Brown MJ, Kashtock ME, et al. Lead exposures in U.S. children, 2008: implications for prevention. Environ Health Perspect 2008;116:1285-93. CrossRef

11. St Clair WS, Benjamin J. Lead intoxication from ingestion of fishing sinkers: a case study and review of the literature. Clin Pediatr (Phila) 2008;47:66-70. CrossRef

12. Wu ML, Deng JF, Lin KP, Tsai WJ. Lead, mercury, and arsenic poisoning due to topical use of traditional Chinese medicines. Am J Med 2013;126:451-4. CrossRef

13. Hsiao CM. Dao of alchemy. Available from: http://taiwanpedia.culture.tw/en/content?ID=2081. Accessed 18 Sep 2013.

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18. Porru S, Alessio L. The use of chelating agents in occupational lead poisoning. Occup Med (Lond) 1996;46:41-8. CrossRef

Haemophagocytic lymphohistiocytosis (HLH) is characterised by fever, hepatosplenomegaly, central nervous system symptoms, cytopenia, coagulopathy, and lipid changes because of pathological immune activation, hypercytokinaemia and organ infiltration by phagocytosing histiocytes. Despite being an aggressive disease, effective treatment does exist. A treatment protocol was firstly designed in 19941 and later revised in 2004 by the HLH Study Group of the Histiocyte Society.2 Since the implementation of the treatment protocol of HLH 1994, its 5-year survival rate has improved from around 20% to more than 50%.1

Notably, HLH is comprised of two different conditions: familial/primary HLH (FHL) and secondary HLH (Table 1),3 with the former being an autosomal recessive condition. Five mutations that lead to FHL (Nos 1-5) have now been identified and the underlying genetic defect described in four. They are: PRF1, UNC13D, STX11, and STXBP2. For genetic defect in FHL1, the potential gene locus has been identified but not the specific genetic defect. The perforin gene (PRF1) mutation is the first genetic defect described in FHL (FHL2) and accounts for 20% to 50% of all affected FHL families identified in a Japanese study.4 Perforin is a soluble, pore-forming cytolytic protein synthesised in cytotoxic lymphocytes. This molecule plays a crucial role in regulating the access of granzymes to the cytosol of target cells, where they cleave key substrates to initiate apoptotic cell death. It is sequestered, along with granzyme serine proteases, in secretory cytotoxic granules. The PRF1 mutation results in reduction of perforin protein production and its cytotoxic function. This in turn impairs the control of lymphocyte homeostasis during immune responses and leads to hypercytokinaemia and continued expansion of populations of histiocytes and activated cytotoxic lymphocytes.5 Patients without an identifiable genetic cause but with a clear familial history of HLH are also classified as having FHL.

The differentiation of primary and secondary HLH is notoriously difficult. The only definite way is by genetic study to find the causative mutation. In Asia, the perforin gene mutation has mostly been identified in HLH patients in Japan.6 7 The case reported here is the first and the only HLH perforin gene mutation identified in Hong Kong.

The patient was the first child in a non-consanguineous family, with no history of previous unexplained deaths in the parents’ families. The child presented at 34 days of life with fever, hepatosplenomegaly, and pancytopenia in June 2009. The ferritin level was markedly increased to 18 513 (reference range [RR], 29-333) pmol/L and there was hypofibrinogenaemia with a level of 0.54 (RR, 1.85-3.83) g/L. Bone marrow examination showed features of haemophagocytosis. The diagnostic criteria for HLH were therefore met. Initial magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid examination were normal. Virology investigations including serology for Epstein-Barr virus (EBV), human herpesvirus 6, herpes simplex virus, and cytomegalovirus were all negative. The patient was treated according to HLH 2004 protocol with dexamethasone, cyclosporine A, and etoposide. Her clinical condition deteriorated with severe metabolic acidosis and she underwent haemodialysis. She experienced persistent neutropenia after the first dose of etoposide. Repeat bone marrow examinations showed markedly depressed granulopoiesis with residual haemophagocytic activity. Further doses of etoposide were therefore withheld while dexamethasone and cyclosporine A were continued. The first course of chemotherapy was stopped after the 11th week of treatment. However, the patient had a relapse of HLH 3 weeks after stopping chemotherapy (manifesting as fever and hepatosplenomegaly). Repeat bone marrow examination confirmed the presence of haemophagocytic activity, for which treatment with dexamethasone, etoposide, and cyclosporine A was restarted. She developed progressive metabolic acidosis8 that was once again treated by haemodialysis. Her condition then became stabilised.

