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Encephalopathy of Unknown Origin in a Baclofen Patient: Case Report and Review of the Literature
Journal Pre-proof Encephalopathy of Unknown Origin in a Baclofen Patient: A Case Report and Review of the Literature Justin Gold, B.S, Kevin Zhao, D.O, Mickey Abraham, M.S, Rosemary Behmer Hansen, M.A., M.P.H, Meeki Lad, M.P.H, Antonios Mammis, M.D PII:
S1878-8750(20)30052-8
DOI:
https://doi.org/10.1016/j.wneu.2020.01.044
Reference:
WNEU 14074
To appear in:
World Neurosurgery
Received Date: 6 November 2019 Revised Date:
6 January 2020
Accepted Date: 7 January 2020
Please cite this article as: Gold J, Zhao K, Abraham M, Hansen RB, Lad M, Mammis A, Encephalopathy of Unknown Origin in a Baclofen Patient: A Case Report and Review of the Literature, World Neurosurgery (2020), doi: https://doi.org/10.1016/j.wneu.2020.01.044. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Encephalopathy of Unknown Origin in a Baclofen Patient: A Case Report and Review of the Literature Justin Gold1, B.S.; Kevin Zhao1, D.O.; Mickey Abraham1, M.S.; Rosemary Behmer Hansen1, M.A., M.P.H.; Meeki Lad1, M.P.H; Antonios Mammis1, M.D.
1. Department of Neurological Surgery, Rutgers New Jersey Medical School, Newark NJ Doctor's Office Center 90 Bergen Street Newark, NJ 07101-1709 (T) 973-972-2323 (F) 973-972-2333
Corresponding author: Justin Gold 605 Binghampton Lane Livingston, NJ 07039 [email protected] 973-943-5929 Keywords: Baclofen; Intrathecal baclofen; Encephalopathy; Renal disease; Acute kidney injury
Introduction: Encephalopathy is a broad label to describe any diffuse disease of the brain which changes brain structure or function. Possible etiologies include infection, metabolic disorders, brain tumor, increased intracranial pressure, increased exposure to virulent particles, deficient nutrition, chronic trauma, or reduced oxygen to the brain. Encephalopathy is reported to have affected over 250,000 individuals in the United States over the last decade, and is correlated with considerable morbidity and mortality.1 Encephalopathy alters consciousness with symptoms of headache, disorientation and neurological signs diagnosed through clinical, laboratory, radiologic, and electrophysiologic findings.1 Baclofen is a drug that acts on the central nervous system and is used to treat spasticity. Particularly Baclofen can relieve flexor spasms, concomitant pain, clonus, muscular rigidity, and chronic hiccups.2,3 Baclofen is a gamma-aminobutyric acid (GABA) agonist and acts through inhibition of presynaptic motor neurons. Although baclofen toxicity is uncommon, it has been linked most frequently in patients with renal disease, as it is primarily excreted via the kidneys.3 Baclofen has multiple routes of administration. Specifically, Baclofen can be administered orally or intrathecally. In order to control spasticity, oral baclofen is first initiated, as intrathecal baclofen requires a surgical procedure to place the internal pump and catheter system. Furthermore, intrathecal baclofen requires replacement of the battery every 5-7 years, and pump refills every 6 months.4 Because only a fraction of oral baclofen can pass the bloodbrain barrier for central effects, greater doses are required to reach therapeutic levels which unfortunately increase the likelihood of peripheral side effects. Alternatively, the intrathecal route allows for much lower dosages and has been linked with an enhanced control of spasticity with less adverse effects. A case of encephalopathy of unknown origin is presented. We describe an adult patient with unknown encephalopathy, an intrathecal baclofen pump, renal disease, and a chronic exposure to West Nile Virus (WNV). The published literature is reviewed for cases of encephalopathy secondary to baclofen withdrawal and renal disease. Case Report: The patient was a 35-year-old male who had a past medical history of cervical spine trauma after a diving accident at age 17. He underwent a Baclofen pump placement in December, 2018 due to spasms in his lower extremities (modified Ashworth score of 4). His course was complicated by exposed hardware and underwent revision surgery in March, 2019. Patient presented to University Hospital on day 1 with complaint of persistent fevers and seizures. At presentation he had normal mentation, full strength in upper extremities, and paraplegic in the lower extremities. He was febrile, with a white count of 7.3 K/µ L. A lumbar puncture (LP), which was performed at outside hospital prior to transfer, was suggestive of CNS infection (RBC 10k cells/µL, WBC 1.4k cells/µ L, Glucose 43 mg/dL, Protein 127 gm/dL, Segs 78%, Lymphs 9%, Monos 12%). Encephalitis panel of the CSF was negative for viral infections, bacteria, and fungus. Vancomycin and Meropenem were initiated prophylactically. Inflammatory markers included ESR of 33 mm/hr, CRP of 37 µ g/mL, and procalcitonin of 0.10 ng/mL. CT chest, abdomen and pelvis was performed on day 1 and abscess was ruled out. His home dose of Baclofen (30mg 4 times a day) was prescribed. Brain MRI with and without gadolinium was performed on day 4 and did not show a brain abscess. Patient experienced acute kidney injury on day 4, which persisted and improved towards the end of hospitalization. On day 7, the patient had a change in
mental status, with no spontaneous opening of eyes, no following of commands, and only localizing to painful stimuli in the upper extremities. He was intubated and put on video EEG monitoring, which showed burst suppression. His urine culture was positive for E. coli. A repeat LP was performed on day 7, opening pressure noted to be 43cm H2O. RBC was 14 million cells per mcl, WBC was 126 cells/µL, Glucose was 141 mg/dL, and Protein was 41 gm/dL. He remained afebrile without elevation in white count throughout his stay. Due to the presence of burst suppression on EEG, baclofen dosage was tapered gradually (oral dosage was tapered from 30mg 4 times a day to 20mg 4 times a day and intrathecal dosage tapered from 460 mcg a day to 115 mcg a day). CSF and blood cultures remained negative. Due to his declining mental status, his baclofen pump was removed on day 9 as it was a possible source of infection. On postoperative day 3, patient started following commands and mental status started to return back to normal. He was eventually extubated and his neurologic exam returned to baseline. During his post-operative course on Day 10, IgG CSF WNV was positive for IgG, with negative IgM. He finished a course of 14 days antibiotics and was discharged to rehab on day 16. Patient suffered acute kidney injury likely from antibiotics, therefore vancomycin was held half way through his hospital course. Acute kidney injury improved after vancomycin cessation and IV hydration initiation.
