Advertisement

Journal of Medical Toxicology

, Volume 8, Issue 2, pp 124–129 | Cite as

Autonomic Dysfunction as a Delayed Sequelae of Acute Ethylene Glycol Ingestion

A Case Report and Review of the Literature
  • Sayed S. RahmanEmail author
  • Satish Kadakia
  • Leah Balsam
  • Sofia Rubinstein
Toxicology Observation

Abstract

Ethylene glycol poisoning is a common form of poisoning worldwide. The clinical course of ethylene glycol poisoning usually follows a three-stage progression, although these stages may overlap. A fourth stage of delayed neurological dysfunction consisting of cranial neuropathies has been suggested in several case reports. We describe a patient with unique findings of postural hypotension and gastroparesis following ethylene glycol toxicity with the additional uncommon features of albuminocytologic dissociation and increased intracranial pressure with papilledema. In addition, we provide a review of the literature on delayed neurological manifestations in ethylene glycol toxicity and further elucidate a description of a fourth stage of delayed neurological dysfunction following ethylene glycol poisoning.

Keywords

Ethylene glycol poisoning Neurological sequelae Autonomic dysfunction Postural hypotension Gastroparesis 

Introduction

Ethylene glycol (EG) poisoning is a relatively common occurrence worldwide that can lead to significant morbidity and mortality [1]. Ethylene glycol (C2H6O2) has a small molecular weight enabling it to increase the osmol gap early in toxic ingestions. However, it is EG’s metabolism in the liver and the production of its toxic metabolites (glycoaldehyde, glycolic acid, glyoxalate, and oxalate) that are responsible for most of the clinical manifestations of poisoning.

The clinical course of ethylene glycol poisoning usually follows a three-step progression, the stages of which may overlap considerably [2, 3]:
  • Stage 1 (0.5 to 12 h post ingestion) consists of central nervous system (CNS) symptoms of inebriation, ataxia, seizure, coma and, with large enough doses, death. Irritation to the stomach may cause nausea and vomiting.

  • Stage 2 (12 to 24 h post ingestion) is a result of accumulation of organic acids leading to cardiopulmonary syndrome that manifests as tachycardia, hypertension, tachypnea and pulmonary edema (cardiogenic and noncardiogenic).

  • Stage 3 (24 to 72 h post ingestion) consists of renal failure resulting from osmotic damage and calcium oxalate deposition in the kidney. Metabolic acidosis can be found in all three stages of EG poisoning.

An additional stage four (days to weeks after ingestion) that manifests as delayed neurological deficits was originally suggested by Factor and Lava [4] in 1987 based on three case reports exhibiting cranial nerve deficits [5, 6, 7] following EG poisoning. The manifestation of this finding was likely due to better survival outcomes of severe EG poisoning which was often fatal in the first three phases before widespread use of hemodialysis. Since then, there have been other cases reporting findings of delayed cranial neuropathies [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. Reports also describe cerebral edema [20, 21], seizures [20, 22], increased intracranial pressure with papilledema [16] and communicating hydrocephalus [11], stroke [14, 23, 24] (one of which involved development of rapid onset Parkinson disease due to basal ganglia hemorrhagic infarction [24]), diaphragmatic paralysis [13], sensory radiculopathies [10, 12, 17, 25], cerebrospinal fluid (CSF) findings of albuminocytologic dissociation [4, 9, 13, 25] as well as aseptic meningitis [8, 21, 26]. Some features of autonomic nervous system (ANS) dysfunction such as the bradycardia/tachycardia syndrome [14] and urinary retention with paralytic ileus [17] were reported; however, to our knowledge, postural hypotension and confirmed gastroparesis have not been previously described. Vomiting with delayed transit by barium follow through [12] has been reported; however, this is not a confirmatory test for gastroparesis and could represent a paralytic ileus. We report a case of EG poisoning that resulted in ANS dysfunction with postural hypotension and confirmed gastroparesis with the additional uncommon features of albuminocytologic dissociation (as seen in Guillain–Barre syndrome) and increased intracranial pressure with papilledema. We provide a review of late neurological manifestations of EG poisoning and further characterize a fourth stage of this illness consisting of delayed neurological dysfunction.

