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A harmless high?
Case Report
A harmless high? Esther M Sammler, Peter L Foley, Gavin D Lauder, Simon J Wilson, Andrew R Goudie, Jonathan I O’Riordan Lancet 2010; 376: 742 Departments of Neurology (E M Sammler MD, P L Foley MRCP, S J Wilson MBChB, J I O’Riordan MD), Biochemical Medicine (G D Lauder MSc), and Medicine (A R Goudie MRCP), Ninewells Hospital and Medical School, Dundee, UK Correspondence to: Esther M Sammler, Department of Neurology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK [email protected]:
In March, 2010, a 15-year-old girl presented to our accident and emergency department with altered mental status, nausea, and vomiting. During the previous evening she had been out with friends, and had consumed a white powdery substance together with alcohol. On the day of admission she had become increasingly unwell, with symptoms that could not be attributed to a hangover and presented to us in the afternoon. Upon arrival, our patient was somnolent with a Glasgow Coma Score of 11 she opened her eyes in response to speech, uttered inappropriate words, and localised to pain. Blood pressure was 108/58 mm Hg; pulse rate was 54 beats per min; respiratory rate was 15 breaths per min; and ear-temperature was 36°C. Arterial blood gas analysis and 12-lead electrocardiogram were normal. There was no evidence of external injury, neck stiffness, or localising neurological signs. Her pupils were dilated but reactive to light; there was no papilloedema. The remainder of the physical examination was normal. Brain CT scan was unremarkable; however, the cerebrospinal fluid (CSF) opening pressure during lumbar puncture in the lateral decubitus position was raised at 350 mm of water. The CSF was otherwise normal with no signs of infection. Blood tests showed profound hyponatraemia at 118 mmol/L. Other relevant blood tests included: potassium, 4·5 mmol/L; bicarbonate, 23 mmol/L; urea, 3·3 mmol/L; creatinine, 46 umol/L; and blood glucose, 5·3 mmol/L. Serum osmolality was low at 256 mmol/kg, whereas urine osmolality was high at 742 mmol/kg. We suspected drug intoxication and did gas chromatography-mass spectroscopy of the patient’s urine; this was unequivocally positive for mephedrone metabolites, but was negative for opioids, methadone, barbiturates, cocaine, cannabinoids, alcohol, benzodiazepines, and amphetamines including ecstasy. Analysis of the white powder was consistent with mephedrone. A presumptive diagnosis of mephedrone-induced euvolaemic hypo-osmotic hyponatraemia with encephalopathy and A
B
Figure: Cerebral MRI 3 days after admission Coronal FLAIR (a) and axial T2 (b) weighted sequences showing subcortical white matter signal changes (arrowed) in the frontal and parietal lobes with sparing of the pons.
742
raised intracranial pressure was made. The patient was managed with fluid restriction and close surveillance. Her electrolyte imbalance resolved over 24 h and she became alert and oriented, with no focal neurological abnormalities other than mild dysphasia and anterograde amnesia. Three days after admission, cerebral MRI showed multifocal subcortical signal abnormalities (figure). Over the next few days her symptoms gradually improved and at follow-up in May, 2010, she had made a full recovery. Mephedrone is a synthetic derivate of cathinone, a monoamine alkaloid found in the shrub Catha edulis; it has amphetamine-like psychostimulant effects.1 This drug’s easy availability and previous status as a legal high may have contributed to its increasing popularity among recreational drug users. However, mephedrone has recently been implicated in teenage morbidity and mortality, resulting in a heated media and public debate which has expedited a change in legislation.2,3 As of April 16, 2010, possessing or supplying mephedrone is illegal in the UK.3 Little is known about mephedrone’s mechanism of action, spectrum of clinical signs and symptoms, and in particular, potential neurotoxic effects.2 Given its chemical structure, mephedrone is thought to stimulate release and inhibit reuptake of monoamine neurotransmitters.2 There is ample evidence that other amphetamines such as ecstasy are associated with clinically significant hyponatraemia.4,5 Excessive sweating with electrolyte loss and increased fluid intake may be confounding factors, but there is also evidence from human and animal studies of ecstasyinduced secretion of antidiuretic hormone (ADH) mediated via serotonin.4,5 We think that mephedrone, like ecstasy, promotes serotonin-mediated ADH release, and that a mephedrone-induced syndrome of inappropriate ADH secretion resulted in our patient’s hyponatraemia and altered mental status. In the clinical setting, it is important to be aware of the possibility of mephedrone intoxication and possible neurological complications. Contributors All authors were involved with managing the patient and writing the report. Written consent to publish was obtained. References: 1 Wood DM, Davies S, Puchnaewicz M, et al. Recreational use of mephedrone (4-methylmethcathinone, 4-MMC) with associated sympathomimetic toxicity. J Med Toxicol (in press) DOI: 10.1007/ s13181-010-0018-5 2 Winstock AR, Marsden J, Mitcheson L. What should be done about mephedrone? BMJ; 340: c1605. 3 2010 No. 1207 DANGEROUS DRUGS. The Misuse of Drugs Act 1971 (Amendment) Order 2010 http://www.opsi.gov.uk/si/si2010/ pdf/uksi_20101207_en.pdf (accessed Aug 3, 2010). 4 Rosenson J, Smollin C, Sporer KA, Blanc P, Olson KR. Patterns of ecstasy-associated hyponatremia in California. Ann Emerg Med 2007; 49: 164–71, 71 e1. 5 Henry JA, Fallon JK, Kicman AT, Hutt AJ, Cowan DA, Forsling M. Low-dose MDMA (“ecstasy”) induces vasopressin secretion. Lancet 1998; 351: 1784.