Discussion: Baclofen is an antispastic drug that can precipitate serious side effects, especially with renal impairment. Baclofen is an agonist at GABA-B receptors which is a metabotropic GProtein coupled receptor.5 While baclofen dosing varies with indication, it is usually dosed at 5mg three times each day.6 Oral baclofen is absorbed in the gastrointestinal tract, and peak plasma concentrations are observed within three to four hours after administration.6,7 Because baclofen is a moderately lipophilic drug, it can cross the blood brain barrier at higher doses.7 The kidneys are responsible for approximately 70% of baclofen’s elimination. Therefore, renal disease will increase baclofen serum levels.5 Signs and symptoms of baclofen overdose comprise of hypotonia, hypothermia, impaired consciousness, respiratory depression, and abnormal heart conductions.5,8 It is common for patients’ with baclofen overdose to initially appear to have serious brain injury, however full patient recovery can occur in less than 72 hours.5 Mechanical ventilation is the primary treatment for baclofen overdose.5 Hemodialysis can decrease serum concentrations of baclofen to resolve neurological symptoms.7 Patients with kidney dysfunction have been reported to experience baclofen-induced encephalopathy.9 Particularly, Wu et al. described an 81-year-old woman with chronic kidney disease who presented to the emergency department with comatose consciousness and hypotonia.10 Two days prior to admission, the patient started oral baclofen with a dose of 5mg twice a day to treat muscle spasms. The patient was found to have high serum baclofen levels, possibly secondary to her preexisting renal dysfunction.10 With two sessions of hemodialysis, serum baclofen levels and subsequent neurological symptoms improved. Radhakrishnan et al. reported a 58-year-old male who developed encephalopathy when treated with 10mg of baclofen twice a day.11 Upon admission, the patient was unconscious with a Glasgow Coma Scale score of
8.11 Baclofen was discontinued and patient sensorium improved with hemodialysis. Similarly, Ijaz et al. described a 57-year-old female who experienced encephalopathy and hypotonia due to baclofen toxicity.9 One week before admission, the patient had initiated 10mg baclofen twice daily to treat muscle spasms.9 As with all aforementioned cases, hemodialysis was an effective treatment. As reported by Dennison et al in 2016, encephalopathy may develop secondary to baclofen withdrawal. Specifically, a 68-year-old female developed encephalopathy after discontinuing 120 mg daily of chronic oral baclofen. The patient presented with altered mental status and increased spasticity. Mild symptomatic improvement was noted upon initiation of 10mg baclofen twice daily.12 Furthermore, major improvements occurred when the dose was increased to 30mg four times daily. There are not any dosing recommendations for patients with renal impairment taking baclofen. There have been proposals to discontinue baclofen in patients with GFR<30mL/min/1.73m2.7,13 A pharmacokinetic study with 21 patients found that the clearance for 5mg oral baclofen decreased by 34% for individuals with mild kidney disease which was defined as a creatinine clearance >50mL/min. Furthermore, the clearance for baclofen decreased by 49% and 64% for patients with moderate kidney disease (creatinine clearance 30-50mL/min) and severe kidney disease (creatinine clearance <30mL/min).14 Current studies recommend that the dose of baclofen be decreased in patients with renal impairment.6 Furthermore, oral baclofen has a black box warning, and abrupt discontinuation of baclofen has been linked with hallucinations, confusion, and exacerbation of spasticity.6 In order to wane patients off baclofen, the dose should be gradually reduced over a period of several weeks.6 The patient described in this case presented with IgG positive and IgM negative antibodies for West Nile Virus, likely conveying a chronic WNV exposure. To date, we are not aware of any cases in the published literature describing chronic exposure of WNV causing encephalopathy.15-18 However, acute exposure to WNV can result in encephalitis. West Nile Virus (WNV) is a zoonotic infection that was first found in Europe in the 1960s and introduced to the United States in 1999.13,19 The West Nile virus is transmitted to humans through an infected mosquito bite. Humans are a “dead end host” because humans do not give rise to a large enough viremia to allow the virus to continue transmission to another organism. Although human West Nile Virus infection has increased over the last few decades, 80% of infections are asymptomatic. Additionally, 20% of WNV infections result in West Nile fever and only 1% produce serious neuroinvasive diseases such as encephalitis or meningitis.20,21 WNV neuroinvasive diseases are more frequently reported in adults, however WNV neuroinvasive disease have also been found in children.21 There have been extensive data on IgM positive (plus or minus IgG positive) WNV antibodies leading to encephalopathy, representing an acute infection.15-18 Presence of IgM indicates an acute infection where detectable levels usually last two to three months after initial infection.18 As a result, we believe the patient became encephalopathic due to increased serum levels of baclofen. Baclofen should be considered in the differential diagnosis of patients who display encephalopathy of unknown origin. Renal disease can also contribute to baclofen overdose and encephalopathy. Clinicians should also monitor the possibility of baclofen withdrawal symptoms in patients who have used baclofen chronically. Sudden cessation of baclofen therapy may cause spasticity, pruritis, anxiety, disorientation, sedation, somnolence, and weakness.22,23