Case Report

An 18-year-old white male with a history of depression was brought to the emergency department in a state of confusion and agitation. His suicidal note stated that he had ingested half a gallon of ethylene glycol 10 h prior. On presentation he was tachycardic at 109 beats/min, his blood pressure was 178/100 mmHg and his respiratory rate was 22 breaths/min. He appeared combative and confused; the rest of the physical examination including his neurological examination was unremarkable. The patient was intubated for airway control and 100 g of activated charcoal was given via a nasogastric tube. Initial laboratory studies revealed a leukocytosis of 27,000 per cm3, blood urea nitrogen (BUN) of 11 mg/dl, serum creatinine concentration of 1.5 mg/dl, glucose of 145 mg/dl, serum sodium (Na) was 141 mmol/l, chloride (Cl) was 104 mmol/l and bicarbonate (HCO3) of 6 mmol/l (anion gap was 31). An arterial blood gas was significant for evidence of metabolic acidosis with a serum pH of 7.05 and a PCO2 of 35 mmHg, HCO3 of 9.5 mmol/l, and a serum lactate of 9.7 mmol/l. His measured serum osmolality was 356 mOsm/kg, his calculated serum osmolarity was 294 mOsm/l yielding an osmol gap of 62 mOsm/kg. His serum alanine aminotransferase (ALT) was 72 units/dl, aspartate aminotransferase (AST) was 50 units/dl and a total bilirubin was 0.8 mg/dl. A serum toxicology screen for acetaminophen, salicylate, ethanol, and methanol was negative. A serum EG concentration was 1958 μg/ml (195 mg/dl). An electrocardiogram (EKG) was remarkable for sinus tachycardia of 109 beats/min and his chest radiograph was within normal limits. He was started on a continuous intravenous infusion of bicarbonate, was given appropriate intravenous doses of fomepizole (loading dose of 1.6 g followed by a maintenance dose of 1.1 g every 12 h for an additional two doses), and single doses of folate (100 mg), thiamine (100 mg) and pyridoxine (50 mg). The patient was emergently hemodialyzed for EG poisoning 5 h after initial presentation. Over the ensuing 16 h, the patient became anuric with a rising serum creatinine concentration. His metabolic acidosis progressively improved (pH 7.38, pCO2 35 mmHg, HCO3 23 mmol/l) and serum osmolality improved to 284 mOsm/kg. The patient was extubated 39 h after presentation to the ER. Hemodialysis was continued for his renal failure.

On day 13 of his hospitalization, the patient complained of a headache, photophobia, and blurring of vision with diplopia. Ophthalmological and neurological examinations revealed bilateral papilledema with normal visual acuity and a left sixth cranial nerve palsy. A lumbar puncture revealed a raised opening CSF pressure of 31 cm of H2O (normal <21 cm of H2O), a glucose of 61 mg/dl, a protein of 157 mg/dl and zero white blood cells (albuminocytologic dissociation). Magnetic resonance imaging (MRI) with gadolinium of the patient’s head was within normal limits. The patient was started on acetazolamide to treat his elevated intracranial pressure with papilledema. One week later, the patient developed a left seventh cranial nerve palsy, and evidence of a sensory neuropathy in both feet (sharp pain and parasthesias on plantar surfaces). Strength, deep tendon reflexes, sensation to touch, temperature and vibration were all normal. Gabapentin was initiated to treat the neuropathy with improvement in symptoms noted.

In addition, the patient started to complain of dizziness on standing and was found to have postural hypotension (supine BP, 141/81 mmHg, standing BP, 108/66 mmHg) which did not resolve despite discontinuing his anti-hypertensive medications (labetolol and amlodipine). He also complained of persistent nausea and vomiting after meals. A gastric emptying study done 4 weeks after initiation of gastrointestinal symptoms showed mildly delayed gastric emptying of 111 min (normal, up to 90 min). His symptoms improved on oral metoclopromide of 10 mg every 6 h as needed.

Hemodialysis was discontinued 40 days after the initial presentation due to recovery of renal function and the patient was discharged home. The sixth and seventh cranial nerve palsies, papilledema, sensory radiculopathies and gastroparesis gradually resolved by 3 weeks after discharge; however, he continued to have asymptomatic orthostatic hypotension off all medications.

