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Guillain-Barré syndrome in an older man following influenza vaccination Natalie A. Finch, Anthony J. Guarascio, and Katie J. Suda

Received July 23, 2013, and in revised form September 26, 2013. Accepted for publication November 11, 2013.

Abstract Objective: To report an atypical case of Guillain-Barré syndrome (GBS) after administration of the 2012–13 influenza vaccine. Setting: Urban tertiary hospital. Patient Description: An 81-year-old man was admitted to the hospital after he began experiencing numbness and tingling in both feet that began ascending toward the waistline. The patient complained of intense neuropathic pain in his lower extremities and eventually lost the deep tendon reflexes in his ankles. Case summary: In addition to clinical manifestations of GBS, electromyography revealed a sensorimotor, polyneuropathy, predominantly axonal, with prolonged F-waves in all nerves tested. A lumbar puncture revealed clear and colorless cerebrospinal fluid with an elevated protein level of 66 mg/dL (reference, 15–60 mg/dL) despite the lack of a normal cell count, indicating albuminocytologic dissociation. Based on these findings, the patient met Brighton level 3 diagnostic certainty and was diagnosed with GBS. Main outcomes measure: Signs and symptoms of GBS. Results: On day 5 of hospitalization, intravenous immunoglobulin 0.4 mg/ kg/d was initiated for 5 days in combination with gabapentin 100 mg at bedtime for neuropathic pain. After completing treatment, the patient experienced progressively improved sensation in his extremities and was discharged.

Natalie A. Finch, BS, is a PharmD candidate and student pharmacist, University of Tennessee Health Science Center College of Pharmacy, Memphis. Anthony J. Guarascio, PharmD, BCPS, is Assistant Professor, University of Tennessee Health Science Center College of Pharmacy, Knoxville. Katie J. Suda, PharmD, MS, is Research Health Scientist, Center of Innovation for Complex Chronic Healthcare, Hines Veterans Affairs Hospital, Chicago; at the time this work was done, she was Associate Professor, University of Tennessee Health Science Center College of Pharmacy, Memphis. Correspondence: Katie J. Suda, PharmD, MS, Hines Veterans Affairs Hospital 151-H, 5000 South Fifth Avenue, Bldg. 1, B-260, Hines, IL 60141. Fax: 708-202-2316. E-mail: [email protected] Disclosure: The authors declare no conflicts of interest or financial interests in any product or service mentioned in this article, including grants, employment, gifts, stock holdings, or honoraria. Published online ahead of print at www. japha.org on February 12, 2014.

Conclusion: This is a rare report of GBS lacking albuminocytologic dissociation after an older patient received the 2012–13 influenza vaccine. J Am Pharm Assoc. 2014;54:188–192. doi: 10.1331/JAPhA.2014.13152

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uillain-Barré syndrome (GBS) is a condition characterized by the acute or subacute onset of weakness or paralysis in the limbs accompanied by decreased or absent deep tendon reflexes.1 GBS encompasses a variety of acute immune-mediated polyneuropathies and is defined as a heterogeneous condition with variant forms. Since poliomyelitis has been virtually eliminated, GBS is the most frequent cause of acute flaccid paralysis and is considered a serious emergency in neurology.2 According to a meta-analysis by Sejvar et al.,1 the incidence of GBS from any cause increases by 20% for every 10-year increase in age and is more frequent in men than women. Overall, the annual incidence of GBS is low, approximately 1 to 2 cases per 100,000 population per year3; however, it can sometimes have fatal outcomes. Although the underlying etiology is unknown, various preceding events are known to trigger an immune response that result in an acute polyneuropathy, including bacterial and viral infections, specifically Campylobacter jejuni, cytomegalovirus (CMV), Epstein–Barr virus (EBV), varicella zoster virus (VZV), and Mycoplasma pneumoniae, and the administration of various vaccines.1 Although administration of the influenza vaccine has been associated with GBS, various case reports have associated GBS with other vaccines, including tetanus toxoid, hepatitis B, rabies, and 23-valent pneumococcal.1 The greatest concern regarding GBS and the influenza vaccine occurred during a 1976 national influenza

At a Glance Synopsis: This report describes Guillain-Barré syndrome (GBS) lacking albuminocytologic dissociation in an older man after he received the 2012–13 influenza vaccine. After a 10-day hospitalization, the patient was discharged with minimal residual symptoms. Analysis: GBS is the most common cause of acute flaccid paralysis and usually presents with acute onset of weakness or paralysis in the limbs accompanied by decreased or absent deep tendon reflexes. Although the etiology is unknown, GBS is a rare adverse effect of vaccinations. The influenza vaccine is associated with the highest incidence of GBS among all vaccines, and older men have the highest risk of developing this adverse effect. As the number of patients receiving the annual influenza vaccine increases, further research is needed to understand which patient populations are at the highest risk for developing this possible life-threatening disease. Despite the seriousness of this disease, the benefits of receiving an annual influenza vaccine outweigh the risk of developing GBS. Clinicians should be cognizant of both typical and atypical presentations of GBS to initiate prompt, appropriate care. Journal of the American Pharmacists Association