www.thelancet.com Vol 376 August 28, 2010
A harmless high? Esther M Sammler, Peter L Foley, Gavin D Lauder, Simon J Wilson, Andrew R Goudie, Jonathan I O’Riordan Lancet 2010; 376: 742 Departments of Neurology (E M Sammler MD, P L Foley MRCP, S J Wilson MBChB, J I O’Riordan MD), Biochemical Medicine (G D Lauder MSc), and Medicine (A R Goudie MRCP), Ninewells Hospital and Medical School, Dundee, UK Correspondence to: Esther M Sammler, Department of Neurology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK [email protected]:
In March, 2010, a 15-year-old girl presented to our accident and emergency department with altered mental status, nausea, and vomiting. During the previous evening she had been out with friends, and had consumed a white powdery substance together with alcohol. On the day of admission she had become increasingly unwell, with symptoms that could not be attributed to a hangover and presented to us in the afternoon. Upon arrival, our patient was somnolent with a Glasgow Coma Score of 11 she opened her eyes in response to speech, uttered inappropriate words, and localised to pain. Blood pressure was 108/58 mm Hg; pulse rate was 54 beats per min; respiratory rate was 15 breaths per min; and ear-temperature was 36°C. Arterial blood gas analysis and 12-lead electrocardiogram were normal. There was no evidence of external injury, neck stiffness, or localising neurological signs. Her pupils were dilated but reactive to light; there was no papilloedema. The remainder of the physical examination was normal. Brain CT scan was unremarkable; however, the cerebrospinal fluid (CSF) opening pressure during lumbar puncture in the lateral decubitus position was raised at 350 mm of water. The CSF was otherwise normal with no signs of infection. Blood tests showed profound hyponatraemia at 118 mmol/L. Other relevant blood tests included: potassium, 4·5 mmol/L; bicarbonate, 23 mmol/L; urea, 3·3 mmol/L; creatinine, 46 umol/L; and blood glucose, 5·3 mmol/L. Serum osmolality was low at 256 mmol/kg, whereas urine osmolality was high at 742 mmol/kg. We suspected drug intoxication and did gas chromatography-mass spectroscopy of the patient’s urine; this was unequivocally positive for mephedrone metabolites, but was negative for opioids, methadone, barbiturates, cocaine, cannabinoids, alcohol, benzodiazepines, and amphetamines including ecstasy. Analysis of the white powder was consistent with mephedrone. A presumptive diagnosis of mephedrone-induced euvolaemic hypo-osmotic hyponatraemia with encephalopathy and A
B
Figure: Cerebral MRI 3 days after admission Coronal FLAIR (a) and axial T2 (b) weighted sequences showing subcortical white matter signal changes (arrowed) in the frontal and parietal lobes with sparing of the pons.
742
raised intracranial pressure was made. The patient was managed with fluid restriction and close surveillance. Her electrolyte imbalance resolved over 24 h and she became alert and oriented, with no focal neurological abnormalities other than mild dysphasia and anterograde amnesia. Three days after admission, cerebral MRI showed multifocal subcortical signal abnormalities (figure). Over the next few days her symptoms gradually improved and at follow-up in May, 2010, she had made a full recovery. Mephedrone is a synthetic derivate of cathinone, a monoamine alkaloid found in the shrub Catha edulis; it has amphetamine-like psychostimulant effects.1 This drug’s easy availability and previous status as a legal high may have contributed to its increasing popularity among recreational drug users. However, mephedrone has recently been implicated in teenage morbidity and mortality, resulting in a heated media and public debate which has expedited a change in legislation.2,3 As of April 16, 2010, possessing or supplying mephedrone is illegal in the UK.3 Little is known about mephedrone’s mechanism of action, spectrum of clinical signs and symptoms, and in particular, potential neurotoxic effects.2 Given its chemical structure, mephedrone is thought to stimulate release and inhibit reuptake of monoamine neurotransmitters.2 There is ample evidence that other amphetamines such as ecstasy are associated with clinically significant hyponatraemia.4,5 Excessive sweating with electrolyte loss and increased fluid intake may be confounding factors, but there is also evidence from human and animal studies of ecstasyinduced secretion of antidiuretic hormone (ADH) mediated via serotonin.4,5 We think that mephedrone, like ecstasy, promotes serotonin-mediated ADH release, and that a mephedrone-induced syndrome of inappropriate ADH secretion resulted in our patient’s hyponatraemia and altered mental status. In the clinical setting, it is important to be aware of the possibility of mephedrone intoxication and possible neurological complications. Contributors All authors were involved with managing the patient and writing the report. Written consent to publish was obtained. References: 1 Wood DM, Davies S, Puchnaewicz M, et al. Recreational use of mephedrone (4-methylmethcathinone, 4-MMC) with associated sympathomimetic toxicity. J Med Toxicol (in press) DOI: 10.1007/ s13181-010-0018-5 2 Winstock AR, Marsden J, Mitcheson L. What should be done about mephedrone? BMJ; 340: c1605. 3 2010 No. 1207 DANGEROUS DRUGS. The Misuse of Drugs Act 1971 (Amendment) Order 2010 http://www.opsi.gov.uk/si/si2010/ pdf/uksi_20101207_en.pdf (accessed Aug 3, 2010). 4 Rosenson J, Smollin C, Sporer KA, Blanc P, Olson KR. Patterns of ecstasy-associated hyponatremia in California. Ann Emerg Med 2007; 49: 164–71, 71 e1. 5 Henry JA, Fallon JK, Kicman AT, Hutt AJ, Cowan DA, Forsling M. Low-dose MDMA (“ecstasy”) induces vasopressin secretion. Lancet 1998; 351: 1784.
www.thelancet.com Vol 376 August 28, 2010