Conducting a thorough history is crucial in order to evaluate patients with unknown encephalopathy who also utilize a baclofen pump. Specifically, health care providers should check for past infections, recent travel, military status, sexual history, kidney functioning including blood urea nitrogen (BUN) and creatinine (Cr), and run a comprehensive infectious disease workup. Baclofen levels should be monitored and the pump should be stopped when encephalopathy occurs in patients who are taking baclofen. There are various tools that are used to help monitor a patient with encephalopathy. In the instance of a patient with unknown encephalopathy a chest X-ray, cerebrospinal fluid (CSF) analysis, video electroencephalograph (EEG) can all be used to monitor the patient’s status. If the patient does not get better and still shows signs of infection such as fever and tachycardia, clinicians must attempt to improve kidney function. In addition to baclofen withdrawal, patients may present with concerning signs of baclofen overdose. These include confusion, areflexia, hypothermia, and sialorrhoea.24 Furthermore, patients with baclofen toxicity can become flaccid, lethargic, and have loss of muscle tone. This can then be followed by respiratory depression, bradycardia and depressed consciousness. In addition, transient elevations in lactic dehydrogenase alkaline phosphatase, and aspartate transaminase have been found.24 Baclofen overdose can usually be observed 2 to 6 hours after ingestion. Infections secondary to intrathecal baclofen pump are rare, and usually occur during the first weeks after pump insertion. Patients commonly present with fever, nuchal rigidity, and alterations in levels of consciousness.25 The infection is validated with positive bacterial CSF cultures. Removal of the pump and antibiotic initiation is normally warranted.25 The incidence of seizures in baclofen pump patients who also have multiple sclerosis is reported to be 7%.26 It is believed that seizures occur due to a disparity in the excitatory glutamate neurotransmitter and the inhibitory GABA neurotransmitter.27 Abrupt discontinuation of oral baclofen can also precipitate seizures.28 In addition, seizures have also been reported in baclofen overdose.29 In our patient we suspected baclofen toxicity because of the patient’s seizure, however we did not remove the baclofen pump in our patient earlier than day 9 because the patient did not show classic signs of infection including leukocytosis and fever. Furthermore, there were overlapping symptoms between pump infection and baclofen toxicity. There are three major factors to consider in order to effectively treat encephalopathy in a patient who is taking baclofen. Particularly, baclofen toxicity from renal disease may be occurring and would require correcting renal function. In addition the infection source, often times caused by the baclofen pump, can cause encephalopathy. Effective treatment would require the removal of the pump. Furthermore, baclofen withdrawal can lead to encephalopathy and would require careful dosing of oral baclofen after pump removal. Moreover, kidney function must be monitored to ensure the kidneys are working. The patient will likely need a very high dose of oral baclofen to achieve effect after receiving intrathecal dose directly to CNS. We propose that patients presenting with encephalitis who are currently taking baclofen and have preexisting renal disease immediately get dialyzed. If there is no improvement in 48 hours, other sources of infection should be considered and the baclofen pump should be removed. Thorough care must be taken to not precipitate symptoms of baclofen withdrawal.
References: 1. Venkatesan A, Geocadin RG. Diagnosis and management of acute encephalitis: A practical approach. Neurol Clin Pract. 2014;4(3):206–215. doi:10.1212/CPJ.0000000000000036 2. Ijaz, Mohsin, Hassan Tariq, Muhammad Kashif, and Jose Gomez Marquez. "Encephalopathy and Hypotonia Due to Baclofen Toxicity in a Patient with End-stage Renal Disease." The American Journal of Case Reports 16 (2015): 232-235. Web. 3. Lee, Junseop, Ho Sik Shin, Yeon Soon Jung, and Hark Rim. "Two Cases of Baclofeninduced Encephalopathy in Hemodialysis and Peritoneal Dialysis Patients." Renal Failure 35.6 (2013): 860-62. Web. 4. Mccormick, Chu, Binler, Neudorf, Mathur, Lee, and Marciniak. "Intrathecal Versus Oral Baclofen: A Matched Cohort Study of Spasticity, Pain, Sleep, Fatigue, and Quality of Life." PM&R 8.6 (2016): 553-62. Web. 5. Miller, John J. "Baclofen Overdose Mimicking Anoxic Encephalopathy: A Case Report and Review of the Literature." Therapeutic Advances in Drug Safety 8.5 (2017): 165-67. Web. 6. Witenko, Corey, Robin Moorman-Li, Carol Motycka, Kevin Duane, Juan HincapieCastillo, Paul Leonard, and Christopher Valaer. "Considerations for the Appropriate Use of Skeletal Muscle Relaxants for the Management of Acute Low Back Pain." P & T : A Peer-reviewed Journal for Formulary Management 39.6 (2014): 427-35. Web. 7. Andrew Meillier, Cara Heller, and Shyam Patel, “Baclofen-Induced Encephalopathy in End Stage Renal Disease,” Case Reports in Medicine, vol. 2015, Article ID 203936, 3 pages, 2015. https://doi.org/10.1155/2015/203936. 