an immunosuppressed woman presenting with acute … · an immunosuppressed woman presenting with...

298 J La state Med soc vOL 159 November/December 2007

Journal of the Louisiana State Medical Society

cliNical case oF the moNth

an immunosuppressed woman Presenting with acute Flaccid Paralysis

and Progressive Respiratory Failure

Credit

The LSMS Educational and Research Foundation designates this educational activity for a maximum of one (1) AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

disClosure

Drs. Monreal, Vega, Simeone, Hamm, Palacios, and Maylin have nothing to disclose.Dr. Lopez discloses that he is a member of the Journal Board of Trustees and the Journal Editorial Board.

originalreleasedateexpirationdate 11/30/2007 11/30/2008

cme iNFormatioNtargetaudienCe

The November/December Clinical Case of the Month is intended for medical students, general practitioners, pediatricians, medicine subspecialists, emergency medicine physicians, radiologists, neurologists, and pathologists.

eduCationalobjeCtives

The Clinical Case of the Month is a regular educational feature. Medical students, residents, postdoctoral fellows, and faculty collaborate in the preparation of these discussions. After reading this article, physicians should be better able to identify and understand the pathophysiology, microbiology, epidemiology, clinical presentation, diagnosis and treatment of West Nile Virus infections. Estimated time to complete this activity is one (1) hour.

Rebeca Monreal, DO; Arturo vega, MD; Francesco Simeone, MD; Lee Hamm, MD; Enrique Palacios, MD; Marlow Maylin, MD; and Fred A. Lopez, MD (Section Editor)

A 68-year-old woman with membranous glomerulo-nephritis and hypertension presented in late August with a tremor, weakness of the upper and lower extremities, headache and nausea. She had not been feeling well for the previous two weeks and also reported sore throat and nasal congestion. Four days prior to admission her temperature was 100.8˚ F. Other symptoms included loose stools, head-ache, fatigue, muscle weakness, dyspnea, dry heaves, and double vision. She initially saw her primary care physician. Her serum creatinine at that time was 3.9 mg/dL (baseline 2.7) and her creatine phosphokinase (CPK) was 275 U/L. Ciprofloxacin by mouth was prescribed and oral hydration recommended. Her weakness progressed and her tremor extended to her facial muscles. She developed difficulty eat-ing and was admitted to the hospital. There was no weight loss, cough, dysuria, arthralgia, or skin rash.

Her medical treatment included mycophenolate mofetil, furosemide, valsartan, enalapril, labetalol, and clonidine. She had a hysterectomy and appendectomy remotely in time. Her father had systemic lupus erythematosus. She denied drug allergies, tobacco, alcohol, or recreational drug

use. She lived with her husband on the Mississippi Gulf Coast. Previously she was functional and independent with all activities of daily living.

On physical examination her temperature was 98.6˚ F (though as high as 101.2˚ F); blood pressure 116/83 mmHg; pulse rate of 85 beats per minute; and a respiratory rate 12 breaths per minute. She appeared anxious, but was in no respiratory distress. She was able to follow commands and move all extremities, but had generalized muscle weakness (strength 3/5 throughout) and an intentional tremor of her arms bilaterally.

Vancomycin, ceftriaxone, and acyclovir were started empirically. Computed tomography (CT) scan of the head without contrast was unremarkable. Renal ultrasound (US) revealed kidney sizes of 10.6 cm on the right and 8.2 cm on the left.

The day after admission her muscle weakness wors-ened. Her Achilles and patellar reflexes were absent; biceps and triceps reflexes were 2+/4+ bilaterally. Her intentional tremor worsened. She also developed asterixis and myoclonus. Cranial nerve function was intact, and fun-

J La state Med soc vOL 159 November/December 2007 299

doscopic exam was normal. There was decreased sensation to pin-prick and light touch in the distal lower extremities. Cerebellar function could not be assessed due to weakness and tremor.

Her condition deteriorated further on the second hospital day. She became paraparetic, obtunded and developed respiratory distress. She was transferred to the intensive care unit (ICU). The presence of shallow breaths and a paradoxical motion of her chest wall prompted intubation and initiation of mechanical ventilation.

Cerebrospinal fluid (CSF) examination showed red blood cell count (RBC) 1180, white blood cell count (WBC) 114 (16% polymorphonuclear neutrophilic leukocytes (PMN), 59% lymphocytes, 25% monocytes), protein 78.3 mg/dl, glucose 78mg/dl, and negative Gram stain, India ink, potassium hydroxide (KOH), and acid-fast stains. Cultures for herpes virus (HSV), cytomegalovirus (CMV), tuberculosis, and fungi were obtained and later found to be negative. An arbovirus panel, including West Nile Virus (WNV) serology, was requested. Serology was negative for California encephalitis, eastern equine encephalitis, western equine encephalitis, and St. Louis encephalitis. Serum and CSF studies targeting the presence of WNV infection were positive.

