Delayed-onset central neurotoxic syndrome with predominant cerebellar dysfunction following combined chlorpyrifos and cypermethrin poisoning: a case report

Abstract

Organophosphate (OP) poisoning typically manifests in three phases: the acute cholinergic crisis, the intermediate syndrome, and OP-induced delayed neuropathy (OPIDN). Delayed central nervous system sequelae with predominant cerebellar dysfunction are exceptionally rare and poorly characterized. We report the case of a woman in her early thirties with a history of chronic alcohol use who ingested a commercial insecticide containing chlorpyrifos (50%) and cypermethrin (2%). Following the resolution of an acute cholinergic crisis and a brief period of cardiac arrest (return of spontaneous circulation within 3 minutes), she demonstrated neurological recovery. However, 21 days post-ingestion, she developed acute-onset gait unsteadiness. Neurological examination revealed predominant cerebellar dysfunction, including limb dysmetria, gaze-evoked nystagmus, and ataxic gait, together with bilateral extensor plantar responses, while cognition remained preserved and there was no evidence of distal motor neuropathy. Neuroimaging (magnetic resonance imaging) was unremarkable, and metabolic, infectious, autoimmune, and hypoxic causes were carefully evaluated, with no supporting evidence identified. The patient showed gradual improvement with supportive care. This case highlights a rare delayed central neurotoxic syndrome distinct from OPIDN. The delayed onset of a central neurotoxic syndrome with predominant cerebellar dysfunction, likely exacerbated by pyrethroid synergism, emphasizes the need for prolonged neurological surveillance in mixed pesticide poisonings, even when initial imaging is normal.

Introduction

Organophosphate (OP) insecticide self-poisoning is a major clinical challenge in developing regions. The neurotoxic sequelae of OPs are traditionally categorized into three phases: the acute cholinergic crisis (minutes to hours), the intermediate syndrome (24–96 hours), and OP-induced delayed neuropathy (OPIDN) (1–3 weeks).^[1,2^] OPIDN is classically a distal, symmetric, sensorimotor axonal neuropathy caused by the inhibition of neuropathy target esterase[2].

HIGHLIGHTS

• Delayed cerebellar ataxia occurred 21 days after ingestion of mixed pesticides.

• Magnetic resonance imaging, including diffusion-weighted imaging and apparent diffusion coefficient sequences, showed no structural abnormality.

• The clinical features were distinct from those of organophosphate (OP)-induced delayed neuropathy.

• A brief cardiac arrest did not result in the typical post-anoxic deficits.

• Mixed OP–pyrethroid toxicity may cause delayed central nervous system dysfunction.

While peripheral delayed neurotoxicity is well-documented, delayed central nervous system (CNS) toxicity remains uncommon and poorly understood. Delayed central neurotoxic syndromes with predominant cerebellar dysfunction occurring weeks after exposure are exceptionally rare, with only a handful of cases reported in the literature^[3–5^]. Furthermore, many commercial insecticides are mixtures of OPs and pyrethroids. Pyrethroids, such as cypermethrin, target sodium channels and are known to cause acute tremors and ataxia, but their potential to contribute to delayed CNS pathology in humans remains under-investigated6.

We present a case of a patient who developed a delayed central neurotoxic syndrome characterized by predominant cerebellar dysfunction and bilateral pyramidal signs 3 weeks after ingesting a chlorpyrifos-cypermethrin mixture. This case is notable for the delayed onset, the absence of radiological findings despite severe symptoms, and the need to differentiate a toxic etiology from alcoholic, hypoxic-ischemic, metabolic, and autoimmune causes.

Presentation of case

A 32-year-old female presented to the emergency department 3 hours after the intentional ingestion of approximately 25 mL of a commercial insecticide. The bottle was identified as containing a mixture of 50% chlorpyrifos (an OP) and 2% cypermethrin (a type II pyrethroid). Her medical history was significant for chronic alcohol use (approximately 60–80 g of ethanol per week) for 7 years.

Upon arrival, she exhibited classic signs of a cholinergic crisis, including hypersalivation, bronchorrhea, and miosis. An odor of pesticides was noted. Her family had induced emesis prior to arrival. Initial management included fluid resuscitation and atropinization (total of 27 mg) alongside pralidoxime. She was admitted to the Medical Intensive Care Unit and required mechanical ventilation for 48 hours. During the acute phase, she suffered a cardiac arrest; cardiopulmonary resuscitation was initiated immediately, achieving return of spontaneous circulation (ROSC) within approximately 3 minutes. Following ROSC, the patient did not remain comatose. She regained consciousness within hours and was able to obey commands appropriately. Targeted temperature management was not instituted. No post-anoxic myoclonus was observed. Electroencephalography performed during recovery was reported as normal. Serum lactate levels during the peri-arrest period were not available. She was successfully extubated on Day 3 and transferred to the ward with stable hemodynamics and normal neurological status. The chronological progression of the patient’s clinical course is summarized in Fig. 1.

Figure 1.

Chronological timeline of the case presentation.