vaccine program, which was implemented to prevent high morbidity and mortality from swine influenza A virus.4 From this program, an estimated risk of vaccinerelated GBS in an adult population was approximately 1 per 100,000 vaccines.4 Many subsequent studies have shown differing results regarding the relationship between the influenza vaccine and GBS. An analysis of the 2009–10 United States H1N1 influenza pandemic calculated the estimated risk of GBS following vaccination to be approximately 1.1–5 confirmed cases per million doses.5 This report describes a case of an older man who developed GBS after the administration of the 2012–13 influenza vaccine. While no specific information regarding the type of influenza vaccine is known with absolute certainty, details of this report were collected from patient interview and review of the inpatient electronic medical record. The hospital medication administration record was reviewed to verify that prescribed medications were administered as ordered.

Case summary An 81-year-old white man presented to the hospital after receiving the intradermal, trivalent 2012–13 influenza vaccine [A/California/7/2009 (H1N1)-like, A/Victoria/361/2011 (H3N2)-like, and B/Wisconsin/1/2010like (Yamagata lineage) antigens] at his primary care physician’s office approximately 5 weeks before admission. Unfortunately, specific details regarding vaccine type, such as whether or not the patient received the high-dose vaccine indicated for people 65 years and older, are unknown. About 2 weeks after receiving the vaccination, the patient began to experience numbness and tingling in the soles of his feet. The patient presented to the hospital after paresthesias began ascending toward his waistline. He complained of an intense neuropathic pain in his lower extremities. On presentation, the patient’s gait and coordination were not entirely intact, but there was no reported weakness in his extremities. When the patient was admitted, he was not taking any medications; however, he was prescribed dronabinol 2.5 mg as needed for appetite stimulation approximately 6 weeks before admission. The patient discontinued the use of dronabinol 3 weeks before admission because he thought the medication might have been responsible for his symptoms. His past medical history was significant for chronic obstructive pulmonary disorder (COPD), although he was not currently taking any medications for the condition, nor was there a history of previous medications for COPD. The patient could not recall any history of previous immunizations. He had lost weight a few months before admission. Although the patient had hernia, foot, and cataract surgeries decades before this admission, he did not have any recent hospitalizations, and his previous admissions were considered noncontributory. j apha.org

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The patient’s social history was positive for cigar and cigarette smoking, and he claimed to smoke about 10 cigars per day. There was no recent history of fever, diarrhea, or upper respiratory symptoms as well as no history of head trauma. He had no known drug allergies. A physical examination at admission revealed a blood pressure of 155–169/74–92 mm Hg, respiratory rate of 16–18 breaths/min, heart rate of 64–92 beats/ min, and temperature of 36.3–36.5 °C. Heart and lung examinations were normal. During the neurologic examination, the patient was noted to be calm, alert, and oriented. Although he displayed no weakness in all four extremities, the patient lacked deep tendon reflexes in his ankles. An electromyography (EMG) indicated a sensorimotor polyneuropathy, predominantly axonal, with prolonged F-waves in all nerves tested. Magnetic resonance imaging of the lumbar and thoracic spine and computed tomography of thorax, brain, head, abdomen, and pelvis were all negative for pathogenic signs of neuropathy as well as for alternative diagnoses. On admission, the patient’s metabolic panel and complete blood count were all within normal limits with the exception of an elevated serum creatinine of 1.5 mg/ dL (normal, 0.5–1.2 mg/dL in men). His creatinine level decreased to 1.2 mg/dL on hospital day 3, with a calculated Cockcroft–Gault creatinine clearance estimate of 46.7 mL/min. A lumbar puncture revealed clear and colorless cerebrospinal fluid (CSF) with a slightly elevated CSF protein of 66 mg/dL (reference, 15–60 mg/ dL). Lumbar puncture also revealed an elevated CSF white blood cell (WBC) count, 17 cells/mm3 (reference, 0–10 cells/mm3) and elevated CSF immunoglobulin G, 19.4 mg/dL (reference, up to 5.8 mg/dL). Other values of the lumbar puncture included red blood count, 0 (reference, 0), monocytes, 24 (reference, 60 mg/dL) , elevated CSF IgG (19.4 mg/dL), and elevated CSF index (2.61), with normal WBC count (17 cells/mm3) by the third week of disease onset is a diagnostic laboratory marker of GBS.2 This patient presented with an elevated CSF protein but lacked the normal cell count, and therefore, lacked diagnostic albuminocytologic dissociation. According to Yuki et al.,2 albuminocytologic dissociation is not always required for diagnosis; however, 75% of patients present with albuminocytologic dissociation by 3 weeks of disease onset. Elevated CSF protein may be caused by an increased permeability of the blood-CSF barrier from various conditions, including infections, intracranial hemorrhages, multiple sclerosis, GBS, malignancies, endocrine abnormalities, certain medications, and a variety of other inflammatory conditions.13,14 The patient discussed in this report presented with ascending, bilateral, and symmetrical paresthesias originating from the lower extremities. Later in the disease course, the patient lost deep tendon reflexes in his ankles although he had no apparent weakness in any extremities. This is a typical physical presentation of GBS. Based on the findings of the patient’s EMG, the GBS was found to be sensorimotor and axonal in nature. By analyzing the various subtypes of GBS (acute inflammatory demyelinating polyneuropathy, acute motor axonal neuropathy, acute motor–sensory axonal neuropathy, and Miller Fisher syndrome), this patient’s condition could most likely be classified as the acute motor–sensory axonal neuropathy subtype. Studies have shown that this GBS variant involves sensory nerves with acute motor axonal neuropathy.2 Although the patient presented with typical physical findings of GBS, the lack of laboratory albuminocytologic in the CSF indicates this patient meets only Brighton level 3 diagnostic certainty and makes this a unique presentation. Based on the modified World Health Organization (WHO) causality criteria, the manifestation of GBS and the administration of the influenza vaccine are possibly related in this patient.15 Although the specific manufacturer, lot, or dose of the influenza vaccine is unknown and should be considered a limitation of this report, there was a temporal relationship between time of administration of the vaccine and disease presentation. In addition, the case was biologically plausible and other known infectious causes for the event had been excluded through laboratory and imaging studies. Journal of the American Pharmacists Association

