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New-Onset Refractory Status Epilepticus Associated With the Use of Synthetic Cannabinoids
Psychosomatics 2017:58:180–186
& 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Case Reports New-Onset Refractory Status Epilepticus Associated With the Use of Synthetic Cannabinoids Neil A. Patel, M.D., M.B.A., Jason M. Jerry, M.D., F.A.P.A., F.A.S.A.M., Xavier F. Jimenez, M.D., M.A., Stephen T. Hantus, M.D.
Introduction Synthetic cannabinoids (SCs) appeared in the United States (US) in 2008 as a drug of abuse. Although most commonly known as “K2” or “Spice,” SCs are distributed under a vast number of different names such as “Black Mamba,” “Funky Monkey,” “Happy Tiger Incense,” and “Crazy Monkey.” Today, abuse of these drugs has reached near epidemic levels in US urban areas such as New York and Los Angeles. SCs were initially touted as natural alternatives to cannabis that avoided detection on employer urine drug screens and were marketed as consumer products such as incense that were labeled as “not for human consumption” in an attempt to bypass scrutiny by legal authorities.1 The Synthetic Drug Abuse Prevention Act of 2012 designated several SCs as Schedule I, making them illegal to possess. Despite such legislation, abuse of these drugs remains widespread as evidenced by an increase in SCrelated calls to poison control centers over time.2 According to the Substance Abuse and Mental Health Services Administration (SAMHSA) and Drug Abuse Warning Network (DAWN) data, the number of emergency department visits involving SCs increased significantly from 11,406–28,531 between 2010 and 2011. Over the same timeframe, SC-related visits to emergency departments doubled among 12–17-year olds, quadrupled among 18–20-year olds, and tripled among females.3 These statistics reinforce the increasing prevalence of SCs in the community. Though epileptic seizures are not typically associated with the use of natural marijuana, numerous case reports have suggested an association with SCs (Table 1). 180
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Here, we present a case of a 19-year old, heavy SC user with a previous history of SC-associated seizures, who developed refractory epilepsy within this context.
Case Report Mr. M a 19-year-old man with a past medical history of hepatitis C and severe polysubstance use disorder, was transferred from an outside community hospital to our tertiary care, academic medical center, with persistent seizure activity. Collateral information was obtained from Mr. M’s girlfriend who revealed that he was in his usual state of health until a day before admission. She described that after entering the shower, he was observed to be unresponsive and staring in a bizarre fashion, subsequently falling with generalized jerking movements and bladder incontinence. Emergency medical services personnel originally transported Mr. M to a community hospital where he was diagnosed with an agitated delirium in addition to recurrent seizures. He was transferred to the neurologic intensive care unit at our Received September 15, 2016; accepted October 17, 2016. From the Department of Adult Psychiatry (NP), Cleveland Clinic, Cleveland, OH; Cleveland Clinic Alcohol and Drug Recovery Center (JJ), Cleveland Clinic Lutheran Hospital, Cleveland, OH; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (JJ, XJ, SH) and Consultation-Liaison Psychiatry (XJ) and Epilepsy Center (SH), Cleveland Clinic, Cleveland, OH. Send correspondence and reprint requests to Jason M. Jerry, M.D., F.A.P.A., F.A.S.A.M., Cleveland Clinic Alcohol and Drug Recovery Center, Cleveland Clinic Lutheran Hospital, Cleveland, OH. & 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
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Patel et al. TABLE 1.
Selected Cases of SC-Related Seizure Episodes
Year Case description
SC compound
Reference
2011 A 48-year-old otherwise healthy man with generalized seizure after ingesting ethanol mixture containing white powder bought online, later confirmed to be synthetic cannabinoids. 2011 Several cases of men aged 21–27 with seizures, some with agitation, and normal drug screens, who all admitted to smoking Spicy XXX 2011 Several cases of males aged 15–19 with seizure activity after smoking SCs, and urine toxicology positive for JWH-018 and metabolites with or without JWH-073 2011 Case (1) A 24-year-old man with schizophrenia, experiencing 2 isolated GTC seizures. Case (2) A 36-year-old woman with substance abuse in remission and depression with GTC seizure progressing to status epilepticus requiring intubation 2012 A 19-year-old otherwise healthy man with 1–2 minute convulsion while smoking “Happy Tiger Incense.” 2012 A 48-year-old man who lost consciousness and had several seizures after smoking herbal blend 2012 A 48-year-old man with 2 GTCs who smoked 3 grams of Spice in addition to drinking alcohol 2013 A 19-year-old who smoked “Bonzai,” later developing tonic-clonic seizures, eventually requiring intubation and mechanical ventilation 2013 A 20-year-old man with self-limited tonic-clonic seizures after smoking “Black Mamba” 2014 A 22-year-old man with GTC seizure and combativeness, whose canine also had seizure after smoking “Crazy Monkey” 2014 A 23-year-old man, a daily user of SCs, with multiple GTC seizures
JWH-018
4
3 cases: “Spicy XXX”
5
3 cases: JWH-018
6
Two cases: “Funky Monkey” and “Black Mamba”
7
JWH-018, JWH-081, JWH-250, 8 AM-2201 “K2 Summit Blend” and 9 JWH-018 JWH-018 10 JWH-018, JWH-122, JWH-210 11 AM2201 PB-22 (“Crazy Monkey”)
BB-22; AM2233; PB-22; 5F-PB-22; JWH-122 2016 Three patients, including 2 of whom had pre-existing bipolar disorder, with seizures after MAB-CHMINACA SC use and required sedatives for agitation
12 13 14 15
GTC ¼ generalized tonic-clonic; SC ¼ synthetic cannabinoid.