8. Cooper, D, Bergman, J. “Massive Baclofen Overdose.” Critical Care and Resuscitation 2000; 2: 195-197). 9. Ijaz M, et al. Encephalopathy and hypotonia due to baclofen toxicity in a patient with end-Stage renal disease. American Journal of Case Reports 16: 232-235, 20 Apr 2015. Available from: URL: http://doi.org/10.12659/AJCR.893222 - USA 10. Wu K-L, et al. Altered consciousness following head injury in advanced renal failure: Find the culprit. Journal of Medical Sciences 36: 28-30, No. 1, Feb 2016. Available from: URL: http://doi.org/10.4103/1011-4564.177175 - Taiwan 11. Radhakrishnan H. Baclofen-induced neurotoxicity in a patient with end-stage renal disease. Saudi Journal of Kidney Diseases and Transplantation 27: 595-7, No. 3, May 2016. Available from: URL: http://doi.org/10.4103/1319-2442.182437 - India 12. Dennison MA, et al. Batty for baclofen: An acute baclofen withdrawal encephalopathy. Journal of the American Geriatrics Society 64 (Suppl. 1): S223, May 2016. Available from: URL: http://doi.org/10.1111/jgs.14231 [abstract] - USA 13. Ferrarini I, Rigo A, Gandini A, Vinante F. West Nile Virus Encephalitis in Haematological Setting: Report of Two Cases and a Brief Review of the Literature. Mediterr J Hematol Infect Dis. 2019;11(1):e2019033. Published 2019 May 1. doi:10.4084/MJHID.2019.033 14. Vlavonou, R. , Perreault, M. M., Barrière, O. , Shink, E. , Tremblay, P. , Larouche, R. , Pichette, V. and Tanguay, M. (2014), Pharmacokinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations. The Journal of Clinical Pharmacology, 54: 584-592. doi:10.1002/jcph.247
15. Savasta, Salvatore, Francesca Rovida, Thomas Foiadelli, Anna Maria Campana, Elena Percivalle, Gian Luigi Marseglia, and Fausto Baldanti. "West-Nile Virus Encephalitis in an Immunocompetent Pediatric Patient: Successful Recovery." Italian Journal of Pediatrics 44.1 (2018): 140. Web. 16. Burden, Fasen, Judkins, and Isache. "A Case of West Nile Virus Encephalitis Accompanied by Diabetic Ketoacidosis and Rhabdomyolysis." IDCases 15 (2019): E00505. Web. 17. Tabain, Vilibic-Cavlek, Kristofic, Savic, Kolaric, Bogdanic, Barbic, Santini, Peric, Sabadi, Pandak, Miklausic, Potocnik-Hunjadi, Zember, Stevanovic, Capak, Listes, Klobucar, Jungic, Krcmar, and Savini. "The Role of IgG Avidity Determination in Diagnosis of West Nile Virus Infection." International Journal of Infectious Diseases 79.S1 (2019): 116-17. Web. 18. Murray, Kristy O, Melissa N Garcia, Chris Yan, and Rodion Gorchakov. "Persistence of Detectable Immunoglobulin M Antibodies up to 8 Years after Infection with West Nile Virus." The American Journal of Tropical Medicine and Hygiene 89.5 (2013): 996-1000. Web. 19. Kleinschmidt‐DeMasters, B. K. and Beckham, J. D. (2015), West Nile Virus Encephalitis 16 Years Later. Brain Pathology, 25: 625-633. doi:10.1111/bpa.12280 20. Giordano BV, Kaur S, Hunter FF. West Nile virus in Ontario, Canada: A twelve-year analysis of human case prevalence, mosquito surveillance, and climate data. PLOS ONE. 2017;12(8):e0183568. doi:10.1371/journal.pone.0183568 21. Savasta S, Rovida F, Foiadelli T, et al. West-Nile virus encephalitis in an immunocompetent pediatric patient: successful recovery. Ital J Pediatr. 2018;44(1):140. doi:10.1186/s13052-018-0574-x 22. Mohammed, Imran, and Asif Hussain. "Intrathecal Baclofen Withdrawal Syndrome- a Life-threatening Complication of Baclofen Pump: A Case Report." BMC Clinical Pharmacology 4.1 (2004): 6. Web. 23. Alvis, Bret D, and Christopher M Sobey. "Oral Baclofen Withdrawal Resulting in Progressive Weakness and Sedation Requiring Intensive Care Admission." The Neurohospitalist 7.1 (2017): 39-40. Web. 24. Arbouw, M E L, H L Hoge, J. Meulenbelt, and F G A Jansman. "Increase of Baclofen Intoxications: Risks Involved and Management." The Netherlands Journal of Medicine 72.9 (2014): 497-499. Web. 25. Aristedis, Rovlias, Papoutsakis Dimitrios, Paidakakos Nikolaos, and Blionas Alexandros. "Intrathecal Baclofen Pump Infection Treated by Adjunct Intrareservoir Teicoplanin Instillation." Surgical Neurology International 8.1 (2017): 38. Web. 26. Schuele, Kellinghaus, Shook, Boulis, Bethoux, and Loddenkemper. "Incidence of Seizures in Patients with Multiple Sclerosis Treated with Intrathecal Baclofen." Neurology 64.6 (2005): 1086-087. Web. 27. Rolland, Benjamin, Sylvie Deheul, Thierry Danel, Régis Bordet, and Olivier Cottencin. "A Case of De Novo Seizures following a Probable Interaction of High-dose Baclofen with Alcohol." Alcohol and Alcoholism (Oxford, Oxfordshire) 47.5 (2012): 577-580. Web. 28. Meythaler, J M, S. Guin-Renfroe, P. Grabb, and M N Hadley. "Long-term Continuously Infused Intrathecal Baclofen for Spastic-dystonic Hypertonia in Traumatic Brain Injury:
1-year Experience." Archives of Physical Medicine and Rehabilitation 80.1 (1999): 13-9. Web. 29. Franchitto, Rolland, Pelissier, and Simon. "How to Manage Self-Poisoning With Baclofen in Alcohol Use Disorder? Current Updates." Frontiers in Psychiatry 9 (2018): 417. Web.