On Day 21 post-ingestion, the patient reported the new-onset gait instability and difficulty coordinating limb movements. Neurological examination demonstrated preserved higher mental functions (Mini-Mental State Examination score, 30/30). Cranial nerve examination was normal except for horizontal left-beating gaze-evoked nystagmus on left lateral gaze. Motor examination revealed normal muscle bulk and tone, with mild symmetric weakness (Medical Research Council grade 4/5) in all four limbs without focal motor deficits. Deep tendon reflexes were preserved and symmetric, while plantar responses were bilaterally extensor. Cerebellar examination demonstrated marked bilateral dysmetria on finger-to-nose and heel-to-shin testing, dysdiadochokinesia, and impaired tandem walking. Her gait was broad-based, consistent with predominant cerebellar dysfunction. Sensory examination, including light touch, pinprick, vibration, and joint position sense, was intact. There were no signs of meningeal irritation or autonomic dysfunction.

Laboratory investigations revealed a complete blood count, comprehensive metabolic panel, and liver function tests within normal limits. Serum vitamin B12 levels and thyroid function tests were also normal. To screen for autoimmune markers, antinuclear antibody (ANA) testing was performed and returned negative results. Serologic testing for syphilis (venereal disease research laboratory test/treponema pallidum haemagglutination assay test) was non-reactive. Furthermore, cerebrospinal fluid (CSF) analysis showed normal opening pressure, with cell counts, protein, and glucose levels all within standard ranges. Magnetic resonance imaging (MRI) of the brain was performed on Day 23 post-ingestion. T1-weighted, T2-weighted, FLAIR, diffusion-weighted imaging (DWI), and corresponding apparent diffusion coefficient sequences demonstrated preserved cerebellar architecture. There was no evidence of cerebellar atrophy, focal signal abnormalities, infarction, hemorrhage, demyelination, edema, or restricted diffusion. The brainstem, basal ganglia, cerebral cortex, and white matter appeared unremarkable, with no features suggestive of hypoxic-ischemic injury or other structural pathology (Fig. 2). While paraneoplastic and specific autoimmune antibody titers were considered to exclude other rare causes of ataxia, these advanced tests were not performed due to the patient’s financial constraints.

Figure 2.

(A) Axial T2-weighted image demonstrating normal signal intensity and preserved architecture of the cerebellar hemispheres and vermis, without focal lesion or edema. (B) Axial FLAIR image demonstrating normal signal intensity of the cerebellar hemispheres and vermis, with preserved cerebellar architecture and no evidence of focal abnormality, edema, or gliosis. (C) Diffusion-weighted imaging (DWI) showing no areas of diffusion hyperintensity within the cerebellum. (D) Corresponding apparent diffusion coefficient (ADC) map confirming the absence of restricted diffusion.

The patient was diagnosed with delayed central neurotoxic syndrome characterized by predominantly cerebellar dysfunction and bilateral pyramidal signs after exclusion of alternative metabolic, infectious, autoimmune, structural, and nutritional etiologies. She was managed supportively with a high-protein diet, thiamine supplementation, and an intensive program of vestibular rehabilitation and physiotherapy. During hospitalization, the patient’s gait instability and limb incoordination gradually improved with intensive physiotherapy and vestibular rehabilitation. Horizontal nystagmus became less prominent, and coordination testing showed a progressive reduction in bilateral dysmetria. At discharge (Day 35), she was able to ambulate independently without assistive devices, although mild residual dysmetria persisted.

Discussion

The neurological presentation in this patient represents a rare delayed central neurotoxic syndrome that extends the recognized spectrum of OP neurotoxicity. Although symptom onset (Day 21) coincided with the typical window for OPIDN, the clinical phenotype was predominantly central, characterized by gait ataxia, dysmetria, gaze-evoked nystagmus, and bilateral extensor plantar responses, rather than the distal, length-dependent flaccid paralysis characteristic of OPIDN[2]. While cerebellar dysfunction predominated clinically, the presence of bilateral extensor plantar responses indicated concomitant corticospinal tract involvement, suggesting a broader central neurotoxic syndrome rather than an isolated cerebellar syndrome. This pattern raises the possibility that mixed chlorpyrifos–cypermethrin exposure may affect multiple central motor pathways despite the absence of structural abnormalities on conventional MRI.

Differential Diagnosis: Given the patient’s history and clinical course, three major differential diagnoses were systematically evaluated:

1. Alcohol-related pathology: Alcoholic cerebellar degeneration typically presents with vermian atrophy on MRI and evolves chronically. Our patient had a normal MRI and an acute/subacute onset. Wernicke’s encephalopathy was unlikely given the absence of confusion and ophthalmoplegia and the fact that she received prophylactic thiamine throughout her admission[7].

2. Hypoxic-ischemic Injury: The transient cardiac arrest raises the possibility of hypoxic injury. Purkinje cells are notably oxygen-sensitive. However, hypoxic encephalopathy typically results in diffuse cortical injury (coma, cognitive deficits) or myoclonus (Lance–Adams syndrome). An isolated cerebellar syndrome with preserved cognition and normal diffusion-weighted MRI sequences is highly atypical for hypoxic injury following such a brief (3-minute) arrest[8]. Furthermore, the delayed onset of neurological symptoms on Day 21 is inconsistent with typical post-anoxic cerebellar injury, which usually manifests within days of the hypoxic event[8]. The presence of bilateral extensor plantar responses may indicate transient pyramidal tract involvement; however, preserved cognition and normal DWI argue against global hypoxic cortical injury. These pyramidal signs may reflect subtle toxic or metabolic effects rather than structural cortical damage.