hospital 19 days after the initial admission to the outside community hospital where he was found to have repeated seizures diagnosed as status epilepticus on continuous electroencephalography monitoring (Fig. 1). His medical course was complicated by sepsis, respiratory failure (requiring intubation with ventilation, and tracheostomy), nonischemic cardiomyopathy, acute kidney injury (requiring temporary dialysis), and Clostridium difficile infection. The first 24-hour bedside electroencephalography monitoring indicated right hemispheric cortical dysfunction with 3 seizures lasting 7–14 minutes each from right temporal and parietal regions (Fig. 1). He was having seizures several times per week. Despite multiple scheduled antiepileptic drugs, Mr. M required multiple doses of 2 mg intravenous (IV) lorazepam during these episodes to abort seizure activity. He also received several doses of quetiapine for control of agitation. Magnetic resonance imaging and computed tomography imaging of his brain performed days after initial incident were found to be unremarkable. Serum laboratory analyses showed elevated lipase and leukocytosis, each attributed to acute pancreatitis. Urine Psychosomatics 58:2, March/April 2017
drug screen at an outside hospital was positive for benzodiazepines only (which he had received while in the hospital), and no additional routine drug screen (including serum screening) was performed on arrival to our hospital. Urine screening performed 19 days after the initial incident by enzyme-linked immunosorbent assay detection by NMS Laboratories SynCann Screen 3 and 4 was negative for metabolites of SCs. Urine Pain panel 19 days after the incident was tested for 20 of the most common opioid analgesics and derivatives and was positive for fentanyl and its metabolite, which he had received while in the hospital. A lumbar puncture was performed for the following tests: routine cultures, paraneoplastic panel, fungal, cryptococcal, cytomegalovirus, herpes simplex, N-methyl-D-asparate receptor, Epstein-Barr, West Nile Virus, venereal disease research laboratory test, histoplasma, varicella-zoster virus, toxoplasma virus, listeria, Whipples studies—all of which were negative. Given the improvement in respiratory function and seizure control, Mr. M was extubated. At this time, he was able to communicate, and consultation psychiatry www.psychosomaticsjournal.org
181
Case Reports FIGURE 1.
Electroencephalography at Initial ICU Presentation
was consulted to assess agitation, hallucinations, and paranoia. During the initial psychiatric interview, Mr. M was inattentive, disoriented (to place, month, and context), and was unable to provide significant history. Pertinent neurological findings were diffuse hyperreflexia, horizontal nystagmus, and generalized myoclonus. Haloperidol was recommended for agitation, but used judiciously on account of concern for its ability to lower seizure threshold. Approximately 4 weeks after his last SC use, Mr. M was still experiencing seizures every 2–3 days, and some days he was having multiple recorded seizures. Seizures were often accompanied by upper extremity twitching, saccadic eye movements, or myoclonic jerks. Electroencephalography generally showed diffuse generalized encephalopathy, bilateral cortical dysfunction, and epileptogenicity arising from parietal-occipital areas. Seizures were effectively aborted with IV lorazepam. 182
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Given his delirium, Mr. M’s family was relied upon to provide most of his history. He had no formal prior psychiatric history, though the family expressed some concern that he may have had depressive symptoms as a child. He was on no scheduled home medications before admission. On the day before the shower seizure incident, he was noted to be withdrawn and in bed most of the day. The exact nature of his substance use leading up to this episode was unclear, but his girlfriend was highly concerned that he may have used SC as he had previously experienced seizures in relation to SC intoxication and was known to have been abusing the substance extensively during the 6 months preceding the event. The family corroborated that Mr. M had been using SCs in a binge-like fashion, but exact amounts were unknown. He was often noted to be lying around his home, withdrawn and appearing confused after smoking SCs, and he was thought to be Psychosomatics 58:2, March/April 2017
Patel et al. addicted based on witnessed behavioral outbursts when he was unable to obtain SCs. In addition, family described at least 2 seizure episodes temporally associated with SC binging. The family denied any history of seizures preceding his 6-month routine of using SCs. He had normal birth and developmental history, no family history of seizures, and no known history of traumatic brain injury or intracranial pathology. He was seronegative for human immunodeficiency virus. Family added that SCs were known to be a popular drug of abuse in their home town, expressing that they had heard of others in their small community who had experienced seizures after using SC products that were assumed to be procured from the same distributor used by Mr. M. Mr. M had a history of severe polysubstance use disorder which included sporadic use of cocaine, frequent use of marijuana, very sporadic use (perhaps once per month) of alprazolam to limit effects of intoxication or withdrawal from other substances, and a remote use history of opioids (oral therapeutic opioids and intravenous heroin). He had no significant history of