Magnetic resonance imaging (MRI) of her brain, with and without contrast, (Figures 1, 2), was obtained on hospital day four and demonstrated meningeal enhancement, a high-density focal lesion in the left caudate nucleus and thalamus (post contrast administration). Small-vessel white-matter disease was also noted. An MRI done for comparison nine days later showed increased intensity in the basal ganglia

and thalamic region, petechial hemorrhages and cystic necrosis. These MRI findings were consistent with WNV-associated encephalitis.

An electroencephalogram (EEG) done on day five showed periods of moderate amplitude 5 Hz theta activity alternating with periods of lower amplitude 2-3 Hz delta activity with brief, less than 0.5 second, attenuations. There was a generalized attenuation of activity with stimulation.

The patient was treated supportively in the ICU, but no improvement in her neurological deficits was noted. One month later and still ventilator-dependent, she was transferred to a long-term acute care facility. Two and a half months later, after many complications including recurrent episodes of ventilator-acquired pneumonia, sepsis, acute renal failure, fluid and electrolyte imbalances, and Clostridium difficile-associated colitis, she remained ventilator-dependent, with persistent paralysis and a waxing and waning level of consciousness. In consultation with her family and based on her previously expressed wishes, care was withdrawn, and she expired.

Discussion

This case of confirmed WNV encephalitis and acute flaccid paralysis (AFP) in an immunosuppressed patient was complicated by respiratory failure and ventilator dependency. Outlook for neurological recovery remained poor despite prolonged supportive care.

The WNV belongs to the flavivirus family, which also includes Japanese encephalitis, St Louis encephalitis, Kunjin virus, and Murray River Valley encephalitis (found

Figure 1. MR Axial Sections (A) Fluid Attenuation Inversion Recovery revealed abnormal signal intensity in the left basal ganglia, (B) T2 Weighted image revealed an abnormal signal intensity in the left basal ganglia (arrow), and (C) T1 post-contrast demonstrated a focal area of abnormal enhancement in the region of the globus pallidus on the left.

A B C



in Australia). WNV was first isolated in the West Nile province of Uganda in 1937. According to the Centers for Disease Control (CDC), a total 4,269 cases were reported in the United States in the year 2006. These were divided into three categories: 1) WNV fever, 1,459 cases (a milder disease without neurologic involvement); 2) encephalitis/meningitis, 2,616 cases (neuroinvasive); 3) clinically unspecified, 194 patients. Of the 2,616 neuroinvasive cases, 101 had acute flaccid paralysis. Of all the 4,269 reported

cases, 177 (4.1%) were fatal. The areas in the United States with a caseload of more than 275 included California (278), Colorado (345), Idaho (996) and Texas (354). In Louisiana, 180 cases were reported in 2006. In the New Orleans area, 17 cases were reported in Orleans Parish and 14 in Jefferson Parish. Of note, 12 cases were reported in Harrison County, Mississippi.1

Figure 2. MRI follow-up nine days after previous examination (Figure1) revealed significant progression with bilateral abnormal intensities in the basal ganglia, more pronounced on the left and associated with a minimal hemorrhagic component. Axial sections: (A) T1 Weighted image, (B) T2 Weighted image (arrow), (C) Fluid Attenuation Inversion Recovery and (D) Diffusion Weighted image. Abnormal enhancement post-contrast is identified in both basal ganglia, more pronounced on the left (E, axial section; and F, coronal section).

A

D

CB

FE


TransmissionThe primary route of transmission is through the bite

of an infected Culex mosquito (although 36 other species of mosquito also have been known to carry WNV). Mosquitoes acquire WNV by feeding on infected birds that serve as the reservoir for the virus. Birds can remain viremic for up to two weeks. WNV is known to infect other animals such as horses, cats, bats, chipmunks, skunks, squirrels, and domestic rabbits. The virus, which is in the salivary glands of the mosquito, is later injected into humans or animals during the mosquito’s blood meals. Other rare routes of transmission include organ transplantation,2 blood transfusions, transplacental, or via breast milk.3 Since 2004, new blood donor screening strategies have been used (ie, WNV nucleic acid-amplification tests) to identify potentially infectious donations; thus, this route of transmission has probably become less frequent.4 Once the virus reaches the blood stream, it multiplies, crosses the blood-brain barrier and can cause inflammation, damage to parenchymal cells, and altered central nervous system (CNS) function.