Since this patient presented at early age and had a recurrence after cessation of chemotherapy, she was suspected to suffer from FHL, for which the ultimate treatment is haematopoietic stem cell transplant (HSCT). Search for a related or unrelated donor was started while the patient continued to receive chemotherapy.

While waiting for the HSCT, the patient developed tremors of the lower limbs, and bilateral ankle clonus, limb spasticity and intermittent squints (with no definite visual fixation) were noted. The developmental age regressed from 8 to 3 months, whilst brain MRI revealed diffuse parenchymal and leptomeningeal enhancing lesions suggestive of lymphohistiocytic infiltration. Cerebrospinal fluid also showed presence of pleocytosis and a lymphohistiocytic infiltrate. The patient was diagnosed to have central nervous system involvement by HLH. Three doses of intrathecal chemotherapy with methotrexate 6 mg and hydrocortisone 8 mg were given over a 10-day period.

The patient received an unrelated double-unit cord blood transplant after conditioning with oral busulphan (23 mg/kg), etoposide (30 mg/kg), cyclophosphamide (120 mg/kg), and thymoglobulin (7.5 mg/kg). She had a neutropenic fever on post-transplant day 12. Donor cell engraftment was achieved on post-transplant day 16. Regrettably, she developed veno-occlusive disease causing hyperbilirubinaemia, fluid retention, progressive hepatosplenomegaly, and respiratory distress. The maximum bilirubin level was 209 μmol/L. Despite intensive care unit treatment, intubation, and positive pressure ventilation, the patient developed respiratory failure and died on day 45 after cord blood transplant. The parents refused a full postmortem. A postmortem liver biopsy showed marked sinusoidal dilatation and congestion with atrophy of central hepatocytes. These features were compatible with sinusoidal obstruction due to veno-occlusive disease.

Genetic analysis of the patient and the parents’ blood was performed, with the coding region of the perforin gene in exons 2 and 3 amplification by a polymerase chain reaction. This revealed a heterozygous one base pair deletion (65 delC) in exon 2 in the patient and her father. There was another mutation 853-855 del AAG in exon 3 of patient and her mother. Collectively, the patient had compound heterozygous mutations of the perforin gene, namely 853-855 del AAG and 65delC.

Previously we reported our seven consecutive cases of HLH encountered from 1991 to 2006.9 Since then, there had been four other patients. Apart from showing haemophagocytosis in bone marrow or lymph node or both (Table 2), all eleven patients had fever, splenomegaly, and cytopenia in at least two cell lines. They also had markedly elevated ferritin levels with or without a raised fasting triglyceride level or hypofibrinogenaemia. The standard diagnostic criteria for HLH were met in all patients. Another teaching hospital in Hong Kong reported nine cases from 1991 to 2006.10 The overall survival of all 20 patients was 58%.

Interestingly, EBV infection was confirmed (by immunoglobulin M vs EBV or EBV DNA) in 11 (55%) of the 20 patients. The overall survival of EBV-related HLH was 55%. In eight patients, their secondary HLH was related to malignant histiocytosis, Still’s disease, and anaplastic large cell lymphoma. Two patients had X-linked lymphoproliferative disorders.10 They all had primary EBV infection and one had died. The other patient received a mismatched unrelated cord blood transplant and had a full recovery without recurrence.

Four patients in our unit were investigated for perforin gene mutations; only one whom had an abnormality (compound heterozygous mutations in the gene). Hence this patient is the first reported case in Hong Kong with a perforin gene mutation causing FHL.

In Asia, most perforin gene mutations of HLH patients have been reported from Japan. Ueda et al6 reported five of 14 HLH patients with perforin gene abnormalities. The 1090-1091delCT and 207delC mutations of the perforin gene were frequently present in Japanese HLH patients. Ueda et al4 also reported a collaborative study which did not show PRF1 gene mutations from Korea (n=4), Malaysia (n=3), Hong Kong (n=2), Australia (n=1), and Taiwan (n=1). Lee et al11 from Taiwan reported 26 HLH patients; none of whom had PRF1, Mun12-4, STX11, or SH2D1A mutations. There was only one case report of a heterozygous PRF1 mutation (Arg390stop) in a young Taiwanese girl who presented with a panniculitis-like T-cell lymphoma and subsequently endured fatal HLH.12

Among the 20 patients in Hong Kong, only one had a PRF1 gene mutation and two had X-linked lymphoproliferative disorders. However, the actual rate of genetic abnormalities in HLH patients remains unknown as not all patients with HLH had genetic testing. This is partially due to inconsistent protocols for genetic investigations in this disease entity and inadequate laboratory support for genetic tests. Clearly, revision of the local clinical and laboratory service protocol is warranted, and more importantly, an international multicentre collaboration to improve immunological assessment and genetic analysis of HLH patients should be promoted.

