An 18-month-old (weight: 10 kg, height: 85 cm) previously medically and neurologically healthy full-term Asian female child was diagnosed with paracetamol overdose. The child was on bottle feeding and normal table food with no known drug or food allergy. She lives with her father and mother with no consanguinity between them as well as a sister and a brother who are all healthy without any family history of neurological disorders. The child accidentally ingested 60 ml (3000 mg; 300 mg/kg) of paracetamol suspension (Revanin suspension 250 mg/5 ml) as she favored its taste despite that she did not have fever or signs and symptoms of infection prior to ingestion. Her mother noticed the presence of a perioral stain on her face and immediately called the emergency that advised her to give the child cold milk until reaching the hospital. In the first community-based hospital, she was doing well without any cognitive impairment. Gastric lavage was done after 15–30 min of paracetamol ingestion and then the patient was transferred to another hospital to complete the management.

Four hours after ingestion, the paracetamol level was drawn, and it was within normal range. Additionally, three doses of N-acetyl cysteine (NAC) were ordered; 150 mg/kg, 50 mg/kg, followed by 100 mg/kg. During NAC infusion, the patient experienced non-projectile coffee ground vomiting, flushing, and rash on her face, abdomen, and neck. These symptoms were immediately managed and followed by the re-initiation of NAC at a slower rate. Several hours after admission, the patient’s condition deteriorated with recurrent episodes of convulsions on the right side that were managed with diazepam and phenobarbital, dilated pupils (sluggish reaction), weak response to pain stimuli, followed by unconsciousness. Over the subsequent days, the patient’s condition has gradually improved where the patient became conscious and responding well to pain stimuli. During the admission, the initial brain computed tomography scan (Philips, MX 16-slice, China) as well as liver, spleen, and kidneys ultrasound (Philips, Affiniti 50G, India) were normal. Additionally, lab results showed initial prolongation in prothrombin time and activated partial thromboplastin clotting time that were gradually normalized over several days after the administration of fresh frozen plasma and vitamin K. Moreover, liver function tests were normal despite a slight elevation in aspartate transaminase (AST) and alkaline phosphatase as well as a slight reduction in the total bilirubin level.

In the fifth day, the patient was transferred to another tertiary hospital for further evaluation and management, where vision loss was observed. Upon admission, the patient was lethargic and drowsy. However, the neurological examination was normal. In this day, the blood film showed leukocytosis with hyper-segmented neutrophils and the patient became febrile. Accordingly, lumbar puncture, cerebrospinal fluid (CSF) differential, CSF analysis, and polymerase chain reaction of the CSF were done, and their results ruled out the presence of encephalitis. Additionally, cultures of the CSF, blood, and urine were drawn and showed no growth. However, CSF analysis revealed high erythrocyte counts (375 cell/mm3) due to traumatic lumbar puncture. Enhanced brain magnetic resonance imaging (MRI) (Philips 1.5 T, Ingenia Rev. R5 V30-rev.02, the Netherlands) showed faint high T2/FLAIR signal intensity in the cortical and subcortical regions of both parieto-occipital lobes with sulcal effacement and restricted diffusion on diffusion-weighted imaging/apparent diffusion coefficient maps images that was reported as AL related to paracetamol toxicity (Fig. 1). Other findings included prominent subarachnoid spaces in both frontotemporal regions with an evidence of right cerebral convexity hyperacute subdural hematoma that depicts iso-T1, high T2, and FLAIR signal intensity measuring about 4 mm in thickness and was observed tracking along the anterior falx cerebri (Figs. 1 and 2). One week later, the patient was discharged on levetiracetam and phenobarbital as she developed recurrent convulsion episodes during her hospital stay.

Brain magnetic resonance imaging (MRI) at presentation. A Axial FLAIR image demonstrating high signal intensity with effacement in brain sulci seen in both parieto-occipital regions (thin white arrows). Notice the late subacute subdural hematoma along the right temporal convexity (thick arrow). B and C Axial diffusion-weighted images and apparent diffusion coefficient (ADC) map demonstrating diffusion restriction in the same areas consistent with paracetamol-induced acute leukoencephalopathy

Brain MRI with contrast after 3-month follow-up. A Coronal FLAIR images demonstrating high signal intensity at the site of previously demonstrated edema (Fig. 1A) consistent with gliosis (thin white arrows). Notice the subacute subdural hematoma at the right cerebral convexity (thick arrow). B This same area showed subtle high T2 signal and volume loss (arrows). C Axial T1 post-contrast images demonstrating leptomeningeal enhancement (arrows). D and E Axial diffusion-weighted images and ADC map demonstrating increased diffusivity in the same areas at follow-up (arrows)

A follow-up enhanced brain MRI scan (Philips 1.5 T, Ingenia Rev. R5 V30-rev.02, the Netherlands) was performed after 3 months (Fig. 2) and showed involutional changes of the AL manifesting as brain volume loss in the same areas with evidence of gyri-form laminar necrosis in both parieto-occipital regions. No restricted diffusion was noted. The patient was re-admitted for methylprednisolone pulse 20 mg/kg/day and then she was discharged on oral prednisolone for several days. The patient still has vision loss despite a newer appreciation to light, can fully talk and walk, and become on levetiracetam alone.