GABA: gamma-aminobutyric acid WNV: West Nile Virus K/uL: thousands per cubic milliliter LP: lumbar puncture Cells/uL: cells/microliter mg/dL: milligrams/deciliter gm/dL: grams/deciliter mm/hr: millimeters/hour ug/mL: micrograms/milliliter ng/mL: nanograms/milliliter CT: computed tomography MRI: magnetic resonance imaging E.coli: Escherichia coli H2O: water EEG: electroencephalogram CSF: cerebrospinal fluid IgG: Immunoglobulin G IV: intravenous IgM: Immunoglobulin M GFR: glomerular filtration rate BUN: blood urea nitrogen Cr: creatinine CNS: central nervous system cm: centimeter mg: milligram mcg: microgram mcl: microliter
S1878-8750(20)30052-8
DOI:
https://doi.org/10.1016/j.wneu.2020.01.044
Reference:
WNEU 14074
To appear in:
World Neurosurgery
Received Date: 6 November 2019 Revised Date:
6 January 2020
Accepted Date: 7 January 2020
Please cite this article as: Gold J, Zhao K, Abraham M, Hansen RB, Lad M, Mammis A, Encephalopathy of Unknown Origin in a Baclofen Patient: A Case Report and Review of the Literature, World Neurosurgery (2020), doi: https://doi.org/10.1016/j.wneu.2020.01.044. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Encephalopathy of Unknown Origin in a Baclofen Patient: A Case Report and Review of the Literature Justin Gold1, B.S.; Kevin Zhao1, D.O.; Mickey Abraham1, M.S.; Rosemary Behmer Hansen1, M.A., M.P.H.; Meeki Lad1, M.P.H; Antonios Mammis1, M.D.
1. Department of Neurological Surgery, Rutgers New Jersey Medical School, Newark NJ Doctor's Office Center 90 Bergen Street Newark, NJ 07101-1709 (T) 973-972-2323 (F) 973-972-2333
Corresponding author: Justin Gold 605 Binghampton Lane Livingston, NJ 07039 [email protected] 973-943-5929 Keywords: Baclofen; Intrathecal baclofen; Encephalopathy; Renal disease; Acute kidney injury
Introduction: Encephalopathy is a broad label to describe any diffuse disease of the brain which changes brain structure or function. Possible etiologies include infection, metabolic disorders, brain tumor, increased intracranial pressure, increased exposure to virulent particles, deficient nutrition, chronic trauma, or reduced oxygen to the brain. Encephalopathy is reported to have affected over 250,000 individuals in the United States over the last decade, and is correlated with considerable morbidity and mortality.1 Encephalopathy alters consciousness with symptoms of headache, disorientation and neurological signs diagnosed through clinical, laboratory, radiologic, and electrophysiologic findings.1 Baclofen is a drug that acts on the central nervous system and is used to treat spasticity. Particularly Baclofen can relieve flexor spasms, concomitant pain, clonus, muscular rigidity, and chronic hiccups.2,3 Baclofen is a gamma-aminobutyric acid (GABA) agonist and acts through inhibition of presynaptic motor neurons. Although baclofen toxicity is uncommon, it has been linked most frequently in patients with renal disease, as it is primarily excreted via the kidneys.3 Baclofen has multiple routes of administration. Specifically, Baclofen can be administered orally or intrathecally. In order to control spasticity, oral baclofen is first initiated, as intrathecal baclofen requires a surgical procedure to place the internal pump and catheter system. Furthermore, intrathecal baclofen requires replacement of the battery every 5-7 years, and pump refills every 6 months.4 Because only a fraction of oral baclofen can pass the bloodbrain barrier for central effects, greater doses are required to reach therapeutic levels which unfortunately increase the likelihood of peripheral side effects. Alternatively, the intrathecal route allows for much lower dosages and has been linked with an enhanced control of spasticity with less adverse effects. A case of encephalopathy of unknown origin is presented. We describe an adult patient with unknown encephalopathy, an intrathecal baclofen pump, renal disease, and a chronic exposure to West Nile Virus (WNV). The published literature is reviewed for cases of encephalopathy secondary to baclofen withdrawal and renal disease. Case Report: The patient was a 35-year-old male who had a past medical history of cervical spine trauma after a diving accident at age 17. He underwent a Baclofen pump placement in December, 2018 due to spasms in his lower extremities (modified Ashworth score of 4). His course was complicated by exposed hardware and underwent revision surgery in March, 2019. Patient presented to University Hospital on day 1 with complaint of persistent fevers and seizures. At presentation he had normal mentation, full strength in upper extremities, and paraplegic in the lower extremities. He was febrile, with a white count of 7.3 K/µ L. A lumbar puncture (LP), which was performed at outside hospital prior to transfer, was suggestive of CNS infection (RBC 10k cells/µL, WBC 1.4k cells/µ L, Glucose 43 mg/dL, Protein 127 gm/dL, Segs 78%, Lymphs 9%, Monos 12%). Encephalitis panel of the CSF was negative for viral infections, bacteria, and fungus. Vancomycin and Meropenem were initiated prophylactically. Inflammatory markers included ESR of 33 mm/hr, CRP of 37 µ g/mL, and procalcitonin of 0.10 ng/mL. CT chest, abdomen and pelvis was performed on day 1 and abscess was ruled out. His home dose of Baclofen (30mg 4 times a day) was prescribed. Brain MRI with and without gadolinium was performed on day 4 and did not show a brain abscess. Patient experienced acute kidney injury on day 4, which persisted and improved towards the end of hospitalization. On day 7, the patient had a change in
mental status, with no spontaneous opening of eyes, no following of commands, and only localizing to painful stimuli in the upper extremities. He was intubated and put on video EEG monitoring, which showed burst suppression. His urine culture was positive for E. coli. A repeat LP was performed on day 7, opening pressure noted to be 43cm H2O. RBC was 14 million cells per mcl, WBC was 126 cells/µL, Glucose was 141 mg/dL, and Protein was 41 gm/dL. He remained afebrile without elevation in white count throughout his stay. Due to the presence of burst suppression on EEG, baclofen dosage was tapered gradually (oral dosage was tapered from 30mg 4 times a day to 20mg 4 times a day and intrathecal dosage tapered from 460 mcg a day to 115 mcg a day). CSF and blood cultures remained negative. Due to his declining mental status, his baclofen pump was removed on day 9 as it was a possible source of infection. On postoperative day 3, patient started following commands and mental status started to return back to normal. He was eventually extubated and his neurologic exam returned to baseline. During his post-operative course on Day 10, IgG CSF WNV was positive for IgG, with negative IgM. He finished a course of 14 days antibiotics and was discharged to rehab on day 16. Patient suffered acute kidney injury likely from antibiotics, therefore vancomycin was held half way through his hospital course. Acute kidney injury improved after vancomycin cessation and IV hydration initiation.
