The Pathophysiology of Marijuana-induced Encephalopathy and Possible Epilepsy after Ingestion in Children: A Case Series

Abstract

Background: Ingestion of marijuana in children presents primarily with encephalopathy and potentially, in severe cases, seizures. There is a growing body of evidence supporting the benefit of medical marijuana as an anticonvulsant treatment for intractable seizures. However, there are limited data regarding its proconvulsant effects after ingestion. In this case series, we review the pathophysiology of marijuana encephalopathy and potential seizures after ingestion of marijuana in infants and young children. Case presentation: We summarized the cases of six children who were admitted to the hospital with neurological symptoms and a positive urine test for tetrahydrocannabinol (THC) between 2016 and 2018. The primary symptom was excessive drowsiness, with two children progressing to an unarousable state. Two cases presented after ingesting a marijuana confectionery, and the caregivers in four cases were unaware that marijuana exposure was responsible for the clinical presentation. All cases resolved without sequelae and were investigated by social services. In one case, a 6-year-old child with developmental delay and a previous episode of seizures presented with recurrent seizures and evidence of marijuana exposure. Marijuana was considered a probable cause due its proconvulsant effects, but a subsequent seizure episode with a negative urine THC ruled this out. Conclusion: Physicians should consider the possibility of ingestion of marijuana in infants and young children who present with symptoms of unexplained drowsiness. Marijuana products have the potential to provoke seizures and affect the developing brain of a child. Self-medication with marijuana products should be dissuaded, particularly in households with young children.

Clinical evidence has emerged regarding the benefit of medical marijuana for the treatment of refractory epilepsy in children. However, research in this area is currently ongoing.^1,2 The mechanism of exogenous cannabinoids is thought to mimic the brain’s endocannabinoid system, protecting against convulsive activity. The psychoactive component, ∆9-tetrahydrocannabinol (∆9-THC), and the nonpsychoactive component cannabidiol, which is found in medical marijuana, exhibit anticonvulsant activity through different mechanisms.³ However, studies investigating its proconvulsant activity in children after ingesting marijuana is limited. The ingestion of marijuana by children presents primarily with encephalopathy, which can be further complicated by seizures and respiratory compromise, requiring ventilator support.^4,5 In this article, we report six cases of marijuana-induced encephalopathy in children, including a case with previous history of seizure and developmental delay. In addition, we explore the mechanism of marijuana-induced encephalopathy and its proconvulsant activity.

CASE REPORTS

All cases were referred to social services for assessment prior to discharge.

Case 1. A six-year-old female patient was admitted to the Cornwall Regional Hospital in Montego Bay, Jamaica, with generalized tonic-clonic seizures lasting 15 minutes. Three months earlier, the patient had been admitted due to two episodes of generalized tonic-clonic seizures lasting 15 and 20 minutes, respectively. Clinical examination at the time of initial admission, including computed tomography (CT), complete blood count (CBC), and measurement of urea and electrolytes (UEs), were unremarkable. Her medical record indicated that the mother had an uncomplicated pregnancy, labor, and delivery. The patient also had a history of motor and communication delay. She began walking at 15 months of age, verbalized single words at two years of age, and spoke in sentences at three years of age. The patient had met appropriate milestones for her age; however, she was unable to follow the age-appropriate curriculum in school. Her social history revealed domestic exposure to second-hand marijuana smoke, and her urine tested positive for THC. Postseizure clinical evaluation was unremarkable, and her electroencephalography was normal. She remained in the hospital until a home evaluation was performed by social services. The patient was readmitted nine days after discharge with a similar episode of seizure. Her urine tested negative for THC, and valproic acid was administered at incremental doses. Thus far, she has remained seizure-free for six months.

Case 2. A previously healthy 10-month-old boy was admitted to the emergency room, presenting with symptoms of excessive drowsiness and inability to be aroused from sleep. The patient did not have a history of trauma, fever, or ingestion of poisonous substances. Clinically, he was lethargic with a pulse rate (PR) of 116 beats per minute, a respiratory rate (RR) of 26 breaths per minute, and an oxygen saturation of 99 percent on room air. Apart from lethargy, the examination was unremarkable. Moreover, CBC, measurement of blood urea nitrogen (BUN) and electrolytes, liver function tests (LFTs), the levels of random blood glucose (RBG), cerebrospinal fluid (CSF) analysis, and brain CT were within the normal range. The patient’s urine was positive for THC. The child’s stool sample had an odor indicative of marijuana. Furthermore, “grabba”—a mixture of marijuana and tobacco —was found on the couch on which the child was playing. The infant recovered after a 24-hour observation period.

