A 63-year-old man complained of chest pain, dizziness, and generalised tremors 15 minutes after ingestion of a teaspoon of herbal powder with water in September 2012. He had started taking herbal decoctions prescribed by a registered Chinese medicine doctor 1 month ago because of suboptimal pain control of his trigeminal neuralgia with western medicine. He presented around 2 to 3 hours post-ingestion to our emergency department because of persistent symptoms. He was fully conscious but the limb tremor was so severe that he could barely walk. There was no numbness, headache, or any gastro-intestinal (GI) symptom. Apart from trigeminal neuralgia, he also had a history of ischaemic heart disease and hypercholesterolaemia. The medication on-hand included aspirin, famotidine, simvastatin, metoprolol, isosorbide mononitrate, diclofenac, dihydrocodeine, tramadol, and carbamazepine but he denied overdosing of any of those drugs. He had not taken any other herbs, over-the-counter medicines, or other suspicious foods such as coral reef fish and shellfish.

On arrival he was fully conscious with a Glasgow Coma Scale score of 15/15. His vital signs were as follows: blood pressure 126/95 mm Hg, pulse rate 66 beats/min, respiratory rate 18 breaths/min, oxygen saturation by pulse oximetry (SaO₂) 99% on supplemental oxygen 2 L/min via a nasal cannula, and tympanic temperature 36.6°C. He appeared nervous with diaphoresis. Both his pupils were 2 mm in size and reactive to light. Cranial nerve examination was unremarkable but generalised involuntary limb twitching with hypertonia was evident. The muscle power in his four limbs was 5/5. Hyperreflexia and bilateral upgoing plantar reflexes were noted; there was no ankle clonus. Cardiovascular examination was unremarkable and his chest was clear. No distended urinary bladder or abnormal bowel sounds were noted. Repeated electrocardiograms showed sinus rhythm with normal axis. First-degree heart block was noted but there were no definite ischaemic changes. The QRS duration and the corrected QT interval were 89 ms and 431 ms, respectively. Chest X-ray revealed marginal cardiomegaly with clear lung field. The spot haemostix level was 6.2 mmol/L. Other blood tests including a complete blood picture, urea and electrolytes, serum calcium level, liver function tests, troponin-I, and arterial blood gas were essentially unremarkable, except a slightly raised creatine kinase (CK) level of 408 IU/L (reference range, 24-180 IU/L), which was likely due to generalised muscle twitching.

His chest pain decreased after administering 3 mg of intravenous (IV) morphine. Subsequently, his blood pressure dropped to 66/48 mm Hg but responded to fluid challenge with 500 mL of IV 0.9% normal saline. Less limb twitching was noted after administering 5 mg of IV diazepam. The provisional diagnosis was suspected Chinese herbal medicine (CHM)–related neurotoxicity but at the time of presentation, the formula of the herbal decoction was not available for identifying the culprit. The patient was admitted to the intensive care unit (ICU) for close monitoring in view of the unstable haemodynamic status upon presentation, which may have been the result of CHM toxicity or hypotensive effect of morphine.

Seven sheets of CHM prescription formula were subsequently traced back by the patient’s son 3 hours after admission. The Hong Kong Poison Information Centre was consulted for opinion. Multiple ingredients, including Quanxie (全蝎, Mesobuthus martensii Karsch), were prescribed according to the formula. However, the patient had remained free of side-effects in the previous month when he took the herbal decoctions as instructed. Further questioning revealed that the patient had found his pain control unsatisfactory even after taking the herbal decoctions. After receiving verbal advice from his Chinese medicine doctor, he took a few pieces of scorpion from the herb package and put them into a food blender. He took a teaspoon of the powder directly with water; this was the first time he took the herb in this form and fashion. He developed symptoms soon after ingestion.

The patient’s twitching decreased gradually after ICU admission but he remained hypertonic, which warranted administering another dose of IV diazepam 2 mg 10 hours after admission. Otherwise, he was fully conscious with a stable haemodynamic status. Computed tomography of the brain was unremarkable. His symptoms gradually resolved and he was discharged from the ICU and transferred to the Emergency Medicine Ward 16 hours after admission. His CK level peaked to 413 IU/L and normalised on day 2. He was discharged 36 hours after admission, and was totally asymptomatic on follow-up 5 days later.