In general, it has been proposed that the effect of paracetamol overdose on the brain could be attributed to excessive oxidative stress that may be explained by several mechanisms [11]. Firstly, the effect of the N-acetyl-p-benzoquinonimine metabolite that may result from the metabolism of paracetamol in nerve cells by cytochrome P450 2E1 isoform that is expressed in the brain [11]. N-Acetyl-p-benzoquinonimine formation may lead to oxidative stress and neurotoxicity by decreasing glutathione levels [11]. Additionally, paracetamol overdose may increase acetylcholine plasma levels and lower the levels of antioxidative stress candidates with a reduction in superoxide dismutase activity [11]. In our case, although alanine transaminase and AST levels were mildly elevated, they were not indicative of hepatotoxicity. It is crucial to note that alanine transaminase and AST are not specific markers for liver injury [12]. According to the literature, children may be less vulnerable to paracetamol-induced hepatic toxicity due to differences in drug metabolism, and detoxification pathways [12]. While many studies have linked neurotoxicity in paracetamol overdose to acute liver failure, emerging evidence suggests that high doses of paracetamol can cause “in situ” brain tissue toxicity without associated hepatic toxicity [9, 10]. This effect may be explained by paracetamol’s action as a direct mitochondrial toxin [9].

Additionally, it has been reported that paracetamol readily crosses the blood-brain barrier and is distributed homogenously throughout the central nervous system, even at low doses [13]. Its role as a cannabinoid system modulator has also been proposed as a factor contributing to neurotoxicity [10]. This could account for the neurological manifestations observed in our patient, despite the lack of definitive evidence of hepatic toxicity.

To our knowledge, this is the second case report stating the occurrence of AL that is complicated by cortical blindness due to paracetamol overdose. The first case report was for a 3-year-old child who experienced AL with restricted diffusion that was complicated with cortical blindness after the ingestion of 200 mg/kg of paracetamol [14]. The findings in this report were consistent with the initial brain MRI findings of the current report in which the AL was associated with restricted diffusion.

Toxic leukoencephalopathy (TL) is defined as a spectrum of histopathological features that are associated with structural alterations in the cerebral white matter in addition to the clinical features that may include personality changes, dementia, inattention, and forgetfulness [15, 16]. TL could be acute or chronic and may result from the administration of leukotoxic agents, involving antineoplastic agents, immunosuppressive agents, cranial irradiation, antimicrobial agents, and environmental agents [15,16,17].

Acute TL (ATL) is an uncommon condition with clinical features that range from mild cognitive impairment to severe neurological impairment [17]. Despite that the exact pathophysiology of ATL is still unclear, it is hypothesized that the effect of the toxic agent in ATL may lead to a damage in the white matter either by direct injury of the myelin sheath and/or indirect injury on the capillary endothelium [17]. The imaging changes associated with ATL may be initially emerged on DWI with focal or symmetric reduced diffusion in the periventricular white matter that may be accompanied with lesions on FLAIR [17]. While the histopathological changes may include both intramyelinic and oligodendroglial swelling [17].

AL in the current report was complicated by cortical blindness which is defined as a vision loss with normal fundus and pupillary light secretions [18]. Cortical blindness-complicated leukoencephalopathy was observed in case reports of selenium and cyclosporine toxicities [19, 20]. While direct evidence linking paracetamol toxicity to AL remains sparse, the exclusion of other potential causes, alongside the growing body of literature on paracetamol-induced CNS toxicity, lends support to our hypothesis. However, the exact association between cortical blindness and ATL is still unclear.

Other brain MRI findings in the current report include subdural hematoma which is defined as an extra-axial collection of blood products in the subdural space that resulted from the tearing of the bridging cortical veins crossing the subdural space [21]. The occurrence of subdural hematoma could be justified by several reasons including the traumatic lumbar puncture and the initial prolongation in prothrombin time and activated partial thromboplastin clotting time since coagulopathic abnormalities may lead to subdural hematoma [21, 22]. Additionally, there is an association between the enlargement of subarachnoid space and subdural hematoma [23]. This association could be explained by two different theories; the first theory suggested that the enlargement may stretch the bridging veins and result in their rupture either spontaneously or by the effect of a minor trauma [23]. On the other hand, the second theory proposed that subdural hematoma may predispose the enlargement in the subarachnoid space that may be partially justified by the alterations in the physiology of CSF absorption after subdural hematoma [23]. However, the enlargement in the subarachnoid space could be a benign self-limiting physiological process [23].

In the current case report, the lack of detailed information in the first two hospitals may be considered a limitation. As an example, the unit of paracetamol level was unknown, and it was reported normal with a number only since the test was conducted in a private laboratory. Such missed information may affect the interpretation of some clinical findings and the overall sequence of the events in the case.

In summary, an 18-month-old child experienced cortical blindness-complicated AL after paracetamol overdose (300 mg/kg). It has been proposed that the toxic agents may result in AL by direct and/or indirect damage of the white matter. Moreover, it has been hypothesized that excessive oxidative stress is the most popular mechanism of paracetamol overdose on the brain. However, further studies at the cellular and genetic levels are still needed to explore the exact neurotoxic effects of paracetamol, particularly in pediatric populations.