Case 3. An 11-month-old boy presented with excessive drowsiness for prolonged periods. His medical record did not indicate recent infection, trauma, or accidental poisoning. Despite lethargy, the clinical and laboratory evaluation (i.e., CBC, electrolytes, BUN, creatinine, LFTs, RBG) was unremarkable. His parents did not consent to performing a lumbar puncture, and the urine was positive for THC. A family member reportedly smoked marijuana. The child fully recovered after a 24-hour observation period.

Case 4. A 15-month-old boy was admitted to the hospital, presenting with symptoms of excessive drowsiness. He was easily awakened but would return to sleep shortly afterward. He had an upper respiratory tract infection two weeks prior to admission and had recovered without other reported adverse events. Physical examination revealed lethargy and irritability when handled. His temperature was 98.0°F, PR was 97 beats per minute, RR was 24 breaths per minute, oxygen saturation was 97 percent on room air, and blood pressure was 93/48mm/Hg (normal: 90/50mm/Hg). In addition, laboratory evaluation, CSF analysis, and brain CT were unremarkable. His urine was positive for THC, and further historical evaluation revealed that a family member smoked marijuana in the household. The infant fully recovered after a 24-hour observation period.

Case 5. A four-year-old boy was admitted to the emergency room with symptoms of tremors of the hands lasting three seconds followed by a blank stare and inability to speak. He reportedly ingested candy infused with marijuana five hours earlier. Although at the time of admission to the emergency room he was alert, he progressively became drowsier and eventually became unresponsive. He was afebrile with a PR of 60 beats per minute (normal 80–120 beats per minute), RR of 24 breaths per minute, oxygen saturation of 93 percent on room air, with sluggish pupils and a Glasgow coma score of 9 out of 15. He received treatment with intravenous atropine, oxygen therapy, and maintenance intravenous fluids with 5% dextrose in 0.2% saline. Laboratory evaluation (CBC, electrolytes, BUN, creatinine, LFTs, and RBG) was normal. His urine tested positive for THC. He recovered after 24 hours of neuro-observation.

Case 6. A 7-year-old boy presented with symptoms of excessive drowsiness, visual and auditory hallucinations, and tachycardia after ingesting a brownie containing marijuana. The CBC, UEs, BUN, RBG, and creatinine were within the normal range, and an electrocardiography was unremarkable. His urine tested positive for THC. He was observed for 24 hours, after which all symptoms resolved.

DISCUSSION

The clinical manifestations of the cases presented in this series are consistent with those reported in earlier studies of marijuana ingestion.^4,5 All children, with the exception of Case 1 (6-year-old patient with developmental delay and prior seizure episode), were previously healthy with normal growth and development and appropriate immunization records for their respective ages. The primary symptom in Cases 2 through 5 was excessive drowsiness, unusually prolonged sleeping, and, in two cases, an inability to be awakened from sleep. The caregivers in four of the cases did not report ingestion of drugs or toxins, injury, or evidence of infection upon presentation to the emergency room. The clinical examinations were unremarkable except for drowsiness and irritability, with two cases reaching unresponsive and unarousable states. Smoking of marijuana by a member of the household was subsequently identified in four cases. Moreover, ingestion of marijuana confectionery (a brownie and cannabis-infused candy) hours prior to the presentation of symptoms was reported in two cases. All children recovered within 24 hours.

It is not unusual for toddlers to explore their environment using their mouths and indiscriminately ingest objects that might have fallen to the floor. In addition to second-hand smoke inhalation and ingestion, children also might be exposed through maternal use of cannabis during pregnancy. Studies have shown that infants born to mothers who used marijuana during pregnancy were more likely to be small relative to their age, have a low birth weight, and/or require admission to the neonatal intensive care unit (NICU).^6,7 Furthermore, examination of these infants using the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) demonstrated mild delays in the development of their visual systems and increased startle response shortly after birth. These findings did not persist at one month of age, and there were no associated behavioral changes identified following further evaluation with the BNBAS.⁷ The child in Case 1 who exhibited developmental delay and epilepsy did not have a record of perinatal exposure to cannabis, and the etiology of her condition was not ascertained historically or from clinical, laboratory, and radiological studies.

The clinical presentation of exposure to cannabis usually includes nausea, vomiting, dry mouth, thirst, pallor, hypothermia, and eye redness. Neurological symptoms include decreased muscular tone, unsteady gait, change in pupillary reflexes, hypothermia, decreased reflexes, irritability, and perceptual disturbances. These symptoms resolve without sequelae in the majority of children. However, severe complications, such as seizures, respiratory depression, or coma requiring admission to the intensive care unit have been documented.^4,5 In Case 1, a positive urine test for THC was documented during a seizure episode, prompted by a history of probable exposure in the household. Seizures are a known complication in severe cases of marijuana ingestion.^4,5 Although exposure to marijuana was considered a probable cause of seizure exacerbation in Case 1, a negative urine test for THC at a subsequent seizure episode ruled out this possibility.

