Methylene blue for treating toxic encephalopathy due to acute nickel poisoning: A case report

Abstract

BACKGROUND

Acute nickel poisoning is a rare clinical entity with no established management guidelines. Diagnosis is often delayed by non-specific clinical presentations that can mimic other common toxidromes, such as organophosphate poisoning.

CASE SUMMARY

A female in her late twenties presented with a Glasgow Coma Scale of 3, profound hypotension, miosis, and hypersalivation following intentional ingestion of an unlabeled toilet cleaner. Initial management for suspected cholinergic toxidrome and corrosive ingestion failed to achieve clinical stability. The patient developed refractory vasoplegic shock and went into a deep coma. Magnetic resonance imaging revealed cytotoxic lesions of the corpus callosum, suggesting toxic encephalopathy. Comprehensive toxicological screening by inductively coupled plasma mass spectrometry confirmed severe nickel toxicity with significantly elevated levels in the blood, urine, and cerebrospinal fluid (55.5 μg/L). Methylene blue, initially administered as a rescue therapy for vasoplegic shock, was associated with a paradoxical spike in urinary nickel excretion (from 8.8 μg/L to 51.9 μg/L) and a rapid decline in serum levels. This biochemical “washout” coincided with dramatic neurological recovery from Glasgow Coma Scale of 3 to 15 within 72 hours.

CONCLUSION

Early comprehensive toxicological screening is essential in patients with suspected poisoning by unknown substances. In this case, nickel toxicity was confirmed by prompt screening. In the absence of standard treatment protocols in rare poisoning cases, treatment is largely supportive. The apparent clinical benefit of methylene blue-mediated nickel clearance in this case remains speculative.

Key Words: Acute nickel toxicity; Toxic encephalopathy; Methylene blue; Corrosive ingestion; Toxidrome; Case report

Core Tip: Standard therapies failed to treat atypical cholinergic toxidrome and refractory vasoplegic shock caused by the ingestion of routine toilet cleaner. An exhaustive toxicology screen revealed acute nickel poisoning, accompanied by central nervous system metal sequestration and a unique cytotoxic lesion of the corpus callosum revealed by brain magnetic resonance imaging. Remarkably, rescue therapy with methylene blue for the shock correlated with a paradoxical spike in urinary nickel excretion and rapid clinical recovery. While the biochemical washout mechanism remains hypothetical, this case offers a crucial clinical framework for managing rare heavy metal toxicity when standard chelators are unavailable.

INTRODUCTION

Poisoning by unknown substances is a challenge frequently encountered in the emergency department, requiring a management strategy guided by clinical toxidromes. While rare, nickel toxicity typically presents with acute gastrointestinal distress, respiratory failure, and neurological symptoms, often requiring chelation therapy as the standard of care[1]. However, initial presentation can be deceptive. Here, we report a case of toilet cleaner ingestion leading to nickel toxicity that initially mimicked the more common organophosphorus poisoning due to similar cholinergic features. Given the absence of standard interventions or established protocols in such rare poisoning, we discuss the unconventional but successful usage of methylene blue (MB) to manage the patient’s symptoms of nickel poisoning.

CASE PRESENTATION

Chief complaints

A female in her late twenties, weighing 63 kg, presented to the emergency department following intentional ingestion of an unknown quantity of an unidentified liquid toilet cleaner.

History of present illness

On arrival, the patient was deeply comatose with a Glasgow Coma Scale (GCS) score of 3 (E1V1M1). Clinical examination revealed miosis, hypersalivation, increased bronchial secretions, and profound hypotension, suggestive of a cholinergic toxidrome[2]. She underwent immediate endotracheal intubation, mechanical ventilation, fluid resuscitation, and vasopressor support. Given the apparent cholinergic presentation and the high regional prevalence of organophosphorus poisoning, atropine therapy was initiated and escalated to 10 mg/hour. This presentation was clinically confounding, as most household toilet cleaners contain phenols or inorganic acids, which do not typically manifest with such features[3,4]. However, persistent shock despite atropine administration, together with the absence of diarrhea, lacrimation, and emesis, prompted reconsideration of the diagnosis. A contrast-enhanced computed tomography scan demonstrated diffuse mucosal edema extending from the esophagus to the terminal ileum without evidence of perforation. Therefore, management was redirected toward supportive treatment for corrosive poisoning with proton pump inhibitors and dual vasopressor support guided by minimally invasive cardiac output monitoring.

Despite cessation of sedation, the patient remained deeply comatose (GCS E1VTM1) with fixed miotic pupils. Subsequently, relatives recovered the empty container used for ingestion. Although the manufacturer's label was absent, residual liquid was available and was submitted for toxicological analysis with blood and urine samples. Gastric sampling was not performed because of concerns regarding gastrointestinal perforation.

