A 54-year-old man with no history of trauma was admitted to the Prince of Wales Hospital for headache of progressive severity accompanied by dizziness in August 2012. He had consulted the emergency room 4 weeks earlier for neck pain, and had an unremarkable computed tomographic (CT) scan of the brain (CTB). Further enquiry revealed an orthostatic component within the headache (worse in upright position and relieved within minutes of assuming supine posture), while admission CTB revealed interval development of bilateral 5 mm–thick frontoparietal subacute subdural haematomas (SDHs) with disproportionate tightness of the basal cisterns.

Cerebral magnetic resonance imaging (MRI) additionally demonstrated compression of the midbrain, but no caudal herniation of the cerebellar tonsils beyond the foramen magnum. Contrast study showed diffuse pachymeningeal enhancement, venous sinus distension, and prominent pituitary gland. Spinal MRI was unremarkable and MRI cisternography/myelography was negative for cerebrospinal fluid (CSF) leakage.

The patient was advised complete bed rest with adequate hydration. His neurological status was intact all along. However, he reported persistent, severe bifrontal headache which, after 2 weeks, was accompanied with repeated projectile vomiting. Computed tomographic scan of the brain at this juncture revealed enlargement of the SDH with development of acute haemorrhage. Emergency evacuation of subdural blood was performed with development of low intracranial pressure during the evacuation process.

The patient’s symptoms improved markedly thereafter, and CTB reassessment showed minor residual blood. The patient was discharged in a neurosurgically stable condition, and currently remains asymptomatic.

Intracranial hypotension is traditionally attributed to leakage of CSF from a dural defect along the craniospinal axis, which can occur spontaneously, such as due to rupture of Tarlov cyst1 or dural weakness in connective tissue disorder.2 Intracranial hypotension can also be precipitated by direct trauma or iatrogenic causes such as a lumbar puncture. The commonest cause, however, is a spontaneous defect of the dura (spontaneous intracranial hypotension [SIH]), though a trivial traumatic event can be elicited retrospectively in around one third of such patients.3 4 The most common sites of leakage identified were at the cervicothoracic junction and thoracic region of the spinal canal.1 5 In the absence of a dural defect, a recent alternative hypothesis proposes increased CSF absorption from negative pressure gradient in the inferior vena cava.6 In both instances, CSF hypovolaemia is the main feature and primary cause of the related clinical and imaging findings.

Spontaneous intracranial hypotension is an increasingly diagnosed cause of headache, with an incidence of one in 50 000 individuals.7 The female-to-male incidence ratio of SIH is 2:1, with a peak incidence occurring around the age of 40 years.3 7

The typical clinical feature of SIH is orthostatic headache, which, according to the International Headache Society, should occur or worsen within 15 minutes in an upright posture together with at least one feature of meningeal irritation (neck stiffness, tinnitus, hypacusia, photophobia, nausea) in addition to imaging features of SIH.8 With chronicity, the postural component may become less prominent.3 Other clinical manifestations include disappearance of or improvement in the headache within 30 minutes after lying supine, and cranial nerve palsies related to traction from caudal displacement of the brainstem.9 Severe midbrain compression may result in nigral dopaminergic dysfunction and manifest as parkinsonism.9 Coma occurs from delayed decompression of brainstem descent.4

Subdural haematoma is a late finding and occurs in around 10% of patients with SIH,3 commonly seen in males and those older than 35 years.10

Computed tomography is the frontline imaging workup for headache. Typically, SIH is not considered unless patients present with non-traumatic SDH in the setting of a normal clotting profile. The proposed mechanism involves rupture of bridging veins in expanding subdural hygromas which, in turn, results from brain sagging due to CSF hypovolaemia.

On CT, SIH in the absence of SDH can be easily interpreted as being unremarkable. With high level of clinical suspicion, however, subtle imaging features may suggest the diagnosis. For instance, the initial CTB of our index patient showed paucity of CSF for his age (Fig 1). On follow-up CTB, the tightness of the basal cisterns appeared rather disproportionate to the small amount of SDH. Thus, it may be possible to detect CSF hypovolaemia on CT if these subtle findings are sought and the diagnosis is borne in mind.

The MRI findings of SIH are well-described in the literature. This preferred modality of imaging depicts characteristic features which may obviate the need for lumbar tap.4 Additionally, the cause or site of dural defect can be investigated.