Data from animal and human studies are contradictory regarding the anticonvulsant and proconvulsive effects of cannabinoids, with the majority of evidence supporting the former.^8,9 In animal studies, the epileptogenic potential of the THC component has been shown to be mediated through cannabinoid receptor Type 1 after intrathecal injections in mice.⁸ However, these levels were at higher doses than those associated with inhalation or ingestion of cannabis in humans. Generalized tonic-clonic seizures following use of synthetic cannabinoid receptor agonists or toxic exposure to marijuana has been reported in adult patients, which supports this theory.¹⁰ The induction of seizures is thought to be due to an increased proportion of ∆9-THC to cannabidiol in the products used and the underlying conditions in the patient.¹¹

A review of the pharmacology of cannabinoids demonstrated that, after inhalation, the substance rapidly enters the bloodstream from the lungs and reaches the brain in 6 to 10 minutes.^12,13 Following oral ingestion, the cannabinoids are slowly absorbed by the gut and metabolized in the liver, resulting in blood concentrations of 25 to 30 percent less than the dose obtained through smoking. The result is a delay in the onset of symptoms by 2 to 6 hours and a prolonged effect due to slow absorption by the gut. Infants who ingest marijuana might experience a delayed onset of symptoms, which might then delay the recognition of the possible ingestion, and the effects might be prolonged. In Case 2 of this series (10-month-old patient), the caregivers did not associate the ingestion of marijuana to the infant’s symptoms until diagnosis through a positive urine test for THC and the discovery of marijuana on a couch on which the child was playing.

The metabolites are excreted from the urine (25%) and the stools (65%), explaining the intense marijuana odor reported in the stool of one of the cases. In addition, the cannabinoids are also sequestered in fat, resulting in a second phase of release into the bloodstream that prolongs complete clearance. This might explain the delayed clearance from the urine 24 hours after initial recovery. Clinical improvement has been correlated with a decline in urinary THC levels.¹⁴

We propose that, in severe cases, the small size of children in relation to the amount of marijuana exposure, along with a developing endocannabinoid system, might trigger the proconvulsant effect previously demonstrated in mouse models.⁸ In the present series, the effect of marijuana did not appear to abate the seizures in Case 1, who had a prior history of seizure. We theorize that, in this case, the effective level or cannabidiol/∆9-THC ratio might not have been present. The suggestion that toxic levels of marijuana might have exacerbated seizures cannot be ascertained due to the subsequent seizure that occurred in Case 1 without evidence of exposure to marijuana.

Because of the increased awareness regarding the medicinal value of marijuana for seizures, patients have been more willing to self-medicate using these compounds, especially after failed medical management.¹⁵ However, there is an inherent danger in the self-administered, unregulated use of marijuana products for therapeutic purposes. The side effects induced by the psychoactive component, which has not been removed in self-administered marijuana extracts, might be deleterious to children. In addition, the endocannabinoid system in children and adolescents is still developing. Long-term exposure to marijuana compounds might lead to cognitive and behavioral changes, with evidence of altered structure and function in the hippocampus, amygdala, prefrontal cortex, and precuneus.⁹

CONCLUSION

Young children who frequently encounter marijuana products in their environment and/or have easy access to marijuana products, by nature, are at high risk of ingesting the products. Additionally, the developing brain of a young child is more vulnerable to the potentially toxic effects of marijuana smoke inhalation than the brain of an adult. The slow absorption by the gut might delay diagnosis after ingestion in infants and children; hence, treating physicians should consider the possibility of exposure to marijuana in children or toddlers who present with unexplained encephalopathy. Public health campaigns should be implemented to educate the public on the potential negative effects of marijuana use, particularly in infants and children. Although there is a substantial body of evidence supporting marijuana’s anticonvulsant effects, ingestion of large doses of marijuana in relation to the small body size of a child might mimic the epileptogenic potential described in animal studies. Marijuana products include a combination of psychoactive and nonpsychoactive components that have the potential to induce seizures, depending on the cannabidiol/∆9-THC ratio, and can exert long-term effects on the developing brain of a child. Therefore, patients should be dissuaded from self-medicating with marijuana products, particularly if they reside with infants and/or young children.

ACKNOWLEDGMENTS

We would like to acknowledge the contribution of Dr. Leila Famouri and Dr. Sarah Bowen, who were visiting Global Health students from the Global Health Program at West Virginia University, and Dr. Judy Tapper, a pediatric neurologist at Bustamante Hospital for Children in Kingston, Jamaica, for review of the final manuscript.