On the second hospital day, the patient developed worsening vasoplegic shock refractory to dual vasopressor therapy and high-dose corticosteroids. Intravenous MB (100 mg over 30 minutes) was administered as rescue therapy, resulting in marked hemodynamic improvement and a reduction in vasopressor requirements[5]. Due to persistent coma, magnetic resonance imaging of the brain was performed and revealed features consistent with toxic encephalopathy and cytotoxic lesions of the corpus callosum (CLOCCs). Toxicological analysis subsequently revealed markedly elevated nickel concentrations in the residual liquid, blood, and urine. Elevated nickel concentrations in the cerebrospinal fluid confirmed central nervous system (CNS) exposure. Based on the favorable hemodynamic response, MB was continued at 100 mg daily for 3 additional days. Treatment was associated with a progressive decrease in serum nickel concentrations, increased urinary nickel excretion, resolution of shock, and neurological recovery. The patient’s GCS improved to 11 (E4VTM6), permitting successful extubation within 48 hours and subsequent transition to oral intake. A chronological summary of events is provided in Table 1.

Table 1 Clinical timeline and treatment milestones.

Timepoint	Clinical status and diagnostic findings	Interventions and management
Day 1 (admission)	GCS 3 (E1V1M1); signs of cholinergic toxidrome (miosis, secretions, shock)	Intubation, mechanical ventilation, and IV atropine infusion
Day 1 (ICU)	Refractory shock; non-responsive to atropine. CECT shows grade 2 corrosive edema	Dual vasopressors (noradrenaline + vasopressin) initiated
Day 2	Comatose with fixed pupils. Refractory vasoplegic shock. Toxicology samples sent	First dose MB (100 mg IV) administered as rescue therapy
Day 2 (post-MB)	Significant hemodynamic stabilization; vasopressors tapered	MRI brain performed (revealing CLOCC pattern/toxic encephalopathy)
Day 3	Sensorium remains low. Toxicology confirms nickel toxicity (blood, urine, and CSF)	Second dose MB (100 mg IV); high-dose PPI continued
Day 4	Hemodynamics stable. Significant drop in serum nickel; spike in urinary clearance	Third dose MB (100 mg IV)
Day 5	Rapid neurological recovery; GCS improves to 11 (E4VTM6)	Vasopressors discontinued; patient successfully extubated
Day 7	Patient alert and oriented (GCS 15)	Transitioned to oral intake; prepared for discharge

CECT: Contrast-enhanced computed tomography; CLOCC: Cytotoxic lesions of the corpus callosum; CSF: Cerebrospinal fluid; GCS: Glasgow Coma Scale; ICU: Intensive care unit; IV: Intravenous; MB: Methylene blue; MRI: Magnetic resonance imaging; PPI: Proton pump inhibitor.

History of past illness

No significant past medical history was reported.

Personal and family history

No significant family history was reported. The ingestion was determined to be intentional.

Physical examination

At presentation, the patient had a GCS score of 3 (E1V1M1), bilateral miosis, hypersalivation, increased bronchial secretions, and profound hypotension.

Laboratory examinations

Comprehensive toxicological analysis demonstrated markedly elevated nickel concentrations in the residual liquid, blood, urine, and cerebrospinal fluid (Table 2). Serial laboratory monitoring demonstrated a rapid decline in serum nickel levels that occurred in close, chronological correlation with a paradoxical spike in urinary nickel clearance following MB therapy.

Table 2 Longitudinal nickel concentrations in relation to methylene blue administration.

Timepoint	Blood nickel (μg/L)	Urine nickel (μg/L)	CSF nickel (μg/L)
Baseline (after 1st dose MB)	15.2	21.0	-
Before 3rd dose MB	7.4	8.8	55.5
After 3rd dose MB	4.8	51.9	-
48 hours post-3rd dose	3.7	1.8	-
72 hours post-3rd dose	2.1	5.6	-
96 hours post-3rd dose	0.0	0.0	-
Reference range	0.14-0.65	< 5.2	-

The ingested toilet cleaner concentration was 3468 μg/L. All levels were analyzed using inductively coupled plasma mass spectrometry. MB: Methylene blue; CSF: Cerebrospinal fluid.

Imaging examinations

Contrast-enhanced computed tomography demonstrated diffuse mucosal edema extending from the esophagus to the terminal ileum without perforation. Magnetic resonance imaging of the brain revealed T2/fluid-attenuated inversion recovery hyperintensities and diffusion restriction involving the splenium of the corpus callosum and bilateral centrum semiovale, with punctate microhemorrhages at the gray-white matter junction (Figure 1). These findings were consistent with CLOCCs[6].