alcohol use disorder. He had no known formal history of detoxification, rehabilitation, or chemical dependency treatment other than having been on buprenorphine for a brief period of time. After 2 months of his initial presentation to the outside hospital, Mr. M was discharged to a skilled nursing facility at which time he was fully alert and oriented, seizure-free for 5 days, and participating in hospital-based physical therapy. Unfortunately, 1 month after discharge, Mr. M was readmitted to an outside hospital for 3 days and subsequently transferred to our neurological intensive care unit owing to reemergence of seizure activity despite the use of 5 antiepileptic agents: lacosamide 200 mg by mouth (PO) 3 times daily (TID) (blood level of 4.2), levetiracetam 1500 mg PO TID (blood level of 23.1), zonisamide 300 mg PO twice daily (BID) (blood level of 10.3), clorazepate 15 mg PO BID (blood level of 297), phenobarbital 400 mg PO TID (blood level of 94.2). Shortly after this admission, he rapidly became increasingly unresponsive, unable to open his eyes on command, and not responding to noxious stimuli. His acute worsening was thought to be related to repeated seizure events as well as from increasing amounts of sedating antiepileptic medications for refractory seizures. Further investigations regarding the etiology of seizures included a repeat paraneoplastic panel that Psychosomatics 58:2, March/April 2017
was negative. Seizure episodes lacking specific foci and lasting up to several hours were repeatedly recorded on bedside electroencephalography monitoring. Multiple pharmacological strategies failed to suppress seizure activity, including ketamine, pentobarbital, a randomized trial of an experimental agent (SAGE-457) as part of a clinical trial for refractory seizures, and 2 rounds of IV immunoglobulin. Plasmapheresis similarly provided no relief. Further, 4 months after the initial presentation to the hospital, a positron emission tomography scan revealed diffuse cortical hypometabolism, without any focal evidence of asymmetry (Fig. 2). An magnetic resonance imaging scan of his brain performed 6 months after initial presentation was remarkable for bilateral symmetric thickening with T2/FLAIR hyperintensity of the fornices and undersurface of corpus callosum as well as diffuse cerebral volume loss (Fig. 3). Per the interpreting neuroradiologist, diagnostic considerations included drug-induced, toxic, or metabolic encephalopathies. Eight months after the initial presentation, Mr. M was discharged to a long-term acute care facility, after being seizure-free for 38 days. He remained unresponsive, requiring various life-sustaining treatments including tracheostomy and intubation with ventilator dependence, and enteral nutrition via percutaneous endoscopic gastrostomy tube. Mr. M’s antiepileptic drug regimen at discharge included the following medications by feeding tube: levitracetam 2000 mg TID, lacosamide 300 mg BID, felbamate 800 mg TID, FIGURE 2.
Positron Emission Tomography Scan (Brain)
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183
Case Reports FIGURE 3.
Axial FLAIR Magnetic Resonance Imaging Scan (Brain)
rufinamide 1200 mg BID, zonisamide 200 mg TID, clobazam 20 mg TID, clonazepam 2 mg 4 times daily (QID), topirimate 100 mg BID, phenytoin 325 mg TID (free blood level of 2.3), and phenobarbital 550 mg TID (blood level of 216). Mr. M was readmitted 3 weeks later with concern for small bowel obstruction, abdominal distension, and low ostomy output. He was operatively managed with exploratory laparotomy and manual bowel decompression. He was again discharged unresponsive to long-term acute care after 2 weeks of admission. He was readmitted 3 weeks following previous discharge with recurrent small bowel obstruction with computed tomographic abdominal imaging revealing pneumatosis and was not determined to be a surgical candidate at that time. He continued to have intractable seizures, with limited ability to decrease antiepileptic drugs without seizure recurrence. After extensive discussion with family and determination of poor neurologic prognosis, life-sustaining care was withdrawn. Mr M was declared deceased, approximately 10 months after the initial onset of status epilepticus. Discussion The differential for Mr. M’s seizures is wide, and includes substance-induced seizures, substance withdrawal seizures, pre-existing epilepsy, anoxic brain injury, traumatic brain injury, psychogenic, infectious, 184
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and metabolic causes. Brain biopsy was not performed but may have yielded findings suggestive of one of these mechanisms. Although the exact etiology of Mr. M’s initial seizure episode may never be confirmed definitively, the association between SCs and seizures is well known. Multiple reports have recently emerged linking SC use with temporally related and selflimiting seizures (Table 1). In a 9-month study of 1353 calls to poison control centers regarding SCs, 3.8% involved seizures with only 1 fatality.16 What makes the case presented here unique is that, unlike other examples reported in the literature, Mr. M’s seizures were not self-limiting and in fact evolved to a refractory state. Furthermore, 10 months after the initial presentation to the hospital, once life-sustaining measures were suspended, Mr. M ultimately died because of refractory seizures and associated morbidity. The association between seizures and SCs may seem counterintuitive because such effects are rarely seen in association with marijuana use, but authors have speculated about a possible etiology underlying this phenomenon. It is known that delta-9tetrahydrocannabinol (THC), the major cannabinoid in marijuana, inhibits gamma-aminobutyric acid (GABA) through its effects at the cannabinoid receptor type 1 (CB-1). Because most SCs are full agonists at CB-1, as compared with THC (only a partial agonist), it appears that GABA inhibition by these agents is more profound than that associated with natural cannabinoids and may explain their ability to induce epileptic seizures.17 Psychosomatics 58:2, March/April 2017