Discussion

Our patient had evidence of ANS dysfunction in the form of radiologically confirmed gastroparesis and postural hypotension; this has not been previously reported as a complication of EG poisoning. None of his medications are known to cause postural hypotension. He received supplemental thiamine and pyridoxine to replenish the respective cofactors during his early hospitalization; thus ruling out their deficiencies as a cause of his neuropathy. Our patient also had the additional uncommon features of albuminocytologic dissociation and increased intracranial pressure with papilledema. This has been described previously in only a few cases as delayed neurotoxicity following EG intoxication.

The originally reported delayed cranial nerves abnormal signs and symptoms occurring five to 20 days later [11] are unlikely to be explained by the immediate formation of toxic metabolites. Similarly, since tissue deposition (particularly in the kidneys, brain and lungs) of calcium oxalate crystals occurs within 3 to 6 h of ethylene glycol ingestion [11], the direct deposition of calcium oxalate crystals in the tissues is also an unlikely explanation. Oxalate is a strong reducing agent and is toxic to endothelial cells [21]. Deposition of calcium oxalate crystals in cases of EG poisoning has been documented within small cerebral blood vessels walls and leptomeninges at post-mortem examinations [21, 26]. In 1979, Levinsky et al. [26] demonstrated deposition of calcium oxalate crystals in the walls of cerebral vessels with an infiltrate of neutrophils and mononuclear cells as well as proteinaceous fluid in the meninges and around parenchymal vessels. These changes can result in patchy focal necrosis with or without hemorrhage throughout the brain and chemical meningitis [26]. More recently, Froberg et al. [21] also found calcium oxalate crystals within vessel walls with prominent perivascular edema and collection of polymorphonuclear leukocytes adjacent to these vessels. Histologic evaluation of tissue sections of meninges showed a neutrophilic infiltrate [21]. Both autopsy investigations following EG poisoning have shown edema, hemorrhage and perivascular inflammation adjacent to small blood vessels in the brain suggesting exudative damage to the endothelial cells in these vessels causing nerve dysfunction [21, 26]. The time required to develop an inflammatory response to the endothelial injury may explain the delay in neurological sign and symptom manifestations [11, 21] (Table 1 [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24]).
Table 1

Published case reports of delayed neurological dysfunction after ethylene glycol intoxication

Author (year)

Age (years)/gender

Ingested dose

Treatment

Delayed neurological dysfunction

Onset (days)

Neurological outcome

Berger [5] (1981)

21 M

120 ml of antifreeze

HD, Fomepizole

Dysarthria, dysphagia, b/l facial weakness, decreased visual acuity, anisocoria, dysmetria

6

Recovered after 1 month

Fellman [6] (1982)

22 M

Not reported

PD followed by HD

Ataxia, Lt arm chorea, deviation of tongue Dysarthria and dysphagia Facial diplegia

8 13 15

Recovered in 7 months, chorea and broad-based gait persisted

Malaya [7] (1986)

26 M

200 ml of antifreeze

Not reported

B/l facial nerve palsies, neurosensory hearing loss, dysphagia

11

Facial weakness and dysphagia persisted after 1 year

Bobbitt [20] (1986)

36 M

Not reported

Ethanol, HD, Dexamethasone

Cerebral edema, seizure, coma

3

Recovered in 17 days

Factor [4] (1987)

46 M

Not reported

PD followed by HD

Facial diplegia, b/l optic nerve dysfunction

14

Recovered in 1 month

Palmer [8] (1989)

57 M

Not reported

HD

Dysarthria, CNs: V, VII, VIII deficits

11

Neurological dysfunction persisted on day 22 (patient expired after cardiac arrest)

Palmer [8] (1989)

53 M

Not reported

HD

Deafness from involvement of cochlear part of CN VIII

8

Neurological dysfunction persisted at 1 year (patient expired after cardiac arrest)

Spillane [9] (1991)

33 M

1 quart of antifreeze

Ethanol, HD

CNs: IX, X deficits B/l CN VII deficit

5 9

CNs defects persisted at 45 days, patient was lost to further follow up

Spillane [9] (1991)