Figure 1 Magnetic resonance imaging findings of nickel-induced toxic encephalopathy. A: T2/flair hyperintensity in corpus callosum (orange arrow); B: Few small microhemorrhages in bilateral cerebral hemispheres at grey-white matter junction on susceptibility-weighted imaging (yellow arrow); C: Diffusion restriction and apparent diffusion coefficient: Diffusion restriction in splenium (green arrow).

FINAL DIAGNOSIS

Acute nickel poisoning following ingestion of a household toilet cleaner, complicated by corrosive gastroenteritis, toxic encephalopathy with CLOCCs, CNS nickel sequestration, and refractory vasoplegic shock.

TREATMENT

The patient was managed with mechanical ventilation, fluid resuscitation, atropine therapy, proton pump inhibitors, vasopressor support with noradrenaline and vasopressin, and intravenous MB.

OUTCOME AND FOLLOW-UP

The initial administration of intravenous MB led to a dramatic and rapid stabilization of the patient's hemodynamic status, which allowed the clinical team to aggressively taper and completely discontinue all vasopressor support. This maintenance regimen was accompanied by a rapid clearance of systemic nickel from the blood and a simultaneous, marked increase in urinary nickel excretion. As the blood nickel levels normalized, the patient’s neurological status substantially improved to a GCS score of 11 (E1VTM1), resulting in successful extubation within 48 hours of therapy completion.

DISCUSSION

Current landscape of nickel toxicology and management constraints

The extreme scarcity of literature on acute nickel poisoning presents a formidable diagnostic and therapeutic challenge, as established treatment guidelines are virtually non-existent. While chelation therapy is often discussed in more common heavy metal poisonings, its clinical utility remains highly controversial in nickel toxicity. Chelating agents such as disulfiram and dimercaprol have sometimes been used; however, their efficacy is questionable, and some data even suggest an associated increase in mortality[7]. Furthermore, disulfiram can paradoxically redistribute nickel into the CNS, potentially exacerbating acute neurotoxicity[8]. Given our patient’s profound neurological impairment and radiological evidence of significant brain involvement, disulfiram was intentionally avoided. Another compound that has been considered an effective nickel chelator is sodium diethyldithiocarbamate[7]. However, lack of its availability in the country required alternative therapeutic strategies.

Extracorporeal elimination techniques such as hemodialysis are not effective therapeutic options in nickel poisoning, as nickel is highly bound to albumin in the blood, rendering it poorly dialyzable[1]. Therefore, treatment options were restricted to supportive care and cautious use of novel rescue approaches.

The methylene blue hypothesis: Observation vs proven mechanism

MB was initially administered as a rescue measure for refractory vasoplegic shock, utilizing its established role as an inhibitor of the nitric oxide-cyclic guanosine monophosphate pathway[4]. It was not intended as a targeted treatment for nickel toxicity. However, the subsequent clinical and biochemical course raises an intriguing, albeit speculative, hypothesis regarding a potential chemical interaction.

While there is no established pharmacokinetic data or prior medical literature describing MB as a heavy metal antidote, chemical industries routinely use nickel-based compounds as highly effective nano-sorbents to remove MB dye from aqueous industrial waste[9]. In retrospect, we hypothesize that a similar molecular affinity might exist in vivo and MB may complex with systemic nickel, potentially reducing its lipophilicity through electrostatic interactions and facilitating its redistribution or clearance[10].

However, in the absence of in vitro binding experiments or controlled pharmacokinetic trials, the role of MB as a potential chelating agent remains strictly hypothetical. The observed clearance patterns must be interpreted as a descriptive correlation rather than definitive clinical efficacy.

Pharmacokinetic observations and tissue redistribution

Under normal physiological conditions, nickel exhibits first-order elimination kinetics, where urinary concentrations typically mirror declining serum levels. However, following MB administration, we observed a highly divergent trend: A dramatic, paradoxical spike in urinary nickel excretion (rising from 8.8 μg/L to 51.9 μg/L) alongside a concomitant decrease in serum levels (Table 2).

While the overall trend in urinary nickel concentration showed a significant downward trajectory, a minor secondary rise was observed between the 48-hour and 72-hour marks (from 1.8 μg/L to 5.6 μg/L). This fluctuation likely represents a rebound phenomenon or late-phase redistribution, where nickel sequestered in deep peripheral tissue compartments, such as viscera or bone, is slowly released into the plasma as systemic concentrations reach a nadir. Such biphasic excretion curves are well-documented in heavy metal kinetics during recovery and may also be influenced by transient variations in renal perfusion and hydration status in a critically ill patient.