Patel et al. We postulate a mechanism that includes a complex multifactorial interplay of substance-induced alterations on central nervous system membrane potential, receptor expression, neurotransmitter conductance, circuitry remodeling, and neuronal loss.18 Presumably, a toxic insult to the central nervous system by this direct SC receptor site binding may injure brain tissue permanently with prolonged heavy use, with increased predisposition to recurrent seizures and limited healthy neural functioning to prevent epileptogenicity. In our case, the presence of an SC was not confirmed, as the only urine testing for SCs was performed on a sample collected 19 days after initial presentation to the hospital, making it very unlikely that any SCs would still be detectable. The history provided by Mr. M’s family indicated an extensive and heavy use of SCs as well as 2 prior discrete episodes of seizures in the preceding year that were temporally related to SC use. Furthermore, an extensive workup over the course of several months on Mr. M revealed no other plausible explanation for seizure activity or maintenance. It is difficult to assign causation; however, the clinical history strongly demonstrates an association of SC use and seizures. This previously healthy male presented with status epilepticus refractory to standard first- and second-line antiepileptic drugs without clear etiology despite thorough workup, a condition known as cryptogenic new-onset refractory status epilepticus, which carries a poor prognosis.19 It is estimated that approximately half of those presenting with status epilepticus do not have a past history of epilepsy. Although cases are usually related to structural, toxic, or metabolic causes, it is estimated that the etiology of 1 in 3 cases cannot be determined. Additionally, there is evidence that cryptogenic etiology predicts the progression of
status epilepticus to become increasingly refractory, consistent with the outcome of this case.20 We offer 2 possible explanations for Mr. M’s presentation. First, he could have been predisposed to a primary generalized epilepsy that may have become refractory because of central nervous system damage caused by SCs. As described in the case, he had a history of episodes of decreased level of consciousness noted by family, which could have been epileptic episodes associated with pre-existing epilepsy. Second, he could have had initial seizures triggered by substance abuse (or withdrawal), which over time evolved into a refractory state via brain circuitry changes akin to a kindling model.21 Although these 2 models may explain his initial hospital presentation, it is still unknown why he suffered a progressive course of increasingly intractable seizures, despite not having any detectable SC metabolites in his urine. We ultimately question whether exposure to SCs can provoke an ongoing and progressive form of status epilepticus, as in this case. Conclusions This case emphasizes the importance of considering SCs in the differential diagnosis of seizures in patients with substance abuse patterns. Additionally, clinicians and the public stand to benefit from awareness of potentially severe risks associated with these relatively novel drugs of abuse. Finally, more research is needed to clarify the possible etiologic link between SCs and seizures—as related both to their onset and refractoriness. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
References 1. Jerry J, Collins G, Streem D: Synthetic legal intoxicating drugs: the emerging ‘incense’ and ‘bath salt’ phenomenon. Cleve Clin J Med 2012; 79(4):258–264 2. American Association of Poison Control Centers: Available from: www.aapcc.org, accessed 06.01.16 3. Bush D, Woodwell D: Update: Drug-Related Emergency Department Visits Involving Synthetic Cannabinoids. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality; 2014. Available from: www.samhsa.gov, accessed 10.11.16
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4. Lapoint J, James LP, Moran CL, Nelson LS, Hoffman RS, Moran JH: Severe toxicity following synthetic cannabinoid ingestion. Clin Toxicol (Phila) 2011; 49: 760–764 5. Simmons JR, Skinner CG, Williams J, et al: Intoxication from smoking spice. Ann Emerg Med 2011; 57(2): 187–188 6. Simmons J, Cookman L, Kang C, Skinner C: Three cases of spice exposure. Clin Toxicol (Phila) 2011; 49(5): 431–433
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Case Reports 7. de Havenon A, Chin B, Thomas KC, Afra P: The secret “spice”: an undetectable toxic cause of seizure. Neurohospitalist 2011; 1(4):182–186 8. Schneir AB, Baumbacher T: Convulsions associated with the use of a synthetic cannabinoid product. J Med Toxicol 2012; 8(1):62–64 9. Tofighi B, Lee JD: Internet highs—seizures after consumption of synthetic cannabinoids purchased online. J Addict Med 2012; 6(3):240–241 10. Pant S, Deshmukh A, Dholaria B, et al: Spicy seizure. Am J Med Sci 2012; 344(1):67–68 11. Hermanns-Clausen M, Kneisel S, Hutter M, Szabo B, Auwarter V: Acute intoxication by synthetic cannabinoids—four case reports. Drug Testing and Analysis 2013; 5:790–794 12. McQuade D, Hudson S, Dargan PI, Wood DM: First European case of convulsions related to analytically confirmed use of the synthetic cannabinoid receptor agonist AM-2201. Eur J Clin Pharmacol 2013; 69(3):373–376 13. Gugelmann H, Gerona R, Li C, Tsutaoka B, Olson KR, Lung D: ‘Crazy Monkey’ poisons man and dog: human and canine seizures due to PB-22, a novel synthetic cannabinoid. Clin Toxicol (Phila) 2014; 52(6):635–638