The patient’s serum and urine samples, together with the unused herbs and herbal powder, were sent to the Hospital Authority Toxicology Reference Laboratory for further analysis. Poisoning due to other toxic herbs, such as aconitine, strychnine, and matrine was ruled out by liquid chromatography-mass spectrometry of the leftover herbal powder. However, detection of the toxic peptides of M martensii was not possible as the laboratory was not equipped to test for these toxins. The patient’s urine sample revealed the presence of diclofenac, dihydrocodeine, carbamazepine metabolite, salicylic acid and famotidine but these were the usual medications taken by the patient. The serum salicylate level was far below the toxic level. Judging from the history and absence of other toxic alkaloids to explain the symptoms, the diagnosis of this case was compatible with neurotoxicity associated with the consumption of M martensii powder, even though it could not be directly confirmed by chemical analysis.

Mesobuthus martensii Karsch (synonym: Buthus martensii Karsch), commonly known as Chinese scorpion or Manchurian scorpion (東亞鉗蝎 or 馬氏鉗蝎), belongs to the Buthidae family, and is widely distributed in China. The whole body of the scorpion has been used in traditional Chinese medicine as Quanxie for more than a thousand years (Fig). It functions through the liver meridian, extinguishing wind, and stopping tremors and convulsion. According to the literature in traditional Chinese medicine, common indications include chronic pain, tetanus, tremors, acute/chronic childhood convulsions, paralysis, cerebral vascular accident, and fire toxic nodules.1 Its use is contra-indicated during pregnancy and should be avoided in cases of internal wind with blood deficiency. The recommended dose is 3 to 6 g for herbal decoction2 and 0.5 to 1 g for herbal powder.3

The venom of M martensii is complex. At least 51 long-chain peptides related to the sodium (Na⁺) channel toxin family and 18 peptides related to the potassium (K⁺) channel toxin family have been described4 and more have yet to be discovered. Neurotoxins affecting the Na⁺ channel consist of α (highly active in mammalian brain) and β (highly active in insects) toxins. Many β toxins, which are not noxious to mammals, were found to have analgesic properties in animal models without the risk of dependence.5 Recently, a novel peptide, BmK-YA, was found to contain an enkephalin-like sequence and can activate the mammalian δ opioid receptor.6 Novel peptides with antiepileptic (eg BmK AEP),7 antitumour (BmK AGAP),8 and antibacterial (BmKn2-7)9 effects in animal models have also been identified in the venom. These findings provide molecular evidence to support its traditional use in Chinese medicine, but relevant clinical studies are still lacking.

Although known to be toxic in traditional Chinese medicine, so far, literature on Quanxie poisoning has been rather limited. Many of the reported cases were due to therapeutic overdose,10 which might be related to the way the scorpions are processed. Traditionally, the captured scorpions are put into water for a few hours to allow them to spit out soil from gut, pass retained faeces, and clean the dirt over their bodies. Thereafter they are either boiled with plain water or salt water, resulting in ‘plain’ Quanxie (淡全蝎) and ‘salted’ Quanxie (鹽全蝎), respectively. Boiling kills the scorpion and decreases its toxicity. The addition of salt serves to preserve the processed scorpions for prolonged periods. The majority of the processing is undertaken in scorpion farms and there is a lack of standardised protocol.11 The details of processing vary from place to place, resulting in variable therapeutic effects, even with the same dose. Moreover, many merchants try to add more salt when processing salted Quanxie to increase its weight, for more profit in sale. The salt content in salted Quanxie could be up to 44.82% in the market,12 resulting in inadequate therapeutic effects with the recommended dose. Therefore, many traditional Chinese medicine doctors may opt to use a higher-than-recommended dose to achieve the targeted effect, thus increasing the risk of clinical toxicities.10

In our case, it is difficult to estimate the amount of Quanxie actually consumed as the powder had not been accurately weighed before consumption. With a standard teaspoon, the patient could have taken 5 to 6 g of the powder, which is higher than the recommended dose. Failure to boil before ingestion might also have contributed to his clinical toxicities.