clinical PresentationAccording to the CDC, less than 1% of individuals

bitten by infected mosquitoes will become severely ill. In a seroprevalence study, an estimated 20% of infected individuals developed fever. In the United States, 1:120-160 persons with seroconversion developed encephalitis.3

The incubation period is from 2 to 15 days, typically 2 to 6 days, with longer incubation periods in immunosuppressed patients, such as our patient.1

WNV infection is typically asymptomatic or is associated with mild symptoms. Initially infected individuals may have flu-like symptoms, fatigue or a clinical picture of viral meningitis. West Nile fever occurs in one in every five individuals infected with WNV. Symptoms may include fever, headache, eye pain, backache, myalgia, anorexia, nausea and vomiting. According to a CDC report of 27 WNV- associated AFP cases, asymmetric weakness is more commonly found in all four extremities (44%), compared to a single extremity (26%), asymmetric lower extremity (22%), and asymmetric upper extremity (7%). The CDC also reports that 25% to 35% of patients with the neuroinvasive form of infection have meningitis without encephalitis. The body’s response to the viral infection includes activation of T-cells and formation of antibodies.1

A large prospective cohort study involving 219 cases of WNV-neuroinvasive disease, describes 32 patients (14.6%) who developed flaccid paralysis.5 Twenty-six (81%) of individuals in this subgroup had combined encephalitis and flaccid paralysis, such as our patient. Respiratory failure and prolonged mechanical ventilation, with need for a tracheostomy, was reported in 12 (38%) of the patients that developed flaccid paralysis. The chances of developing respiratory failure were higher in patients with dysphagia, dysarthria or both, with an odds ratio [OR] of 62 (p < 0.0001). The time from the onset of these symptoms to initiation of

mechanical ventilation ranged from less than 1 to 6 days. The duration of mechanical ventilation in survivors ranged from 21 to 135 days, with a median of 49 days. The long-term management of this complication can be challenging.5

DiagnosisThe cerebrospinal fluid (CSF) cell count typically

shows pleocytocisis with lymphocyte predominance and normal glucose. CSF and serum samples should be sent to local or state health departments, where an IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) is usually performed. Specific IgM antibodies are found in nearly all CSF and serum specimens at the time of presentation. Detection of the specific WNV IgM in the CSF provides a conclusive diagnosis. IgM antibodies do not usually cross the blood-brain barrier, therefore their presence in the CSF suggests an acute CNS infection. When only serum is available, paired acute- (time of presentation) and convalescent- (7 to 14 days later) phase serum samples should be tested. A four-fold increase or more in the titer is diagnostic. If a convalescent-phase specimen cannot be obtained, the absence of the IgM antibody in the acute phase serum makes the WNV infection very unlikely. Its presence suggests an acute infection, but the serum IgM may persist for more than one year and its detection may be due to a prior infection. 6 Furthermore, there may be cross-reaction due to recent infection with or vaccination against related flaviviruses. For this reason, along with WNV serology, a full arbovirus panel should be obtained. 1

An MRI will confirm spinal cord, brain stem and CNS involvement, as shown in figures 1 and 2. Electrodiagnostic findings with nerve conduction studies (NCS) and electromyography (EMG) in WNV associated AFP are typically asymmetrical, similar to poliomyelitis that involves the anterior horn cells or their axons, and include increased insertional activity and abnormal spontaneous activity in the form of positive sharp waves and fibrillations. These findings are more prominent in the proximal muscles of the extremities, in the paraspinal muscles, and are consistent with myotonia.6 The EMG findings in the acute phase help differentiate WNV-associated acute flaccid paralysis from Guillian-Barré Syndrome (GBS) because of the presence of two salient features: 1) asymmetrical axonal involvement and 2) no sensory involvement. In contrast, GBS is an acute inflammatory demyelinating polyneuropathy with symmetrical motor and sensory involvement. Later, electrodiagnostic tests evaluating renervation and collateral sprouting may help assess prognosis. Confirmed cases of WNV infection should be reported to the CDC.