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14. Schep LJ, Slaughter RJ, Hudson S, Place R, Watts M: Delayed seizure-like activity following analytically confirmed use of previously unreported synthetic cannabinoid analogues. Hum Exp Toxicol 2015; 34(5):557–560 15. Katz K, Leonetti A, Bailey B, et al: Case series of synthetic cannabinoid intoxication from one toxicology center. West J Emerg Med 2016; 17(3):290–294 16. Hoyte CO, Jacob J, Monte AA, Al-Jumaan M, Bronstein AC, Heard KJ: A characterization of synthetic cannabinoid exposures reported to the National Poison Data System in 2010. Ann Emerg Med 2012; 60(4):435–438 17. Harris CR, Brown A: Synthetic cannabinoid intoxication: a case series and review. J Emerg Med 2013; 44(2):360–366 18. Coulter D, DeLorenzo R: Basic mechanisms of status epilepticus. Adv Neurol 1999; 79:725–733 19. Dillien P, Santos S, Pesch V, Suin V, Lamoral S, Hanston P: New-onset refractory status epilepticus: more investigations, more questions. Case Rep Neurol 2016; 8:127–133 20. Jayalakshmi S, Vooturi S, Sahu S, Yada P, Mohandas S: Causes and outcomes of new onset status epilepticus and preditors of refractoriness to therapy. J Clin Neurosci 2016; 26:89–94 21. Chauvette S, Soltani S, Seigneur J, Timofeev I: In vivo models of cortical acquired epilepsy. J Neurosci Methods 2016; 260:185–201
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& 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Case Reports New-Onset Refractory Status Epilepticus Associated With the Use of Synthetic Cannabinoids Neil A. Patel, M.D., M.B.A., Jason M. Jerry, M.D., F.A.P.A., F.A.S.A.M., Xavier F. Jimenez, M.D., M.A., Stephen T. Hantus, M.D.
Introduction Synthetic cannabinoids (SCs) appeared in the United States (US) in 2008 as a drug of abuse. Although most commonly known as “K2” or “Spice,” SCs are distributed under a vast number of different names such as “Black Mamba,” “Funky Monkey,” “Happy Tiger Incense,” and “Crazy Monkey.” Today, abuse of these drugs has reached near epidemic levels in US urban areas such as New York and Los Angeles. SCs were initially touted as natural alternatives to cannabis that avoided detection on employer urine drug screens and were marketed as consumer products such as incense that were labeled as “not for human consumption” in an attempt to bypass scrutiny by legal authorities.1 The Synthetic Drug Abuse Prevention Act of 2012 designated several SCs as Schedule I, making them illegal to possess. Despite such legislation, abuse of these drugs remains widespread as evidenced by an increase in SCrelated calls to poison control centers over time.2 According to the Substance Abuse and Mental Health Services Administration (SAMHSA) and Drug Abuse Warning Network (DAWN) data, the number of emergency department visits involving SCs increased significantly from 11,406–28,531 between 2010 and 2011. Over the same timeframe, SC-related visits to emergency departments doubled among 12–17-year olds, quadrupled among 18–20-year olds, and tripled among females.3 These statistics reinforce the increasing prevalence of SCs in the community. Though epileptic seizures are not typically associated with the use of natural marijuana, numerous case reports have suggested an association with SCs (Table 1). 180
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Here, we present a case of a 19-year old, heavy SC user with a previous history of SC-associated seizures, who developed refractory epilepsy within this context.
Case Report Mr. M a 19-year-old man with a past medical history of hepatitis C and severe polysubstance use disorder, was transferred from an outside community hospital to our tertiary care, academic medical center, with persistent seizure activity. Collateral information was obtained from Mr. M’s girlfriend who revealed that he was in his usual state of health until a day before admission. She described that after entering the shower, he was observed to be unresponsive and staring in a bizarre fashion, subsequently falling with generalized jerking movements and bladder incontinence. Emergency medical services personnel originally transported Mr. M to a community hospital where he was diagnosed with an agitated delirium in addition to recurrent seizures. He was transferred to the neurologic intensive care unit at our Received September 15, 2016; accepted October 17, 2016. From the Department of Adult Psychiatry (NP), Cleveland Clinic, Cleveland, OH; Cleveland Clinic Alcohol and Drug Recovery Center (JJ), Cleveland Clinic Lutheran Hospital, Cleveland, OH; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (JJ, XJ, SH) and Consultation-Liaison Psychiatry (XJ) and Epilepsy Center (SH), Cleveland Clinic, Cleveland, OH. Send correspondence and reprint requests to Jason M. Jerry, M.D., F.A.P.A., F.A.S.A.M., Cleveland Clinic Alcohol and Drug Recovery Center, Cleveland Clinic Lutheran Hospital, Cleveland, OH. & 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Psychosomatics 58:2, March/April 2017
Patel et al. TABLE 1.