1. Henter JI, Arico M, Egeler RM, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. Med Pediatr Oncol 1997;28:342-7. CrossRef

2. Henter JI, Home A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31. CrossRef

3. Freeman HR, Ramanan AV. Review of haemophagocytic lymphohistiocytosis. Arch Dis Child 2011;96:688-93. CrossRef

4. Ueda I, Ghim T, Peng LH, et al. Proceedings of the 2nd Congress Asian Society for Pediatric Research; 2006 Dec 8-10; Yokohama, Japan.

5. Usmani GH, Woda BA, Newburger PE. Advances in understanding the pathogenesis of HLH. Br J Haematol 2013;161:609-22. CrossRef

6. Ueda I, Morimoto A, Inaba T, et al. Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan. Br J Haematol 2003;121:503-10. CrossRef

7. Ueda I, Kurokawa Y, Koike K, et al. Late-onset cases of familial hemophagocytic lymphohistiocytosis with missense perforin gene mutations. Am J Hematol 2007;82:427-32. CrossRef

8. Hui WF, Luk CW, Chan WK, Miu TY, Yuen HL. Severe lactic acidosis in an infant with haemophagocytic lymphohistiocytosis. Hong Kong J Paediatr (New Series) 2012;17:183-9.

9. Chan JS, Shing MM, Lee V, Li CK, Yuen P. Haemophagocytic lymphohistiocytosis in Hong Kong children. Hong Kong Med J 2008;14:308-13.

10. Ho MH, Cheuk DK, Lee TL, Ha SY, Lau YL. Haemophagocytic lymphohistiocytosis in Hong Kong children have a wider clinical spectrum. Hong Kong Med J 2008;14:503-4.

11. Lee WI, Chen SH, Hung IJ, et al. Clinical aspects, immunologic assessment, and genetic analysis in Taiwanese children with hemophagocytic lymphohistiocytosis. Pediatr Infect Dis J 2009;28:30-4. CrossRef

12. Chen RL, Hsu YH, Ueda I, et al. Cytophagic histiocytic panniculitis with fatal haemophagocytic lymphohistiocytosis in a paediatric patient with perforin gene mutation. J Clin Pathol 2007;60:1168-9. CrossRef

In September 2010, a 40-year-old man presented to a general practitioner with multiple skin tags and acanthosis nigricans. He was noted to have acromegalic features, including prominent supraorbital ridge, prognathism, and spade-like hands. He was referred to Tseung Kwan O Hospital medical out-patient clinic. In the interim, he visited a private endocrinologist. Investigations demonstrated that his serum insulin-like growth factor 1 (IGF-1) level was markedly elevated, being 719 (reference range, 101-267) ng/mL, and his serum growth hormone (GH) levels were not suppressed following an oral glucose tolerance test (OGTT) with a trough GH level of 9.9 ng/mL, which confirmed the diagnosis of acromegaly. Magnetic resonance imaging (MRI) of the pituitary gland (Fig 1a and b) revealed a bulky pituitary gland with a 1.3 x 1.0 x 1.1 cm (transverse x height x anteroposterior dimensions) subtle roundish area in the central anterior part of the gland. Transsphenoidal resection of the pituitary macroadenoma was planned. However, preoperative chest X-ray (Fig 2a) showed a large mass at the right lower zone. Thus, the operation was cancelled and computed tomography (CT) thorax showed a well-defined lobulated mass (Fig 2b and c), measuring 8.6 x 7.4 x 7.1 cm (lateral x anteroposterior x craniocaudal dimensions), at the basal region of the right lower lobe. Fluorodeoxyglucose-positron emission tomography (FDG-PET) of the whole body suggested that the mass was consistent with a primary lung cancer; there were no intrapulmonary or distant metastases. Right lower lobectomy was performed by a private cardiothoracic surgeon in October 2010. Histology confirmed the tumour to be an atypical bronchial carcinoid. He was first seen by us in November 2012. Evaluation showed that his IGF-1 level and GH response after having an OGTT had normalised. Repeat MRI of the pituitary gland 17 months after the lobectomy (Fig 1c and d) showed that the gland had decreased in size compared with its earlier size and the previously noted structural lesion had vanished. In light of the co-existence of bronchial carcinoid and a history of a pituitary lesion, multiple endocrine neoplasia type 1 (MEN-1) syndrome was suspected, but genetic testing could not detect any mutations. Although growth hormone–releasing hormone (GHRH) level was not available, the patient most likely suffered from a GHRH-secreting bronchial carcinoid as suggested by the presence of a histologically confirmed bronchial carcinoid tumour, and normalisation of serum IGF-1 level and normal GH response following an OGTT upon complete removal of his lung tumour.