22 M

75 ml of EG

HD

B/l CN VII defect

14

Facial nerve palsy persisted after 3 months

Sydor [10] (1996)

39 M

200 ml of antifreeze

HD

Rt CN VII palsy, neurosensory deafness, polyradiculopathy, albuminocytologic dissociation in CSF

14

Recovered in 2 months

Lewis [11] (1997)

31 F

Not reported

Ethanol, HD, Thiamine, Folate, Pyridoxine

CNs: II,V,VII,VIII defects

10

Complete recovery in 11 months

Broadly [12] (1997)

43 M

250 ml of antifreeze

HD

Neurosensory deafness, b/l facial CN palsies, b/l optic atrophy, SM radiculopathies, delayed transit time by barium follow through

7–10

5 months later patient was walking with assistance device with persistent optic atrophy

Auzepsy [13] (1997)

35 M

Not reported

HD, Ethanol

Facial CN palsy, paralysis of diaphragm, SM neuropathy

11

Resolution of diaphragmatic paralysis in 1 month, SM neuropathy in 3 months, facial nerve palsy in 10 months

Morgan [14] (2000)

26 M

1/2 gallon of antifreeze

Ethanol, HD, Charcoal, Thiamine, Pyridoxine

Bradycardia, bradypnea with hypodensities in basal gangla, midbrain and pons on CT B/l CN VI palsy

3 7

Recovered over 4 months

Jaffery [22] (2001)

25 M

10 ml of EG

HD

Seizures with Lt frontal and Rt parietal infarction on MRI

7

Seizure free in 8 weeks

Tobe [15] (2002)

23 M

12 units of alcohol (EG)

HD

Deafness, dysphagia, dysarthria, complete flaccid paralysis

7

Able to breathe spontaneously in 2 months, able to walk with crutches after 16 months, complete deafness persisted

Zhou [24] (2002)

40 M

Not reported

Not mentioned

Polyradiculopathy

12

Persisted after 17 days, lost to further follow up

Delancy [16] (2004)

34 M

Not reported

HD

Lt CN VI palsy, papilledema with increased ICP on LP

7

Recovery of CN deficits in 4 weeks

Ohmori [23] (2004)

36 M

200 ml of EG

HD

Miosis, external opthalmophlegia with low density areas in b/l basal ganglia, mid-brain and pons on CT scan

4

Complete recovery in 36 days

Martinez [17] (2006)

25 M

920 ml of antifreeze

HD

SM polyradiculopathies, CNs: V, VII, IX and X palsies, paralytic ileus, urinary retention

8

Recovery in 37 days

Reddy [24] (2007)

36 F

Not reported

IV Ethanol, HD

Acute onset Parkinson disease from hemorrhagic infarction of basal ganglia (GP, putamen) on MRI

9

Improvement in Parkinson disease within 24 h of starting Levodopa, at 17 days less bradykinetic

Ting [18] (2009)

49 M

Not reported

HD, Ethanol

Rt CN VII palsy

4

Full recovery in 3 months

Baldwin [19] (2010)

53 M

Not reported

CVVH

B/l palsies of CNs III, VI and VII, SM radiculoneuropathy, albuminocytological dissociation

14

Recovery in 10 weeks but neuropathic pain persisted

Our case

18 M

1/2 gallon of antifreeze

HD, Fomepizole, Charcoal, Thiamine, Folate, Pyridoxine

Lt CN VI palsy, b/l papilledema, albuminocytological dissociation Lt CN VII palsy, sensory radiculopathies, gastroparesis, postural hypotension

13 20

Complete recovery of CN palsies, papilledema, sensory radiculopathies, and gastroparesis but persistence of postural hypotension at 9 weeks, lost to further follow up

M male, F female, EG ethylene glycol, HD hemodialysis, PD peritoneal dialysis, CN cranial nerve, SM sensorimotor, Rt right, Lt left, b/l bilateral, IV intravenous, CT computed tomography, MRI magnetic resonance imaging, CSF cerebrospinal fluid, ICP intracranial pressure, LP lumbar puncture, GP globus pallidus

The ANS dysfunction, sensory radiculopathy and CSF finding of albuminocytologic dissociation observed in our patient likely resulted from vascular involvement and injury to the corresponding brain structures. His ANS dysfunction signs and symptoms may have resulted from involvement of the hypothalamus or vasomotor center [14]. The sensory radiculopathy and CSF findings may have resulted from meningial involvement covering the nerve roots.