Discussion: Baclofen is an antispastic drug that can precipitate serious side effects, especially with renal impairment. Baclofen is an agonist at GABA-B receptors which is a metabotropic GProtein coupled receptor.5 While baclofen dosing varies with indication, it is usually dosed at 5mg three times each day.6 Oral baclofen is absorbed in the gastrointestinal tract, and peak plasma concentrations are observed within three to four hours after administration.6,7 Because baclofen is a moderately lipophilic drug, it can cross the blood brain barrier at higher doses.7 The kidneys are responsible for approximately 70% of baclofen’s elimination. Therefore, renal disease will increase baclofen serum levels.5 Signs and symptoms of baclofen overdose comprise of hypotonia, hypothermia, impaired consciousness, respiratory depression, and abnormal heart conductions.5,8 It is common for patients’ with baclofen overdose to initially appear to have serious brain injury, however full patient recovery can occur in less than 72 hours.5 Mechanical ventilation is the primary treatment for baclofen overdose.5 Hemodialysis can decrease serum concentrations of baclofen to resolve neurological symptoms.7 Patients with kidney dysfunction have been reported to experience baclofen-induced encephalopathy.9 Particularly, Wu et al. described an 81-year-old woman with chronic kidney disease who presented to the emergency department with comatose consciousness and hypotonia.10 Two days prior to admission, the patient started oral baclofen with a dose of 5mg twice a day to treat muscle spasms. The patient was found to have high serum baclofen levels, possibly secondary to her preexisting renal dysfunction.10 With two sessions of hemodialysis, serum baclofen levels and subsequent neurological symptoms improved. Radhakrishnan et al. reported a 58-year-old male who developed encephalopathy when treated with 10mg of baclofen twice a day.11 Upon admission, the patient was unconscious with a Glasgow Coma Scale score of
8.11 Baclofen was discontinued and patient sensorium improved with hemodialysis. Similarly, Ijaz et al. described a 57-year-old female who experienced encephalopathy and hypotonia due to baclofen toxicity.9 One week before admission, the patient had initiated 10mg baclofen twice daily to treat muscle spasms.9 As with all aforementioned cases, hemodialysis was an effective treatment. As reported by Dennison et al in 2016, encephalopathy may develop secondary to baclofen withdrawal. Specifically, a 68-year-old female developed encephalopathy after discontinuing 120 mg daily of chronic oral baclofen. The patient presented with altered mental status and increased spasticity. Mild symptomatic improvement was noted upon initiation of 10mg baclofen twice daily.12 Furthermore, major improvements occurred when the dose was increased to 30mg four times daily. There are not any dosing recommendations for patients with renal impairment taking baclofen. There have been proposals to discontinue baclofen in patients with GFR<30mL/min/1.73m2.7,13 A pharmacokinetic study with 21 patients found that the clearance for 5mg oral baclofen decreased by 34% for individuals with mild kidney disease which was defined as a creatinine clearance >50mL/min. Furthermore, the clearance for baclofen decreased by 49% and 64% for patients with moderate kidney disease (creatinine clearance 30-50mL/min) and severe kidney disease (creatinine clearance <30mL/min).14 Current studies recommend that the dose of baclofen be decreased in patients with renal impairment.6 Furthermore, oral baclofen has a black box warning, and abrupt discontinuation of baclofen has been linked with hallucinations, confusion, and exacerbation of spasticity.6 In order to wane patients off baclofen, the dose should be gradually reduced over a period of several weeks.6 The patient described in this case presented with IgG positive and IgM negative antibodies for West Nile Virus, likely conveying a chronic WNV exposure. To date, we are not aware of any cases in the published literature describing chronic exposure of WNV causing encephalopathy.15-18 However, acute exposure to WNV can result in encephalitis. West Nile Virus (WNV) is a zoonotic infection that was first found in Europe in the 1960s and introduced to the United States in 1999.13,19 The West Nile virus is transmitted to humans through an infected mosquito bite. Humans are a “dead end host” because humans do not give rise to a large enough viremia to allow the virus to continue transmission to another organism. Although human West Nile Virus infection has increased over the last few decades, 80% of infections are asymptomatic. Additionally, 20% of WNV infections result in West Nile fever and only 1% produce serious neuroinvasive diseases such as encephalitis or meningitis.20,21 WNV neuroinvasive diseases are more frequently reported in adults, however WNV neuroinvasive disease have also been found in children.21 There have been extensive data on IgM positive (plus or minus IgG positive) WNV antibodies leading to encephalopathy, representing an acute infection.15-18 Presence of IgM indicates an acute infection where detectable levels usually last two to three months after initial infection.18 As a result, we believe the patient became encephalopathic due to increased serum levels of baclofen. Baclofen should be considered in the differential diagnosis of patients who display encephalopathy of unknown origin. Renal disease can also contribute to baclofen overdose and encephalopathy. Clinicians should also monitor the possibility of baclofen withdrawal symptoms in patients who have used baclofen chronically. Sudden cessation of baclofen therapy may cause spasticity, pruritis, anxiety, disorientation, sedation, somnolence, and weakness.22,23