Risk of infection The risk of WNV infection increases with outside

activities during peak mosquito feeding hours (dusk and dawn) and with outside activities near mosquito breeding grounds, such as standing water and high weeds. Rainy weather also increases this risk by intensifying mosquito



breeding. Regions where summer months follow a winter with high amounts of rainfall typically have an increased rate of infection. Several factors predispose to infection including diabetes mellitus, HIV infection, use of steroids, cancer, extremes of age, immunosuppression due to organ transplantation and treatment of autoimmune diseases (particularly with agents inhibiting both T and B cells).8,11

TreatmentTreatment of WNV-associated AFP is supportive in

the acute stage and later includes rehabilitation. IFN α-n3 and ribavirin are effective in-vitro against WNV and have been used in treating some patients, but without proven or suggested efficacy. A randomized double blind clinical trial is currently evaluating the use of IFN α-n3 in patients with acute WNV meningoencephalitis. 10 Another phase II trial is assessing the safety and efficacy of WNV antibodies, derived from individuals with high blood levels, in treat-ment of patients with WNV encephalitis.9

PrognosisPatients with meningo-encephalitis from the 2002

New York outbreak had a mortality rate of 9%. Those with meningo-encephalitis who were older than 70 years had a mortality rate of 21%.11-12 Age clearly affects prognosis. The risk of developing neurological symptoms increases tenfold after the age of 50 years and 43-fold after the age of

80 years.11 A large retrospective data analysis from a 2000 outbreak in Israel is useful in assessing prognosis (WNV is epidemic in Israel, and the viral strains are comparable to those found in the 1999 New York outbreak). Data were obtained from 233 patients hospitalized at 12 different locations.13 Patients were divided into three groups: 1) encephalitis (57.7%), 2) febrile illness (24.4%), and 3) meningitis (15.9%). One hundred thirty-four patients had an age of less than 70 years, and 99 patients were older than 70 years. Thirty-three (14.1%) of the 233 patients died. The mean age of the patients who died was 80 years (range 54-95 years). All patients were older than 68 years with the exception of only one, who was 54 years old (a woman with myasthenia gravis receiving azathioprine). Mortality rate in the subgroup of patients older than 70 years was 29.3%. Mortality in an immunocompromised subgroup was 31.3% (5:16), versus 12.9 % (28:217) in those non-immunocompromised. 13 Other authors have reported that diabetes mellitus is significantly associated with death (age-adjusted relative risk, 5.1; 95% confidence interval, 1.5 to 17.3).14 In this same study, 14% of the patients were immunocompromised because of cancer, HIV, prednisone use for asthma, or alcoholism.

In the 1999 New York outbreak case series, 6 (10%) out of 59 patients had acute flaccid paralysis. Ten (17%) out of 59 required mechanical ventilation. All of them had encephalitis except one who had meningitis. 16 Using phone interviews, their physical, cognitive, and functional status were followed after onset of WNV illness. 15 Only 37% of 35 patients evaluated were fully recovered at 12 months after infection. Young age was a positive predictor for recovery in all three areas. All patients in the group with encephalitis and weakness reported difficulty walking at the six-month interview. The only significant predictor of achieving full recovery was age younger than 65 years.

In a longitudinal cohort with one year follow-up of 32 patients with WNV and paralysis, 27 had AFP, 4 had Guillian-Barré-like Syndrome (symmetrical ascending flaccid paralysis) and one had only brachial plexopathy.

16

Muscle strength, using the manual muscle test, showed improvements at one year (with varied results, and some more than others). Overall those with less initial weakness demonstrated the greatest strength gains at one year. All those with facial weakness showed complete recovery, though it took greater than five months. In nearly all patients there were persistent neurological signs and symptoms such as atrophy, compartmental muscle weakness, and contractures.

16

At one year, 3 out of 27 AFP patients with respiratory failure died. The respiratory function and functional status of survivors at one year was still poor with all of them still experiencing orthopnea, dyspnea on exertion, and a weak cough, and 50% of them still required supplemental oxygen and assistance with their daily activities. Patients required a prolonged weaning period from the ventilator. The reported survival rate was only 50% for patients who spent less than four months on mechanical ventilation


and 0% for those ventilated over four months. Death, as in the case we present, was in almost all cases due to a voluntary withdrawal of ventilatory support; of those patients with respiratory paralysis and quadriplegia from AFP (poliomyelitis-like syndrome), 1 out of 5 survived and remarkably made a complete recovery.

16

In conclusion, although WNV infection is usually asymptomatic or causes few symptoms, it can also be devastating, particularly in those patients who develop encephalitis and myelitis. Patients, such as our case patient, who develop AFP and respiratory failure, have the worst prognosis and a high mortality. When they survive, the recovery period is prolonged, and recovery is most often incomplete.

6 Older age (over 70 years), immunosuppression,

and co-morbidities such as diabetes mellitus are associated with a worse prognosis. There is no reliably proven treatment. Prevention (avoidance of mosquito bites) is fundamental and should be encouraged, particularly in the case of older and immunosuppressed individuals.