The clinical features of M martensii (Quanxie) poisoning are summarised in the Table.10 13 14 15 There is no specific antidote, such as anti-venom, for this condition. The mainstay of treatment is supportive. The toxicokinetics of Quanxie have not yet been thoroughly studied. Judging from the rapid onset of clinical symptoms after oral ingestion, we believe that GI absorption is rapid. Gastro-intestinal decontamination with gastric lavage or activated charcoal can be considered if the patient presents within 1 hour of ingestion and has a protected airway. Such a time frame for GI decontamination has also been recommended for other toxic herbs with rapid GI absorption, such as aconitine. Clinicians may choose to consider GI decontamination in patients presenting beyond 1 hour after ingestion but the benefit and risk should be carefully weighed on a case-to-case basis. The benefit would certainly decline with time, which may not justify the risk of aspiration, especially when neurotoxic features such as generalised twitching have already set in, making the administration of activated charcoal further difficult. As Quanxie has not been shown to have enterohepatic circulation or prolonged GI absorption, multi-dose activated charcoal is not recommended. Benzodiazepines appeared effective in alleviating limb twitching muscle spasm in our case but its role in the management of M martensii poisoning remains to be elucidated.

No conflicts of interests were declared by authors.

1. Li N, Yu M, Hu LN, Lin J. Collation of animal drugs — Quanxie [in Chinese]. Jilin J Tradit Chin Med 2009;29:805-6.

2. Committee of National Pharmacopoeia. Chinese pharmacopoeia [in Chinese]. Vol 1. Beijing: Chemical Industry Press; 2010: 133-4.

3. The editorial committee of “Chinese Herbals”, State Administration of Traditional Chinese Medicine. Chinese Materia Medica [in Chinese]. Vol 9. Shanghai: Shanghai Science & Technology Press; 1999: 129-35.

4. Goudet C, Chi CW, Tytgat J. An overview of toxins and genes from the venom of the Asian scorpion Buthus martensii Karsch. Toxicon 2002;40:1239-58. CrossRef

5. Shao JH, Zhang R, Ge X, Yang B, Zhang JH. Analgesic peptides in Buthus martensii Karsch: a traditional Chinese animal medicine. Asian J Tradit Med 2007;2:45-50.

6. Zhang Y, Xu J, Wang Z, Zhang X, Liang X, Civelli O. Bmk-YA, an encephalin-like peptide in scorpion venom. PLoS One 2012;7:e40417. CrossRef

7. Zhou XH, Yang D, Zhang JH, Liu CM, Lei KJ. Purification and N-terminal partial sequence of anti-epilepsy peptide from venom of the scorpion Buthus martensii Karsch. Biochem J 1989;257:509-17.

8. Liu YF, Zhang ZG, Mao YZ, et al. Production and antitumor efficacy of recombinant Buthus martensii Karsch AGAP. Asian J Tradit Med 2009;4:228-33.

9. Cao L, Dai C, Li Z, et al. Antibacterial activity and mechanism of a scorpion venom peptide derivative in vitro and in vivo. PLoS One 2012;7:e40135. CrossRef

10. Chang JM. Adverse effects of Quanxie [in Chinese]. J China Pharm 2003;14:484-5.

11. Gao ZJ. Brief review of the processing methods of Quanxie [in Chinese]. J Community Med 2006;4:59-60.

12. Shao XH, Kong XS, Fang LH. Processing of Quanxie and its clinical application [in Chinese]. Lishizhen Med Materia Medica Res 2006;17:232-3.

13. Chen XM. Analysis of adverse effects of Quanxie [in Chinese]. Lishizhen Med Materia Medica Res 2003;14:635.

14. Xiao YC. A case report of neurotoxicity induced by centipede and Quanxie [in Chinese]. China J Chin Materia Medica 1996;21:634.