Acromegaly is due to sustained and unregulated hypersecretion of GH. It develops insidiously and progresses slowly, and typically remains undiagnosed for about 10 years.1 More than 95% of cases are caused by autonomous secretion of GH from anterior pituitary tumours and result in clonal expansion of somatotrophs. Less than 1% are due to ectopic GHRH production, with bronchial carcinoids being the most common cause (70%) followed by pancreatic islet cell carcinoids.2

Since the majority of bronchial carcinoids arise in the proximal airways, patients usually present with pulmonary symptoms,3 including cough, shortness of breath, wheeze, haemoptysis, chest pain, or recurrent pneumonia in the same pulmonary segment or lobe (due to bronchial obstruction). Although many of the tumours express immunoreactive GHRH, most patients with bronchial carcinoid are not clinically acromegalic. The first case of a bronchial carcinoid causing acromegaly was reported in 1958.4 Despite the large size and central location of his tumour, our patient did not have any chest symptoms; instead he came to medical attention because of prominent acromegalic features.

The clinical manifestations of acromegaly in patients with the ectopic GHRH syndrome are indistinguishable from those of any GH-secreting pituitary adenoma.5 Similarly, regardless of the cause, serum GH and IGF-1 levels are invariably elevated and GH levels fail to suppress (&lt1 ng/mL) during OGTT in all forms of acromegaly.6 No dynamic tests are helpful in differentiating the causes.7 Among all, plasma GHRH is the most precise and cost-effective test for the diagnosis of ectopic GHRH causing acromegaly. Plasma GHRH levels are usually elevated in patients with peripheral GHRH-secreting tumours, and are normal or low in patients with pituitary acromegaly.8 Regrettably, before the operation plasma GHRH level was not checked in our patient as this test was not available in most of the local hospitals. The presence of positive staining for GHRH could also provide direct evidence of the diagnosis.

Bronchial carcinoids are usually picked up easily on chest X-rays and by CT thorax. Compared with chest X-rays, CT delineates the extent of the tumour and its location better as well as the presence of any mediastinal lymphadenopathy. In our patient, the bronchial carcinoid was visualised by FDG-PET. However, FDG-PET yields conflicting results when it comes to identifying bronchial carcinoids, probably because of their small size and hypometabolic nature. In a retrospective review of 16 patients with surgically resected bronchial carcinoids, preoperative PET detected only 12 (75%).9 The use of other PET tracers, such as 11C-L-DOPA and 11C-5-hydroxytryptophan, improves the sensitivity for imaging neuroendocrine tumours.10 Approximately 80% and 60% of typical and atypical bronchial carcinoids express somatostatin receptors by immunohistochemistry, respectively. They may also be imaged with octreoscan.11 However, specificity is limited because scintigraphy is positive in many other tumours, and not all carcinoid tumours that express somatostatin receptors by immunohistochemistry test positive with octreoscan.

Pituitary gland MRI is necessary to verify the presence and size of a pituitary lesion, even when the diagnosis of ectopic GHRH syndrome has been established. In contrast to patients with classical acromegaly, no pituitary tumour but an enlargement of the sella is detected in the majority of such patients.12 The first MRI of the pituitary gland in our patient suggested the presence of an anterior pituitary macroadenoma, which is unexpected in patients with GHRH-secreting bronchial carcinoid. Thus, three other issues need to be considered. First, the co-existing carcinoid tumour and possible pituitary adenoma alerted us to the possibility of MEN-1. Second, the bronchial carcinoid might have metastasised to the pituitary gland. Third, the acromegaly really was due to the pituitary tumour producing excessive amounts of GH, and that its auto-infarction leads to normalisation of IGF-1, a normal GH response after an OGTT and shrinkage of the tumour on subsequent MRI. The absence of an MEN-1 mutation and hyperparathyroidism, and the resolution of pituitary lesion after lobectomy make the first possibility unlikely. Although we did not have any histology from the pituitary, again, disappearance of the lesion after the lobectomy also makes the second possibility unlikely. Regarding the third possibility, it cannot be proved or disproved in the absence of a plasma GHRH level and tumour histology. Nevertheless, we have to follow the patient closely to obtain the final answer.