In 2012, the IOM report concluded that evidence was inadequate to accept or reject a causal relationship between influenza vaccine formulations and GBS10; thus, this case meets possible and probable WHO causality criteria. However, studies assessed in this IOM report were published no more recently than 2010,10 and because a causal relationship has been established with previous influenza vaccines (1976–77 swine influenza vaccine),4,9 further study is required to determine whether more recently marketed influenza vaccine formulations have the potential to cause GBS.

Conclusion Although GBS is rare, it should be considered in older patients who experience adverse reactions after administration of the influenza vaccine. Despite the seriousness of GBS, the benefits of receiving an annual influenza vaccine outweigh the risk of developing GBS. As the number of patients receiving the annual influenza vaccine increases, further research is needed to understand which patient populations are at the highest risk for developing this possible life-threatening disease. For now, clinicians should be cognizant of both typical and atypical presentations of GBS to initiate prompt, appropriate care. References 1. Sejvar JJ, Baughman AL, Wise M, Morgan OW. Population incidence of Guillain-Barré syndrome: a systematic review and meta-analysis. Neuroepidemiology. 2011;36(2):123–133. 2. Nobuhiro Y, Hartung H. Guillain-Barré syndrome. N Engl J Med. 2012;366(24):2294–2304. 3. Sejvar JJ, Kohl KS, Gidudu J, et al. Guillain-Barré syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine. 2011;29:599–612. 4. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barré syndrome following vaccination in the National Influenza Immunization Program, United States, 1976–1977. Am J Epidemiol. 1979;110(2):105–123. 5. Green SK, Rett M, Weintraub ES, Li L. Risk of confirmed Guillain-Barré syndrome following receipt of monovalent inactivated influenza A (H1N1) and seasonal influenza vaccines in the Vaccine Safety Datalink Project, 2009–2010. Am J Epidemiol. 2012;175(11):1100–1109. 6. Centers for Disease Control and Prevention. Estimates of death associated with seasonal influenza—United States, 1976– 2007. MMWR Morb Mortal Wkly Rep. 2010;59(33):1057–1092. 7. Kisslong E, Valenciano M, Cohen JM, et al. I-MOVE multicentre case control study 2010–11: Overall and stratified estimates of influenza vaccine effectiveness in Europe. PLoS One. 2011;6(11):e27622. 8. Salmon DA, Proschan M, Forshee R, et al. Association between Guillain-Barré syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis. Lancet. 2013;281(9876):1461–1468.

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9. Burwen DR, Ball R, Bryan WW, et al. Evaluation of Guillain-Barré syndrome among recipients of influenza vaccine in 2000 and 2001. Am J Prev Med. 2010;39(4):296–304. 10. Institute of Medicine. Adverse effects of vaccines: evidence and causality. Washington, DC: The National Academies Press; 2012. 11. Kwong JC, Vasa PP, Campitelli MA, et al. Risk of Guillain-Barré syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study. Lancet Infect Dis. 2013;13(9):769–776.

12. Wise ME, Viray M, Sejvar JJ, et al. Guillain-Barré syndrome during the 2009–2010 H1N1 influenza vaccination campaign: population-based surveillance among 45 million Americans. Am J Epidemiol. 2012;175(11):1110–1119. 13. Seehusen D, Reeves M, Fomin D. Cerebrospinal fluid analysis. Am Fam Physician. 2003;68(6):1103–1109. 14. Gonzalez-Quevedo A, Carriera R, O’Farrill Z, Luis I. An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain-Barré syndrome. Neurology India. 2009;57(3):288–294. 15. Loughlin AM, Marchant CD, Adams W, et al. Causality assessment of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS). Vaccine. 2012;30(50):7253–7259.

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