The clinical outcome of patients reported to have developed these delayed neurological findings is variable (Table 1) [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24]. An overwhelming majority of patients who developed the fourth phase of EG toxicity were males (22 cases out of total 24). In those patients in whom treatment was reported, all underwent dialysis. The initial onset of delayed neurological symptoms varied from 3 to 20 days (confirming observation made by Lewis et al. [11]) with an average of 9 days after ingestion of EG. A significant number of patients recovered their neurological function in 1 to 2 months after onset; in some patients the neurological deficits took longer to resolve and yet in others the neurological dysfunction persisted at 1 year of follow-up. The fastest recovery of neurological manifestations (17 days) was observed in a case treated with Dexamethasone [20].

We hypothesize that the fourth phase of delayed neurological dysfunction is not limited to cranial nerve deficits but encompasses all features of neurological dysfunction and stems from the inflammatory response due to endothelial injury from calcium oxalate deposition.

In conclusion, physicians treating patients with EG poisoning should be aware of the potential for delayed neurotoxicity. Autonomic nervous system dysfunction manifesting as postural hypotension and gastroparesis can be associated with EG poisoning and should be recognized as part of the delayed neurological complications that can manifest after recovery from acute poisoning. More research is indicated to further elucidate the etiology of the neurological component of this illness.

Notes

Conflict of Interests

None for all authors.