Selected Cases of SC-Related Seizure Episodes
Year Case description
SC compound
Reference
2011 A 48-year-old otherwise healthy man with generalized seizure after ingesting ethanol mixture containing white powder bought online, later confirmed to be synthetic cannabinoids. 2011 Several cases of men aged 21–27 with seizures, some with agitation, and normal drug screens, who all admitted to smoking Spicy XXX 2011 Several cases of males aged 15–19 with seizure activity after smoking SCs, and urine toxicology positive for JWH-018 and metabolites with or without JWH-073 2011 Case (1) A 24-year-old man with schizophrenia, experiencing 2 isolated GTC seizures. Case (2) A 36-year-old woman with substance abuse in remission and depression with GTC seizure progressing to status epilepticus requiring intubation 2012 A 19-year-old otherwise healthy man with 1–2 minute convulsion while smoking “Happy Tiger Incense.” 2012 A 48-year-old man who lost consciousness and had several seizures after smoking herbal blend 2012 A 48-year-old man with 2 GTCs who smoked 3 grams of Spice in addition to drinking alcohol 2013 A 19-year-old who smoked “Bonzai,” later developing tonic-clonic seizures, eventually requiring intubation and mechanical ventilation 2013 A 20-year-old man with self-limited tonic-clonic seizures after smoking “Black Mamba” 2014 A 22-year-old man with GTC seizure and combativeness, whose canine also had seizure after smoking “Crazy Monkey” 2014 A 23-year-old man, a daily user of SCs, with multiple GTC seizures
JWH-018
4
3 cases: “Spicy XXX”
5
3 cases: JWH-018
6
Two cases: “Funky Monkey” and “Black Mamba”
7
JWH-018, JWH-081, JWH-250, 8 AM-2201 “K2 Summit Blend” and 9 JWH-018 JWH-018 10 JWH-018, JWH-122, JWH-210 11 AM2201 PB-22 (“Crazy Monkey”)
BB-22; AM2233; PB-22; 5F-PB-22; JWH-122 2016 Three patients, including 2 of whom had pre-existing bipolar disorder, with seizures after MAB-CHMINACA SC use and required sedatives for agitation
12 13 14 15
GTC ¼ generalized tonic-clonic; SC ¼ synthetic cannabinoid.
hospital 19 days after the initial admission to the outside community hospital where he was found to have repeated seizures diagnosed as status epilepticus on continuous electroencephalography monitoring (Fig. 1). His medical course was complicated by sepsis, respiratory failure (requiring intubation with ventilation, and tracheostomy), nonischemic cardiomyopathy, acute kidney injury (requiring temporary dialysis), and Clostridium difficile infection. The first 24-hour bedside electroencephalography monitoring indicated right hemispheric cortical dysfunction with 3 seizures lasting 7–14 minutes each from right temporal and parietal regions (Fig. 1). He was having seizures several times per week. Despite multiple scheduled antiepileptic drugs, Mr. M required multiple doses of 2 mg intravenous (IV) lorazepam during these episodes to abort seizure activity. He also received several doses of quetiapine for control of agitation. Magnetic resonance imaging and computed tomography imaging of his brain performed days after initial incident were found to be unremarkable. Serum laboratory analyses showed elevated lipase and leukocytosis, each attributed to acute pancreatitis. Urine Psychosomatics 58:2, March/April 2017
drug screen at an outside hospital was positive for benzodiazepines only (which he had received while in the hospital), and no additional routine drug screen (including serum screening) was performed on arrival to our hospital. Urine screening performed 19 days after the initial incident by enzyme-linked immunosorbent assay detection by NMS Laboratories SynCann Screen 3 and 4 was negative for metabolites of SCs. Urine Pain panel 19 days after the incident was tested for 20 of the most common opioid analgesics and derivatives and was positive for fentanyl and its metabolite, which he had received while in the hospital. A lumbar puncture was performed for the following tests: routine cultures, paraneoplastic panel, fungal, cryptococcal, cytomegalovirus, herpes simplex, N-methyl-D-asparate receptor, Epstein-Barr, West Nile Virus, venereal disease research laboratory test, histoplasma, varicella-zoster virus, toxoplasma virus, listeria, Whipples studies—all of which were negative. Given the improvement in respiratory function and seizure control, Mr. M was extubated. At this time, he was able to communicate, and consultation psychiatry www.psychosomaticsjournal.org
181
Case Reports FIGURE 1.