The MRI appearances are mainly attributed to CSF hypovolaemia, or represent secondary reactive changes following the Monro-Kellie doctrine. Briefly, decrease in CSF volume prompts an increase in dural blood flow and causes venous engorgement. The latter, when prolonged, incites surrounding fibro-proliferation that in turn accounts for diffuse dural thickening and intense enhancement with gadolinium on MRI. Such explanation is confirmed by meningeal biopsy showing proliferation of fibroblasts without inflammation.11 12

The primary feature of brain sagging is a very specific MRI finding in SIH. It is a collaboration of features, including decreased dimension of the suprasellar cistern, bowing of optic chiasma, flattening of the pons against the clivus, effacement of the perimesencephalic cistern and hindbrain herniation (Fig 2a).11 12 A quantitative measurement of brain sagging has been described10 although the degree of descent may be underestimated since patients are scanned in the recumbent position.

Secondary and less-specific signs of SIH are more readily appreciated but represent a later stage of the disease. Findings of MRI in the brain classically show diffuse pachymeningeal thickening which has a sensitivity of up to 94% (Fig 2b).9 The venous distention sign may also be seen and is best appreciated in the mid-portion of the dominant transverse sinus12; on sagittal sections, the sinus, which normally adopts a concave or straight inferior border, bulges with a convex contour. Venous engorgement at the dura mater across the sella turcica could produce reactive hyperaemia and possible increase in size of the pituitary gland. In the spine, MRI findings mirror those of the brain with diffuse dural enhancement, engorgement of venous plexus and extrathecal CSF collection.3

Magnetic resonance imaging cisternography or myelography can be easily added to routine MRI examination. Using a heavy T2-weighted sequence with fat signal suppression, spinal fluid outside the craniospinal axis may be detected with equal or improved accuracy than CT myelography.5 Radiological improvement lags behind clinical recovery. Meningeal enhancement resolves considerably earlier than brain sagging.12 13

Computed tomography myelography and radionuclide cisternography are available locally but seldom performed. These are more invasive and time-consuming to perform, and entail intrathecal injection of contrast/radioisotope label, with fluoroscopic screening or serial imaging with gamma cameras to visualise extrathecal contrast/tracer activity.

Conservative management of SIH includes Trendelenburg positioning, aggressive hydration, caffeine intake and abdominal binder, and has been reported to be successful in most cases. In those patients with increased persistent headache or neurological deterioration, CTB should be immediately performed to rule out expanding SDH.

The timing of active surgical drainage is controversial. In a particular series, surgical drainage was advised in those with focal neurological deficits, decreased level of consciousness, or subdural collection of >1 cm.4 Most surgically managed patients show transient improvement but have high likelihood of re-accumulation of subdural fluid.13

A more active strategy that is gaining international acceptance is epidural blood patch (EBP), which aims at sealing off the spinal leak3 but appears to be useful in those without a definite dural defect.6 The treatment involves placing 10 to 20 mL of autologous blood in the epidural space at the thoracolumbar level. As the patient is put in Trendelenburg position, the blood patch distributes along the epidural space and clots at the site of leakage.

The overall success rate for headache improvement is 30% to 70% after the first EBP and 30% to 50% for the remainder with repeated EBP.10 Epidural blood patch has a success rate of 85% in reverting patients who were comatose due to SIH.13 Under fluoroscopic guidance, EBP may yield a high rate of pain relief and is preferred for those with altered anatomy or failure in the initial attempt.14 A novel technique of multisite EBP via continuous infusion has been described.15

The newest treatment approach developed at the Stanford University recommends emergency subdural clot evacuation in the absence of improvement in Trendelenburg positioning, presence of dilated pupils, and large SDH with mass effect. Otherwise, EBP is the treatment of choice.13

In those with initial improvement with EBP, studies have shown concomitant spontaneous resolution of significant SDH.13 Epidural blood patch may even be performed after surgical evacuation, and has been proven to further reduce the recurrence of headache and SDH.13 16 As the brain has a tendency to sag downwards in SIH, pneumocephalus during clot evacuation may cause further downward herniation of the brain. Hence, surgical evacuation after EBP may not be advisable. Most of these patients, like our index case, have shown low-pressure subdural collection during craniotomy.

The diagnosis of SIH should be considered for any patient presenting with headache and neck pain. A high level of clinical suspicion could assist identification of subtle signs on initial CT which could facilitate early recognition and prompt treatment and, consequently, improve outcomes. However, MRI remains an important, highly sensitive, and specific method for depicting imaging markers that allow confident clinical diagnosis. Further, MRI cisternography/myelography for CSF leak localisation can be added with ease. Currently, the medical practice in Hong Kong for SIH predominantly comprises conservative treatment and symptomatic clot evacuation. More novel interventions that have been successfully employed overseas may need to be reconsidered to improve current therapeutic strategies.