15. Dai Y. A case report of free decoction for treatment of Quanxie [in Chinese]. J Jilin Med Coll 2009;3:342.

A 59-year-old woman with good past health, except for post-radioiodine hypothyroidism on T4 replacement, had a 3-week history of cough with yellowish sputum but no fever. She visited a general practitioner and was prescribed a course of ciprofloxacin for possible respiratory tract infection. Three days after starting the drug, she noticed pain and swelling over the left heel. She was not on any other medications including steroid. She went hiking regularly and there was no history of trauma. There was no history of joint or tendon problems. On presentation in May 2012, physical examination revealed tenderness and swelling over the left Achilles tendon (Fig 1). Ultrasound revealed Achilles tendinitis with increased flow on power Doppler signal. There were no signs of tear or calcium deposition (Fig 2). Due to the temporal relationship and the absence of other obvious causes, the diagnosis was ciprofloxacin-induced Achilles tendinitis (the Naranjo Scale was 7, ie probable adverse drug reaction).1 Ciprofloxacin was stopped and the patient was advised to avoid hiking until symptoms subsided completely. She recovered fully 2 weeks later.

Fluoroquinolone-induced tendinopathy was first reported in 19832 and, since then, more than 100 cases have been reported in the literature. A case-control study from Italy found that use of fluoroquinolone was associated with higher risk of tendon disorders as well as Achilles tendon rupture (odds ratios, 1.7 and 4.1, respectively) compared with the control population.3 Another case-control study done in the United Kingdom estimated the risk to be 3.2 cases per 1000 patient-years.4

The commonest fluoroquinolones in the reported cases included ciprofloxacin and pefloxacin but, essentially, all the commonly used fluoroquinolones such as levofloxacin, ofloxacin, and norfloxacin have been associated with this adverse event.

Achilles tendon is the commonest affected site, accounting for nearly 90% of the reported cases. Other tendons like quadriceps tendon, rotator cuff tendon, as well as the site of tendon insertion may also be affected (there were two cases of epicondylitis reported after quinolone use).5 Tendinitis was the commonest pathology, present in 83.7% of the cases. Tendon rupture occurred in about 40% of the patients.6 A case-control study found that patients taking fluoroquinolones had a 4-fold increased risk of Achilles tendon rupture compared with the general population.3 Other complications related to tendinitis, such as carpal tunnel syndrome, are also possible.7

The mean time of symptom onset was about 2 weeks after initiation of the culprit medication, although it could range from 2 hours to as long as 6 months and, in 50% of the cases, it started within 6 days of drug intake. The mean age of affected subjects was 59 years.6

Several risk factors have been identified in the development of tendinopathy in patients taking fluoroquinolones. Among them, steroid use was the most significant risk factor. Most of the time, this was related to long-term use of systemic steroids, although even inhaled steroids were thought to be associated with the development of quinolone-induced tendinopathy.8 Other risk factors include old age (>60 years old), haemodialysis, renal impairment, renal transplant recipients, participation in sports activities, and history of rheumatic disorders.6 9 One previous review stated that males were more likely to develop this side-effect.6 One more recent case-crossover study, however, found that the association of tendinopathy and fluoroquinolone use was stronger in females, although not statistically significant.10 Therefore, it is not sure whether a particular gender is more likely to have this problem.

The underlying pathophysiology of the tendinopathy is not entirely known. A number of possible mechanisms have been proposed in animal and in-vitro studies. Ciprofloxacin could affect the metabolism of fibroblasts in tendon structures by reducing collagen synthesis and increasing extracellular matrix degradation.11 The chelating property of fluoroquinolones may also disturb the physiological interaction between cells and extracellular matrix.12 There was also evidence that fluoroquinolone increased apotosis in human tenocytes.13 In renal transplant recipients, the clearance of the drug may be impaired resulting in elevated concentrations in the tendon structures. Other risk factors like age, repeated trauma due to sports activities, or steroid therapy may impair the repair process of the tendon, thus, increasing the risk of tendinopathy in this group of patients.6 14

The tendinopathy usually presents with acute or subacute onset of pain and swelling over the tendon. Together with a history of recent consumption of fluoroquinolones and absence of other obvious causes of the tendinopathy, the diagnosis can be established. Imaging like ultrasound or magnetic resonance imaging is not mandatory but can aid in diagnosis, especially for visualising deep structures. Typical ultrasound findings of tendinopathy include thickened tendon with increased flow on colour Doppler examination.