References

  1. 1.
    Watson WA, Litovitz TL, Klein-Schwartz W, Rodgers GC Jr, Youniss J, Reid N, Rouse WG, Rembert RS, Borys D (2004) 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 22(5):335PubMedCrossRefGoogle Scholar
  2. 2.
    Eder AF, McGrath CM, Dowdy YG, Tomaszewski JE, Rosenberg FM, Wilson RB, Wolf BA, Shaw LM (1998) Ethylene glycol poisoning: toxicokinetic and analytical factors affecting laboratory diagnosis. Clin Chem 44:168PubMedGoogle Scholar
  3. 3.
    Kraut JA, Kurtz I (2008) Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol 3:208PubMedCrossRefGoogle Scholar
  4. 4.
    Factor SA, Lava NS (1987) Ethylene glycol intoxication: a new stage in clinical syndrome. NY State J Med 87:179Google Scholar
  5. 5.
    Berger JR, Ayyar RA (1981) Neurological complication of ethylene glycol intoxication. Report of a case. Arch Neurol 38:724PubMedCrossRefGoogle Scholar
  6. 6.
    Fellman DM (1982) Facial diplegia following ethylene glycol. Arch Neurol 39:739PubMedCrossRefGoogle Scholar
  7. 7.
    Mallya KB, Mendis T, Guberman A (1986) Bilateral facial paralysis following ethylene glycol ingestion. Can J Neurol Sci 13(4):340PubMedGoogle Scholar
  8. 8.
    Palmer BF, Eigenbrodt EH, Henrich WL (1989) Cranial nerve deficit: a clue to the diagnosis of ethylene glycol poisoning. Am J Med 87(1):91PubMedCrossRefGoogle Scholar
  9. 9.
    Spillane L, Roberts JR, Meyer AE (1991) Multiple cranial nerve deficits after ethylene glycol poisoning. Ann Emerg Med 20:208PubMedCrossRefGoogle Scholar
  10. 10.
    Sydor A, Kolasa M (1996) Late complications after ethylene glycol poisoning—case history. Przegl Lek 53(3):190PubMedGoogle Scholar
  11. 11.
    Lewis LD, Smith BW, Mamourian AC (1997) Delayed sequelae after acute overdoses or poisonings: cranial neuropathy related to ethylene glycol ingestion. Clin Pharmacol Ther 61:69CrossRefGoogle Scholar
  12. 12.
    Broadley SA, Ferguson IT, Walton B, Tomson CR (1997) Severe sensorimotor polyradiculoneurophathy after ingestion of ethylene glycol. J Neurol Neurosurg Psychiatry 63(2):261PubMedCrossRefGoogle Scholar
  13. 13.
    Auzépy P, Masnou P, Métral S, Foucher R, Charpentier B (1997) Diaphragm paralysis and facial diplegia with albumin-cell count dissociation in acute ethylene glycol poisoning. Presse Med 26(18):856PubMedGoogle Scholar
  14. 14.
    Morgan BW, Ford MD, Follmer R (2000) Ethylene glycol ingestion resulting in brainstem and midbrain dysfunction. J Toxicol Clin Toxicol 38(4):445PubMedCrossRefGoogle Scholar
  15. 15.
    Tobé TJ, Braam GB, Meulenbelt J, van Dijk GW (2002) Ethylene glycol poisoning mimicking Snow White. Lancet 359(9304):444PubMedCrossRefGoogle Scholar
  16. 16.
    Delany C, Jay WM (2004) Papilledema and abducens nerve palsy following ethylene glycol ingestion. Semin Ophthalmol 19(3–4):72PubMedCrossRefGoogle Scholar
  17. 17.
    Martínez Miguel P, Rengel MA, Ortega M, Rodríguez Ferrero M, Goicoechea M, Verde E, Muñoz-Blanco JL, Luño J (2006) Prolonged acute renal failure and severe polyradiculopathy in ethylene glycol intoxication. Nefrologia 26(6):738PubMedGoogle Scholar
  18. 18.
    Ting SM, Ching I, Nair H, Langman G, Suresh V, Temple RM (2009) Early and late presentations of ethylene glycol poisoning. Am J Kidney Dis 53(6):1091PubMedCrossRefGoogle Scholar
  19. 19.
    Baldwin F, Sran H (2010) Delayed ethylene glycol poisoning presenting with abdominal pain and multiple cranial and peripheral neuropathies: a case report. J Med Case Rep 4:220PubMedCrossRefGoogle Scholar
  20. 20.
    Bobbit WH, Williams RM, Freed CR (1986) Severe ethylene glycol intoxication with multisystem failure. West J Med 144:225Google Scholar
  21. 21.
    Froberg K, Dorion RP, McMartin KE (2006) The role of calcium oxalate crystal deposition in cerebral vessels during ethylene glycol poisoning. Clin Toxicol 44:315CrossRefGoogle Scholar
  22. 22.
    Jaffery JB, Aggarwal A, Ades PA, Welse WJ (2001) A long sweet sleep with sour consequences. Lancet 358(9289):1236PubMedCrossRefGoogle Scholar
  23. 23.
    Ohmori K, Kumada K, Kimura F, Ishihara S, Fukuda M, Suzuki K, Kohama A (2004) Ethylene glycol poisoning complicated by central nervous system abnormalities. Chudoku Kenkyu 17(4):365PubMedGoogle Scholar
  24. 24.
    Reddy NJ, Lewis LD, Gardner TB, Osterling W, Eskey CJ, Nierenberg DW (2007) Two cases of rapid onset Parkinson’s syndrome following toxic ingestion of ethylene glycol and methanol. Clin Pharmacol Ther 81(1):114PubMedCrossRefGoogle Scholar
  25. 25.
    Zhou L, Zabad R, Lewis RA (2002) Ethylene glycol intoxication: electrophysiological studies suggest a polyradiculopathy. Neurology 59(11):1809PubMedCrossRefGoogle Scholar
  26. 26.
    Levinsky NG, McCluskey RT, Ropper AH, Daniel TO, Brodsky GL (1979) Case records of the Massachusetts General Hospital—case 38–1979. N Engl J Med 301:650CrossRefGoogle Scholar

Copyright information

© American College of Medical Toxicology 2011

Authors and Affiliations

  • Sayed S. Rahman
    • 1
    Email author
  • Satish Kadakia
    • 2
  • Leah Balsam
    • 1
  • Sofia Rubinstein
    • 1
  1. 1.Department of Medicine, Division of Nephrology and HypertensionNassau University Medical CenterEast MeadowUSA
  2. 2.Department of NeurologyNassau University Medical CenterEast MeadowUSA

Personalised recommendations