1. Cheng MF, Pan MH, Wu YE, Tsai WC, Yen RF, Tzen KY. Radionuclide cisternography in diagnosing spontaneous intracranial hypotension. Ann Nucl Med Sci 2004;17:167-72.

2. Schievink WI, Gordon OK, Tourje J. Connective tissue disorders with spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension: a prospective study. Neurosurgery 2004;54:65-70; discussion 70-1. CrossRef

3. Schievink WI. Spontaneous spinal cerebrospinal fluid leaks: a review. Neurosurg Focus 2000;9:e8. CrossRef

4. Chen HH, Huang CI, Hseu SS, Lirng JF. Bilateral subdural hematomas caused by spontaneous intracranial hypotension. J Chin Med Assoc 2008;71:147-51. CrossRef

5. Wang YF, Lirng JF, Fuh JL, Hseu SS, Wang SJ. Heavily T2-weighted MR myelography vs CT myelography in spontaneous intracranial hypotension. Neurology 2009;73:1892-8. CrossRef

6. Franzini A, Messina G, Nazzi V, et al. Spontaneous intracranial hypotension syndrome: a novel speculative physiopathological hypothesis and a novel patch method in a series of 28 consecutive patients. J Neurosurg 2010;112:300-6. CrossRef

7. Diaz JH. Epidemiology and outcome of postural headache management in spontaneous intracranial hypotension. Reg Anesth Pain Med 2001;26:582-7. CrossRef

8. International Headache Society, Headache Classification Subcommittee. The International classification of headache disorders, 2nd ed. Cephalalgia 2004; ICHD–II code: 7.2.3.

9. Pakiam AS, Lee C, Lang AE. Intracranial hypotension with parkinsonism, ataxia, and bulbar weakness. Arch Neurol 1999;56:869-72. CrossRef

10. Rahman M, Bidari SS, Quisling RG, Friedman WA. Spontaneous intracranial hypotension: dilemmas in diagnosis. Neurosurgery 2011;69:4-14. CrossRef

11. Metafratzi Z, Argyropoulou MI, Mokou-Kanta C, Konitsiotis S, Zikou A, Efremidis SC. Spontaneous intracranial hypotension: morphological findings and CSF flow dynamics studied by MRI. Eur Radiol 2004;14:1013-6. CrossRef

12. Farb RI, Forghani R, Lee SK, Mikulis DJ, Agid R. The venous distension sign: a diagnostic sign of intracranial hypotension at MR imaging of the brain. AJNR Am J Neuroradiol 2007;28:1489-93. CrossRef

13. Loya JJ, Mindea SA, Yu H, Venkatasubramanian C, Chang SD, Burns TC. Intracranial hypotension producing reversible coma: a systematic review, including three new cases. J Neurosurg 2012;117:615-28. CrossRef

14. Watanabe K, Hashizume K, Kawaguchi M, Fujiwara A, Sasaoka N, Furuya H. Fluoroscopically guided epidural blood patch with subsequent spinal CT scans in the treatment of spontaneous cerebrospinal fluid hypovolemia. J Neurosurg 2011;114:1731-5. CrossRef

15. Ohtonari T, Ota S, Nishihara N, et al. A novel technique of multiple-site epidural blood patch administration for the treatment of cerebrospinal fluid hypovolemia. J Neurosurg 2012;116:1049-53. CrossRef

16. Mendes FF, Gonçalces AN, Novelo B, Mariano da Rocha CR, Marques NF. Spontaneous intracranial hypotension treated with epidural blood patch. Revista Dor 2012;13:1806-13.

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.

14. Lead and motor neurone disease. BMJ 1978;2:308. CrossRef

15. Kamel F, Umbach DM, Munsat TL, Shefner JM, Hu H, Sandler DP. Lead exposure and amyotrophic lateral sclerosis. Epidemiology 2002;13:311-9. CrossRef

16. Rademakers R, van Blitterswijk M. Motor neuron disease in 2012: novel causal genes and disease modifiers. Nat Rev Neurol 2013;9:63-4. CrossRef

17. Windebank A J, McCall JT, Dyck PJ. Metal neuropathy: peripheral neuropathy. 3rd ed. Philadelphia: WB Sanders; 1993: 1549-70.

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