Surgical resection of the bronchial carcinoids offers the best chance of cure, the prognosis of following resection of a typical carcinoid is excellent, with reported 5-year survival rates of 87% to 100%. While for atypical carcinoid, 5-year survival of 30% to 95% has been reported.3 13 Chemotherapy and radiotherapy are generally not effective. For those with non-resectable, disseminated tumours; who refuse surgery; or who are unsuitable because of medical co-morbidities, long-acting somatostatin analogues provide an effective option to control symptoms, and according to some studies, may also slow tumour progression.14

Ectopic GHRH acromegaly is so rare that routine screening would have a very low yield. Instead, clinicians should bear this diagnosis in mind, and search for an extrapituitary source of GH excess in those with unexpected clinical features (eg breathlessness, wheeze, or facial flushing), absence of a pituitary tumour on imaging, and the presence of tumours known to be associated with extrapituitary acromegaly. Measurement of plasma GHRH is the most cost-effective means of arriving at a diagnosis, but is not widely available. Chest X-ray, CT thorax and abdomen could be performed, if plasma GHRH testing is not available. A correct diagnosis is important, as the primary treatment for extrapituitary acromegaly entails surgical removal of the underlying tumour. Long-acting somatostatin analogues might be used to control symptoms, if resection is incomplete or not feasible.

1. Cordero RA, Barkan AL. Current diagnosis of acromegaly. Rev Endo Metab Discord 2008;9:13-9. CrossRef

2. Sano T, Asa SL, Kovacs K. Growth hormone-releasing hormone-producing tumors: clinical, biochemical, and morphological manifestations. Endocr Rev 1988;9:357-73. CrossRef

3. Skuladottir H, Hirsch FR, Hansen HH, Olsen JH. Pulmonary neuroendocrine tumors: incidence and prognosis of histological subtypes. A population-based study in Denmark. Lung Cancer 2002;37:127-35. CrossRef

4. Atmann HW, Schutz W. Uber ein knochenhaltiges Bronchuskarzinoid [in German]. Beitr Pathol Anat 1958;120:455-73.

5. Agha A, Farrell L, Downey P, Keeling P, Leen E, Sreenan S. Acromegaly secondary to growth hormone releasing hormone secretion. Ir J Med Sci 2005;173:215-6. CrossRef

6. Bonadonna S, Doga M, Gola M, Mazziotti G, Giustina A. Diagnosis and treatment of acromegaly and its complications: consensus guidelines. J Endocrinol Invest 2008;28(11 Suppl International):43-7.

7. Giustina A, Schettino M, Bodini C, Doga M, Licini M, Giustina G. Effect of galanin on the growth hormone (GH) to GH-releasing hormone in acromegaly. Metabolism 1992;41:1291-4. CrossRef

8. Mayo KE. Molecular cloning and expression of a pituitary receptor for growth hormone-releasing hormone. Mol Endocrinol 1991;6:1734-44. CrossRef

9. Daniels CE, Lowe VJ, Aubry MC, Allen MS, Jett JR. The utility of fluorodeoxyglucose positron emission tomography in the evaluation of carcinoid tumors presenting as pulmonary nodules. Chest 2007;131:255-60. CrossRef

10. Orlefors H, Sundin A, Garske U, et al. Whole-body (11)C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and computed tomography. J Clin Endocrinol Metab 2005;90:3392-400. CrossRef

11. Granberg D, Sundin A, Janson ET, Oberg K, Skogseid B, Westlin JE. Octreoscan in patients with bronchial carcinoid tumours. Clin Endocrinol (Oxf) 2003;59:793-9. CrossRef

12. Losa M, Schopohl J, von Werder K. Ectopic secretion of growth hormone-releasing hormone in man. J Endocrinol Invest 1993;16:69-81. CrossRef

13. Asamura H, Kameya T, Matsuno Y, et al. Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol 2006;24:70-6. CrossRef

14. Drange MR, Melmed S. Long-acting lanreotide induces clinical and biochemical remission of acromegaly caused by disseminated growth hormone-releasing hormone-secreting carcinoid. J Clin Endocrinol Metab 1998;83:3104-9. CrossRef