Conducting a thorough history is crucial in order to evaluate patients with unknown encephalopathy who also utilize a baclofen pump. Specifically, health care providers should check for past infections, recent travel, military status, sexual history, kidney functioning including blood urea nitrogen (BUN) and creatinine (Cr), and run a comprehensive infectious disease workup. Baclofen levels should be monitored and the pump should be stopped when encephalopathy occurs in patients who are taking baclofen. There are various tools that are used to help monitor a patient with encephalopathy. In the instance of a patient with unknown encephalopathy a chest X-ray, cerebrospinal fluid (CSF) analysis, video electroencephalograph (EEG) can all be used to monitor the patient’s status. If the patient does not get better and still shows signs of infection such as fever and tachycardia, clinicians must attempt to improve kidney function. In addition to baclofen withdrawal, patients may present with concerning signs of baclofen overdose. These include confusion, areflexia, hypothermia, and sialorrhoea.24 Furthermore, patients with baclofen toxicity can become flaccid, lethargic, and have loss of muscle tone. This can then be followed by respiratory depression, bradycardia and depressed consciousness. In addition, transient elevations in lactic dehydrogenase alkaline phosphatase, and aspartate transaminase have been found.24 Baclofen overdose can usually be observed 2 to 6 hours after ingestion. Infections secondary to intrathecal baclofen pump are rare, and usually occur during the first weeks after pump insertion. Patients commonly present with fever, nuchal rigidity, and alterations in levels of consciousness.25 The infection is validated with positive bacterial CSF cultures. Removal of the pump and antibiotic initiation is normally warranted.25 The incidence of seizures in baclofen pump patients who also have multiple sclerosis is reported to be 7%.26 It is believed that seizures occur due to a disparity in the excitatory glutamate neurotransmitter and the inhibitory GABA neurotransmitter.27 Abrupt discontinuation of oral baclofen can also precipitate seizures.28 In addition, seizures have also been reported in baclofen overdose.29 In our patient we suspected baclofen toxicity because of the patient’s seizure, however we did not remove the baclofen pump in our patient earlier than day 9 because the patient did not show classic signs of infection including leukocytosis and fever. Furthermore, there were overlapping symptoms between pump infection and baclofen toxicity. There are three major factors to consider in order to effectively treat encephalopathy in a patient who is taking baclofen. Particularly, baclofen toxicity from renal disease may be occurring and would require correcting renal function. In addition the infection source, often times caused by the baclofen pump, can cause encephalopathy. Effective treatment would require the removal of the pump. Furthermore, baclofen withdrawal can lead to encephalopathy and would require careful dosing of oral baclofen after pump removal. Moreover, kidney function must be monitored to ensure the kidneys are working. The patient will likely need a very high dose of oral baclofen to achieve effect after receiving intrathecal dose directly to CNS. We propose that patients presenting with encephalitis who are currently taking baclofen and have preexisting renal disease immediately get dialyzed. If there is no improvement in 48 hours, other sources of infection should be considered and the baclofen pump should be removed. Thorough care must be taken to not precipitate symptoms of baclofen withdrawal.
References: 1. Venkatesan A, Geocadin RG. Diagnosis and management of acute encephalitis: A practical approach. Neurol Clin Pract. 2014;4(3):206–215. doi:10.1212/CPJ.0000000000000036 2. Ijaz, Mohsin, Hassan Tariq, Muhammad Kashif, and Jose Gomez Marquez. "Encephalopathy and Hypotonia Due to Baclofen Toxicity in a Patient with End-stage Renal Disease." The American Journal of Case Reports 16 (2015): 232-235. Web. 3. Lee, Junseop, Ho Sik Shin, Yeon Soon Jung, and Hark Rim. "Two Cases of Baclofeninduced Encephalopathy in Hemodialysis and Peritoneal Dialysis Patients." Renal Failure 35.6 (2013): 860-62. Web. 4. Mccormick, Chu, Binler, Neudorf, Mathur, Lee, and Marciniak. "Intrathecal Versus Oral Baclofen: A Matched Cohort Study of Spasticity, Pain, Sleep, Fatigue, and Quality of Life." PM&R 8.6 (2016): 553-62. Web. 5. Miller, John J. "Baclofen Overdose Mimicking Anoxic Encephalopathy: A Case Report and Review of the Literature." Therapeutic Advances in Drug Safety 8.5 (2017): 165-67. Web. 6. Witenko, Corey, Robin Moorman-Li, Carol Motycka, Kevin Duane, Juan HincapieCastillo, Paul Leonard, and Christopher Valaer. "Considerations for the Appropriate Use of Skeletal Muscle Relaxants for the Management of Acute Low Back Pain." P & T : A Peer-reviewed Journal for Formulary Management 39.6 (2014): 427-35. Web. 7. Andrew Meillier, Cara Heller, and Shyam Patel, “Baclofen-Induced Encephalopathy in End Stage Renal Disease,” Case Reports in Medicine, vol. 2015, Article ID 203936, 3 pages, 2015. https://doi.org/10.1155/2015/203936. 8. Cooper, D, Bergman, J. “Massive Baclofen Overdose.” Critical Care and Resuscitation 2000; 2: 195-197). 