The most important step in management is to stop the culprit drug. Appropriate rest and pain control are important. Pain can be well-controlled by non-steroidal anti-inflammatory agents; non-pharmacological treatments include ice therapy and therapeutic ultrasound. In case of tendon rupture, early referral to orthopaedic surgeon is desirable. Treatment options include immobilisation with casting or operative repair.

Prevention is also very important. One should only use fluoroquinolones when really necessary. Our patient’s symptoms did not suggest genuine lower respiratory tract infection; therefore, prescription of antibiotics was indeed not indicated. Moreover, quinolone is not the recommended first-line empirical antibiotic for treatment of chest infection in Hong Kong (it should only be considered in patients who are sensitive to penicillin or macrolide group of antibiotics). When use of antibiotics is really deemed necessary, fluoroquinolones should be avoided in patients with risk factors. Those with a history of fluoroquinolone-related tendinopathy should not be prescribed drugs of this class. We should also avoid co-prescription with steroid. If no better alternative is available, patients should be warned of this potential adverse effect and advised to stop the drug and seek medical advice if there are symptoms suggestive of tendinopathy. Athletes who are prescribed with fluoroquinolones should be advised to alter their training regimen (reduction in high-intensity and ballistic activities, decrease in total training volume) during the course of the antibiotics.14

1. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45. CrossRef

2. Bailey RR, Kirk JA, Peddie BA. Norfloxacin-induced rheumatic disease. N Z Med J 1983;96:590.

3. Corrao G, Zambon A, Bertù L, et al. Evidence of tendinitis provoked by fluoroquinolone treatment: a case control study. Drug Saf 2006;29:889-96. CrossRef

4. van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HG, Stricker BH. Fluoroquinolones and risk of Achilles tendon disorders: case-control study. BMJ 2002;324:1306-7. CrossRef

5. Le Huec JC, Schaeverbeke T, Chauveaux D, Rivel J, Dehais J, Le Rebeller A. Epicondylitis after treatment with fluoroquinolone antibiotics. J Bone Joint Surg Br 1995;77:293-5.

6. Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopathy: a critical review of the literature. Clin Infect Dis 2003;36:1404-10. CrossRef

7. Liang VY, Ghearing GR, Zivkovic SA. Carpal tunnel syndrome after ciprofloxacin-induced tendinitis. J Clin Neuromuscul Dis 2010;11:165-6. CrossRef

8. Schwald N, Debray-Meignan S. Suspected role of ofloxacin in a case of arthralgia, myalgia, and multiple tendinopathy. Rev Rhum Engl Ed 1999;66:419-21.

9. Tsai WC, Yang YM. Fluoroquinolone-associated tendinopathy. Chang Gung Med J 2011;34:461-7.

10. Wise BL, Peloquin C, Choi H, Lane NE, Zhang Y. Impact of age, sex, obesity, and steroid use on quinolone-associated tendon disorders. Am J Med 2012;125:1228.e23-1228.e28.

11. Williams RJ 3rd, Attia E, Wickiewicz TL, Hannafin JA. The effect of ciprofloxacin on tendon, paratenon and capsular fibroblast metabolism. Am J Sports Med 2000;28:364-9.

12. Shakibaei M, Pfister K, Schwabe R, et al. Ultrastructure of Achilles tendons of rats treated with ofloxacin and fed a normal or magnesium-deficient diet. Antimicrob Agents Chemother 2000;44:261-6. CrossRef

13. Sendzik J, Shakibaei M, Schäfer-Korting M, Stahlmann R. Fluoroquinolones cause changes in extracellular matrix, signalling proteins, metalloproteinases and caspase-3 in cultured human tendon cells. Toxicology 2005;212:24-36. CrossRef

14. Hal MM, Finnoff JT, Smith J. Musculoskeletal complications of fluoroquinolones: guidelines and precautions for usage in the athletic population. PM R 2011;3:132-42. CrossRef

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