Electroencephalography at Initial ICU Presentation
was consulted to assess agitation, hallucinations, and paranoia. During the initial psychiatric interview, Mr. M was inattentive, disoriented (to place, month, and context), and was unable to provide significant history. Pertinent neurological findings were diffuse hyperreflexia, horizontal nystagmus, and generalized myoclonus. Haloperidol was recommended for agitation, but used judiciously on account of concern for its ability to lower seizure threshold. Approximately 4 weeks after his last SC use, Mr. M was still experiencing seizures every 2–3 days, and some days he was having multiple recorded seizures. Seizures were often accompanied by upper extremity twitching, saccadic eye movements, or myoclonic jerks. Electroencephalography generally showed diffuse generalized encephalopathy, bilateral cortical dysfunction, and epileptogenicity arising from parietal-occipital areas. Seizures were effectively aborted with IV lorazepam. 182
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Given his delirium, Mr. M’s family was relied upon to provide most of his history. He had no formal prior psychiatric history, though the family expressed some concern that he may have had depressive symptoms as a child. He was on no scheduled home medications before admission. On the day before the shower seizure incident, he was noted to be withdrawn and in bed most of the day. The exact nature of his substance use leading up to this episode was unclear, but his girlfriend was highly concerned that he may have used SC as he had previously experienced seizures in relation to SC intoxication and was known to have been abusing the substance extensively during the 6 months preceding the event. The family corroborated that Mr. M had been using SCs in a binge-like fashion, but exact amounts were unknown. He was often noted to be lying around his home, withdrawn and appearing confused after smoking SCs, and he was thought to be Psychosomatics 58:2, March/April 2017
Patel et al. addicted based on witnessed behavioral outbursts when he was unable to obtain SCs. In addition, family described at least 2 seizure episodes temporally associated with SC binging. The family denied any history of seizures preceding his 6-month routine of using SCs. He had normal birth and developmental history, no family history of seizures, and no known history of traumatic brain injury or intracranial pathology. He was seronegative for human immunodeficiency virus. Family added that SCs were known to be a popular drug of abuse in their home town, expressing that they had heard of others in their small community who had experienced seizures after using SC products that were assumed to be procured from the same distributor used by Mr. M. Mr. M had a history of severe polysubstance use disorder which included sporadic use of cocaine, frequent use of marijuana, very sporadic use (perhaps once per month) of alprazolam to limit effects of intoxication or withdrawal from other substances, and a remote use history of opioids (oral therapeutic opioids and intravenous heroin). He had no significant history of alcohol use disorder. He had no known formal history of detoxification, rehabilitation, or chemical dependency treatment other than having been on buprenorphine for a brief period of time. After 2 months of his initial presentation to the outside hospital, Mr. M was discharged to a skilled nursing facility at which time he was fully alert and oriented, seizure-free for 5 days, and participating in hospital-based physical therapy. Unfortunately, 1 month after discharge, Mr. M was readmitted to an outside hospital for 3 days and subsequently transferred to our neurological intensive care unit owing to reemergence of seizure activity despite the use of 5 antiepileptic agents: lacosamide 200 mg by mouth (PO) 3 times daily (TID) (blood level of 4.2), levetiracetam 1500 mg PO TID (blood level of 23.1), zonisamide 300 mg PO twice daily (BID) (blood level of 10.3), clorazepate 15 mg PO BID (blood level of 297), phenobarbital 400 mg PO TID (blood level of 94.2). Shortly after this admission, he rapidly became increasingly unresponsive, unable to open his eyes on command, and not responding to noxious stimuli. His acute worsening was thought to be related to repeated seizure events as well as from increasing amounts of sedating antiepileptic medications for refractory seizures. Further investigations regarding the etiology of seizures included a repeat paraneoplastic panel that Psychosomatics 58:2, March/April 2017
was negative. Seizure episodes lacking specific foci and lasting up to several hours were repeatedly recorded on bedside electroencephalography monitoring. Multiple pharmacological strategies failed to suppress seizure activity, including ketamine, pentobarbital, a randomized trial of an experimental agent (SAGE-457) as part of a clinical trial for refractory seizures, and 2 rounds of IV immunoglobulin. Plasmapheresis similarly provided no relief. Further, 4 months after the initial presentation to the hospital, a positron emission tomography scan revealed diffuse cortical hypometabolism, without any focal evidence of asymmetry (Fig. 2). An magnetic resonance imaging scan of his brain performed 6 months after initial presentation was remarkable for bilateral symmetric thickening with T2/FLAIR hyperintensity of the fornices and undersurface of corpus callosum as well as diffuse cerebral volume loss (Fig. 3). Per the interpreting neuroradiologist, diagnostic considerations included drug-induced, toxic, or metabolic encephalopathies. Eight months after the initial presentation, Mr. M was discharged to a long-term acute care facility, after being seizure-free for 38 days. He remained unresponsive, requiring various life-sustaining treatments including tracheostomy and intubation with ventilator dependence, and enteral nutrition via percutaneous endoscopic gastrostomy tube. Mr. M’s antiepileptic drug regimen at discharge included the following medications by feeding tube: levitracetam 2000 mg TID, lacosamide 300 mg BID, felbamate 800 mg TID, FIGURE 2.
Positron Emission Tomography Scan (Brain)
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Case Reports FIGURE 3.