9. Ijaz M, et al. Encephalopathy and hypotonia due to baclofen toxicity in a patient with end-Stage renal disease. American Journal of Case Reports 16: 232-235, 20 Apr 2015. Available from: URL: http://doi.org/10.12659/AJCR.893222 - USA 10. Wu K-L, et al. Altered consciousness following head injury in advanced renal failure: Find the culprit. Journal of Medical Sciences 36: 28-30, No. 1, Feb 2016. Available from: URL: http://doi.org/10.4103/1011-4564.177175 - Taiwan 11. Radhakrishnan H. Baclofen-induced neurotoxicity in a patient with end-stage renal disease. Saudi Journal of Kidney Diseases and Transplantation 27: 595-7, No. 3, May 2016. Available from: URL: http://doi.org/10.4103/1319-2442.182437 - India 12. Dennison MA, et al. Batty for baclofen: An acute baclofen withdrawal encephalopathy. Journal of the American Geriatrics Society 64 (Suppl. 1): S223, May 2016. Available from: URL: http://doi.org/10.1111/jgs.14231 [abstract] - USA 13. Ferrarini I, Rigo A, Gandini A, Vinante F. West Nile Virus Encephalitis in Haematological Setting: Report of Two Cases and a Brief Review of the Literature. Mediterr J Hematol Infect Dis. 2019;11(1):e2019033. Published 2019 May 1. doi:10.4084/MJHID.2019.033 14. Vlavonou, R. , Perreault, M. M., Barrière, O. , Shink, E. , Tremblay, P. , Larouche, R. , Pichette, V. and Tanguay, M. (2014), Pharmacokinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations. The Journal of Clinical Pharmacology, 54: 584-592. doi:10.1002/jcph.247
15. Savasta, Salvatore, Francesca Rovida, Thomas Foiadelli, Anna Maria Campana, Elena Percivalle, Gian Luigi Marseglia, and Fausto Baldanti. "West-Nile Virus Encephalitis in an Immunocompetent Pediatric Patient: Successful Recovery." Italian Journal of Pediatrics 44.1 (2018): 140. Web. 16. Burden, Fasen, Judkins, and Isache. "A Case of West Nile Virus Encephalitis Accompanied by Diabetic Ketoacidosis and Rhabdomyolysis." IDCases 15 (2019): E00505. Web. 17. Tabain, Vilibic-Cavlek, Kristofic, Savic, Kolaric, Bogdanic, Barbic, Santini, Peric, Sabadi, Pandak, Miklausic, Potocnik-Hunjadi, Zember, Stevanovic, Capak, Listes, Klobucar, Jungic, Krcmar, and Savini. "The Role of IgG Avidity Determination in Diagnosis of West Nile Virus Infection." International Journal of Infectious Diseases 79.S1 (2019): 116-17. Web. 18. Murray, Kristy O, Melissa N Garcia, Chris Yan, and Rodion Gorchakov. "Persistence of Detectable Immunoglobulin M Antibodies up to 8 Years after Infection with West Nile Virus." The American Journal of Tropical Medicine and Hygiene 89.5 (2013): 996-1000. Web. 19. Kleinschmidt‐DeMasters, B. K. and Beckham, J. D. (2015), West Nile Virus Encephalitis 16 Years Later. Brain Pathology, 25: 625-633. doi:10.1111/bpa.12280 20. Giordano BV, Kaur S, Hunter FF. West Nile virus in Ontario, Canada: A twelve-year analysis of human case prevalence, mosquito surveillance, and climate data. PLOS ONE. 2017;12(8):e0183568. doi:10.1371/journal.pone.0183568 21. Savasta S, Rovida F, Foiadelli T, et al. West-Nile virus encephalitis in an immunocompetent pediatric patient: successful recovery. Ital J Pediatr. 2018;44(1):140. doi:10.1186/s13052-018-0574-x 22. Mohammed, Imran, and Asif Hussain. "Intrathecal Baclofen Withdrawal Syndrome- a Life-threatening Complication of Baclofen Pump: A Case Report." BMC Clinical Pharmacology 4.1 (2004): 6. Web. 23. Alvis, Bret D, and Christopher M Sobey. "Oral Baclofen Withdrawal Resulting in Progressive Weakness and Sedation Requiring Intensive Care Admission." The Neurohospitalist 7.1 (2017): 39-40. Web. 24. Arbouw, M E L, H L Hoge, J. Meulenbelt, and F G A Jansman. "Increase of Baclofen Intoxications: Risks Involved and Management." The Netherlands Journal of Medicine 72.9 (2014): 497-499. Web. 25. Aristedis, Rovlias, Papoutsakis Dimitrios, Paidakakos Nikolaos, and Blionas Alexandros. "Intrathecal Baclofen Pump Infection Treated by Adjunct Intrareservoir Teicoplanin Instillation." Surgical Neurology International 8.1 (2017): 38. Web. 26. Schuele, Kellinghaus, Shook, Boulis, Bethoux, and Loddenkemper. "Incidence of Seizures in Patients with Multiple Sclerosis Treated with Intrathecal Baclofen." Neurology 64.6 (2005): 1086-087. Web. 27. Rolland, Benjamin, Sylvie Deheul, Thierry Danel, Régis Bordet, and Olivier Cottencin. "A Case of De Novo Seizures following a Probable Interaction of High-dose Baclofen with Alcohol." Alcohol and Alcoholism (Oxford, Oxfordshire) 47.5 (2012): 577-580. Web. 28. Meythaler, J M, S. Guin-Renfroe, P. Grabb, and M N Hadley. "Long-term Continuously Infused Intrathecal Baclofen for Spastic-dystonic Hypertonia in Traumatic Brain Injury:
1-year Experience." Archives of Physical Medicine and Rehabilitation 80.1 (1999): 13-9. Web. 29. Franchitto, Rolland, Pelissier, and Simon. "How to Manage Self-Poisoning With Baclofen in Alcohol Use Disorder? Current Updates." Frontiers in Psychiatry 9 (2018): 417. Web.
GABA: gamma-aminobutyric acid WNV: West Nile Virus K/uL: thousands per cubic milliliter LP: lumbar puncture Cells/uL: cells/microliter mg/dL: milligrams/deciliter gm/dL: grams/deciliter mm/hr: millimeters/hour ug/mL: micrograms/milliliter ng/mL: nanograms/milliliter CT: computed tomography MRI: magnetic resonance imaging E.coli: Escherichia coli H2O: water EEG: electroencephalogram CSF: cerebrospinal fluid IgG: Immunoglobulin G IV: intravenous IgM: Immunoglobulin M GFR: glomerular filtration rate BUN: blood urea nitrogen Cr: creatinine CNS: central nervous system cm: centimeter mg: milligram mcg: microgram mcl: microliter