Blood-brain barrier penetration and neurotoxicity mechanisms

If a systemic MB-nickel interaction indeed occurred, the rapid reduction in serum nickel may have established a favorable concentration gradient, encouraging the efflux of nickel out of the CNS and back into systemic circulation. This “washout” effect is particularly clinically relevant given the patient’s initial cerebrospinal fluid nickel concentration of 55.5 μg/L, which was significantly higher than the simultaneous blood level (7.4 μg/L).

Nickel is capable of crossing the blood-brain barrier (BBB) via ionic mimicry and active transport mechanisms. It utilizes divalent metal transporter 1, the primary pathway for physiological iron transport, and can also enter astrocytes and neurons via L-type voltage-gated calcium channels due to its similar ionic radius to calcium. In our patient, the massive systemic load likely saturated these transport pathways and may have caused transient BBB disruption through endothelial oxidative stress, permitting significant central sequestration[11].

The profound CNS accumulation was the likely driver of the CLOCC pattern identified on the patient’s brain magnetic resonance imaging. The CLOCC pattern represents a common, non-specific radiological pathway for various metabolic and toxic insults[6,12]. At the cellular level, nickel ions can disrupt mitochondrial function by directly inhibiting Krebs cycle enzymes and driving the reactive oxygen species production. The splenium of the corpus callosum features a highly dense population of excitatory amino acid receptors and a high baseline metabolic demand, rendering it exquisitely sensitive to the glutamate excitotoxicity and intracellular edema that follow heavy metal-induced adenosine triphosphate depletion.

While the patient’s neurological recovery and coma resolution (GCS improvement from 3 to 11 within 48 hours) coincided with the decrease in nickel levels, further studies are required to determine whether this was a direct result of MB-facilitated clearance or the natural history of the intoxication under meticulous supportive care.

Comprehensive safety monitoring

Because MB dosing was carefully maintained within standard clinical limits (i.e, never exceeding the 2 mg/kg safety threshold), the patient avoided the classic toxicities associated with high-dose regimens, such as methemoglobinemia, hemolytic anemia, and serotonin syndrome[13].

In our patient, safety monitoring extended beyond serial methemoglobin levels, which safely peaked at 5.5% on day 3. The patient was monitored continuously for clinical signs of serotonin syndrome (e.g., clonus, hyperreflexia, autonomic instability), which remained entirely absent. Furthermore, serial laboratory evaluations, including daily complete blood counts, bilirubin levels, and renal and hepatic function panels, demonstrated no clinical or subclinical evidence of hemolysis or drug-induced organ dysfunction, indicating that the rescue doses of MB were well-tolerated in this critical care setting.

Strengths and limitations

The primary strength of this case lies in the successful diagnostic resolution of a complex clinical presentation. The patient initially presented with symptoms suggestive of a cholinergic toxidrome following the alleged ingestion of a corrosive household cleaner, an association that is clinically atypical, as common toilet cleaners usually contain inorganic acids (e.g., hydrochloric acid), which do not manifest with systemic cholinergic features[4]. Through clinical curiosity and an exhaustive toxicological workup, we were able to identify acute heavy metal poisoning as the true underlying etiology. Furthermore, this case introduces a novel, albeit unproven, application of MB as a potential therapeutic adjunct for nickel clearance.

However, several significant limitations must be acknowledged. First, the absence of controlled pharmacokinetic data prevents us from definitively establishing a biochemical mechanism for MB-mediated nickel excretion; as such, our findings remain hypothesis-generating. Second, the lack of follow-up cerebrospinal fluid nickel levels and serial neuroimaging precludes assessment of the long-term reversibility of the observed CLOCC pattern. Finally, in the absence of a control, it is impossible to exclude the possibility that the patient's recovery resulted from intensive supportive care and the natural history of elimination rather than the specific administration of MB.

CONCLUSION

This case highlights the critical importance of early, comprehensive toxicological screening in undifferentiated or atypical poisonings. Relying solely on the “typical” chemical composition of household products like toilet cleaners can lead to significant diagnostic errors, particularly when commercial labels are missing. While the exact biochemical interaction between MB and nickel clearance requires rigorous in vitro and in vivo validation, the favorable outcome in this case demonstrates that integrating cross-disciplinary concepts, from industrial chemistry to clinical pharmacology, can provide key diagnostic and therapeutic pathways when dealing with rare, life-threatening toxicities.

ACKNOWLEDGEMENTS

The authors would like to respectfully acknowledge the late Dr. Gourav Mittal, whose dedication, clinical acumen, and extensive efforts were pivotal in diagnosing and managing this complex case. His contributions were invaluable to the care of the patient and the understanding of this rare presentation. We remember his work with deep respect and gratitude.