Axial FLAIR Magnetic Resonance Imaging Scan (Brain)
rufinamide 1200 mg BID, zonisamide 200 mg TID, clobazam 20 mg TID, clonazepam 2 mg 4 times daily (QID), topirimate 100 mg BID, phenytoin 325 mg TID (free blood level of 2.3), and phenobarbital 550 mg TID (blood level of 216). Mr. M was readmitted 3 weeks later with concern for small bowel obstruction, abdominal distension, and low ostomy output. He was operatively managed with exploratory laparotomy and manual bowel decompression. He was again discharged unresponsive to long-term acute care after 2 weeks of admission. He was readmitted 3 weeks following previous discharge with recurrent small bowel obstruction with computed tomographic abdominal imaging revealing pneumatosis and was not determined to be a surgical candidate at that time. He continued to have intractable seizures, with limited ability to decrease antiepileptic drugs without seizure recurrence. After extensive discussion with family and determination of poor neurologic prognosis, life-sustaining care was withdrawn. Mr M was declared deceased, approximately 10 months after the initial onset of status epilepticus. Discussion The differential for Mr. M’s seizures is wide, and includes substance-induced seizures, substance withdrawal seizures, pre-existing epilepsy, anoxic brain injury, traumatic brain injury, psychogenic, infectious, 184
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and metabolic causes. Brain biopsy was not performed but may have yielded findings suggestive of one of these mechanisms. Although the exact etiology of Mr. M’s initial seizure episode may never be confirmed definitively, the association between SCs and seizures is well known. Multiple reports have recently emerged linking SC use with temporally related and selflimiting seizures (Table 1). In a 9-month study of 1353 calls to poison control centers regarding SCs, 3.8% involved seizures with only 1 fatality.16 What makes the case presented here unique is that, unlike other examples reported in the literature, Mr. M’s seizures were not self-limiting and in fact evolved to a refractory state. Furthermore, 10 months after the initial presentation to the hospital, once life-sustaining measures were suspended, Mr. M ultimately died because of refractory seizures and associated morbidity. The association between seizures and SCs may seem counterintuitive because such effects are rarely seen in association with marijuana use, but authors have speculated about a possible etiology underlying this phenomenon. It is known that delta-9tetrahydrocannabinol (THC), the major cannabinoid in marijuana, inhibits gamma-aminobutyric acid (GABA) through its effects at the cannabinoid receptor type 1 (CB-1). Because most SCs are full agonists at CB-1, as compared with THC (only a partial agonist), it appears that GABA inhibition by these agents is more profound than that associated with natural cannabinoids and may explain their ability to induce epileptic seizures.17 Psychosomatics 58:2, March/April 2017
Patel et al. We postulate a mechanism that includes a complex multifactorial interplay of substance-induced alterations on central nervous system membrane potential, receptor expression, neurotransmitter conductance, circuitry remodeling, and neuronal loss.18 Presumably, a toxic insult to the central nervous system by this direct SC receptor site binding may injure brain tissue permanently with prolonged heavy use, with increased predisposition to recurrent seizures and limited healthy neural functioning to prevent epileptogenicity. In our case, the presence of an SC was not confirmed, as the only urine testing for SCs was performed on a sample collected 19 days after initial presentation to the hospital, making it very unlikely that any SCs would still be detectable. The history provided by Mr. M’s family indicated an extensive and heavy use of SCs as well as 2 prior discrete episodes of seizures in the preceding year that were temporally related to SC use. Furthermore, an extensive workup over the course of several months on Mr. M revealed no other plausible explanation for seizure activity or maintenance. It is difficult to assign causation; however, the clinical history strongly demonstrates an association of SC use and seizures. This previously healthy male presented with status epilepticus refractory to standard first- and second-line antiepileptic drugs without clear etiology despite thorough workup, a condition known as cryptogenic new-onset refractory status epilepticus, which carries a poor prognosis.19 It is estimated that approximately half of those presenting with status epilepticus do not have a past history of epilepsy. Although cases are usually related to structural, toxic, or metabolic causes, it is estimated that the etiology of 1 in 3 cases cannot be determined. Additionally, there is evidence that cryptogenic etiology predicts the progression of
status epilepticus to become increasingly refractory, consistent with the outcome of this case.20 We offer 2 possible explanations for Mr. M’s presentation. First, he could have been predisposed to a primary generalized epilepsy that may have become refractory because of central nervous system damage caused by SCs. As described in the case, he had a history of episodes of decreased level of consciousness noted by family, which could have been epileptic episodes associated with pre-existing epilepsy. Second, he could have had initial seizures triggered by substance abuse (or withdrawal), which over time evolved into a refractory state via brain circuitry changes akin to a kindling model.21 Although these 2 models may explain his initial hospital presentation, it is still unknown why he suffered a progressive course of increasingly intractable seizures, despite not having any detectable SC metabolites in his urine. We ultimately question whether exposure to SCs can provoke an ongoing and progressive form of status epilepticus, as in this case. Conclusions This case emphasizes the importance of considering SCs in the differential diagnosis of seizures in patients with substance abuse patterns. Additionally, clinicians and the public stand to benefit from awareness of potentially severe risks associated with these relatively novel drugs of abuse. Finally, more research is needed to clarify the possible etiologic link between SCs and seizures—as related both to their onset and refractoriness. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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