3. Infectious, metabolic, and autoimmune etiologies: Infectious cerebellitis and subacute combined degeneration were ruled out by normal CSF analysis and serum vitamin B12 levels. Autoimmune cerebellitis and paraneoplastic neurological syndromes were included in the differential diagnosis; however, these were considered less probable because of the close temporal relationship between pesticide exposure and delayed symptom onset, the absence of clinical features suggestive of an underlying malignancy or systemic autoimmune disease, normal CSF findings, and the patient’s gradual improvement with supportive treatment alone. Although serum ANA testing was negative, disease-specific autoimmune and paraneoplastic antibody panels were not performed because of financial constraints. Consequently, these etiologies cannot be completely excluded. Advanced imaging modalities, such as MR spectroscopy or diffusion tensor imaging (DTI), were unavailable. Therefore, subclinical structural injury cannot be completely excluded. However, the specific temporal association with ingestion strongly supports a toxic etiology over these chronic autoimmune processes.

A striking feature of this case was the clinical-radiological paradox – severe ataxia despite normal neuroimaging. This suggests that the underlying injury was predominantly microstructural or functional/metabolic rather than macroscopic structural damage detectable on conventional MRI. This finding aligns with the historical case reported by Michotte et al[3], who described a similar patient with delayed ataxia and normal computed tomography scans, proposing a functional toxicity distinct from Wallerian degeneration. Furthermore, the clinical trajectory of our patient mirrors the case described by Fonseka et al[4], where cerebellar signs appearing 8 days post-ingestion were self-limiting and resolved with supportive care. This contrasts with the report by Kim et al[5], where delayed cerebellar dysfunction resulted in permanent sequelae and eventual atrophy, suggesting a spectrum of severity likely dependent on the dose and specific chemical mixture.

The most plausible etiology is a synergistic toxic effect of the pesticide mixture. Two mechanisms likely contributed:

1. Oxidative stress: OPs induce significant oxidative stress and neuroinflammation. Experimental studies suggest that OPs can cause selective apoptosis of Purkinje cells via mitochondrial dysfunction, intracellular calcium overload, and lipid peroxidation[9]. Recent evidence also supports persistent neuronal injury mediated by oxidative stress, even after the resolution of the acute cholinergic crisis^[10^].

2. Synergism with pyrethroids: Co-ingestion of cypermethrin is significant. Pyrethroids prolong the opening of voltage-gated sodium channels. Studies indicate that simultaneous exposure to OPs and pyrethroids produces synergistic neurotoxicity, in which OPs inhibit the carboxylesterases involved in pyrethroid metabolism, increasing pyrethroid bioavailability and CNS exposure^[6,11,12^]. Concurrent activation of oxidative stress and inflammatory pathways by both compounds may further amplify neuronal injury, lowering the threshold for delayed neuronal dysfunction, particularly involving cerebellar Purkinje cells, and contributing to delayed central neurotoxicity.

Limitations

This case has several limitations. Advanced paraneoplastic and autoimmune antibody panels were not performed. In addition, advanced neuroimaging techniques such as DTI or MR spectroscopy, as well as follow-up brain MRI, were unavailable. Furthermore, serum lactate levels during the peri-arrest period were unavailable, precluding definitive exclusion of hypoxic-ischemic mechanisms despite an atypical delayed presentation, rapid neurological recovery after the ROSC, and normal early neuroimaging.

Conclusion

This case illustrates that mixed-pesticide poisoning can produce delayed central neurotoxic syndromes beyond classic OPIDN, despite normal findings on conventional MRI. The potential for synergistic neurotoxicity between OPs and pyrethroids warrants a high index of suspicion. Clinicians should remain vigilant for delayed CNS symptoms in poisoning survivors, even after apparent recovery from acute mixed-pesticide poisoning.

Ethical approval

Ethical approval was not required for this case report in accordance with institutional guidelines.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Sources of funding

No external funding was received for this study.

Author contributions

S.P. contributed to conceptualization, patient care, data curation, investigation, and drafting of the manuscript. D.A. and S.S. contributed to clinical interpretation, validation, and critical revision of the manuscript. A.A. and J.L. were involved in writing original draft, imaging interpretation, and preparation of figures. B.P.G. supervised the work, provided resources, and contributed to critical revision for important intellectual content. All authors read and approved the final revised manuscript.

Conflicts of interest disclosure

The authors declare no conflicts of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

The corresponding author accepts responsibility for the overall content and integrity of the work.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

The data supporting the findings of this case report are available from the corresponding author upon reasonable request.

Presentation

None.

Artificial intelligence use

The authors used an artificial intelligence tool (ChatGPT, OpenAI) to assist with language editing and improvement of manuscript clarity. All content was critically reviewed and revised by the authors, who take full responsibility for the final manuscript.