ReFeRences

1. Centers for Disease Control. <http://www.CDC.gov> (accessed 02 July, 2007).

2. MMWR Morbidity & Mortality Weekly Report 2007 Feb 2:56(4):76

3. MMWR Morbidity & Mortality Weekly Report 2002 Oct 4:51(39):877

4. MMWR Morbidity & Mortality Weekly Report 2004 April 9:53(13):281

5. Sejvar JJ, Bode AV, Marfin AA, et al. Emerg Infect Dis. 2005; 11:1021–1027.

6. Scott D, Vargo M, Kelly C, et al. Electromyographic Findings of Anterior Horn Cell Disease Associated With West Nile Virus Encephalitis. Arch of Phys Med and Rehab. 2003; 84:E12-13, poster 40.

7. Leis A, Stokic D, Polk J, et al. Acute flaccid paralysis syndrome associated with West Nile virus infection—Mississippi and Louisiana, July-August 2002. JAMA 2002; 288:1839-1840.

8. Petersen LR, Marfin AA. West Nile Virus: a primer for the clinician. Annals of Internal Medicine 2002; 137:173-179.

9. Centers for Disease Control. <http://www.clinicaltrials.gov show/NCT00068055> (accessed 05 May, 2007).

10. <http:/www.nyhq.org/posting/rahal.html> (accessed 02 July, 2007).

11. Peterson LR, Marfin AA, Gubler DJ. West Nile Virus. JAMA 2003; 290:524-528.

12. Sampathkumar P. West Nile virus: epidemiology, clinical presentation, diagnosis, and prevention. Mayo Clin Proc 2003; 78:1136-1144.

13. Chowers MY, Lang R, Nassar F, et al. Clinical characteristics of the West Nile fever outbreak, Israel, 2000. Emerg Infec Dis 2001; 7:675–678.

14. Nash D, Mostashari F, Fine A, et al. The outbreak of West Nile virus infection in the New York City area in 1999. New Eng J of Med 2001; 344:1807-1814.

15. Labowitz-Klee, Nash D. et al. Long-Term Prognosis for Clinical West Nile Virus Infection. Emerg Infect Dis. 2004; 10:1405-1411.

16. Sejvar JJ, Bode AV, Marfin AA, et al. Emerg Infect Dis. 2006; 12:514-516.

17. Marciniak C, Sorosky S, Hynes C. Acute Flaccid paralysis associated with west nile virus: Motor and functional improvement in 4 patients. Arch of Phys Med and Rehab. 2004; 85:1933.

Dr. Monreal is a house officer in the Section of Physical Medicine and Rehabilitation at Louisiana State university School of Medicine in New Orleans, Louisiana. Dr. Vega is a graduated fellow in the Section of Pulmonary, Critical Care and Environmental Medicine at Tulane university School of Medicine in New Orleans, Louisiana. Dr. simeone is assistant professor and associate fellowship program director in the Section of Pulmonary, Critical Care and Environmental Medicine at Tulane university School of Medicine in New Orleans, Louisiana. Dr. hamm is acting dean of the Medical School at Tulane university School of Medicine in New Orleans, Louisiana. Dr. Palacios is a professor of neuroradiology at Tulane university Health Sciences Center in New Orleans, Louisiana. Dr. Maylin is assistant professor in the Department of Medicine at Tulane university School of Medicine in New Orleans, Louisiana. Dr. Lopez is associate professor and vice chair in the Department of Medicine at Louisiana State university School of Medicine in New Orleans, Louisiana.

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cMe QuesTions

Read the preceding CME article and complete the registration, evaluation, and answer form on page 342 to earn CME credit. Mail or fax the registration, evaluation, and answer form to the LSMS Educational and Research Foundation. Answers must be postmarked or faxed prior to November 30, 2008. Participants must attain a minimum score of 75% to receive credit. LSMS members may also go online at http://www.lsms.org. Click on the Journal logo and then click on the Journal CME link. Complete the interactive answer sheet for each CME article.

1. True/False: The chances of developing respiratory failure and

requiring mechanical ventilation in a patient with West Nile Virus associated-acute flaccid paralysis are higher if the patient shows signs of dysphagia, dysarthria or both.

2. All of the following are true concerning West Nile Virus infections causing associated acute flaccid paralysis (AFP), except:a. The likelihood of weaning from ventilatory support

is high even after four months of mechanical ventilation.

b. Cerebrospinal fluid analysis usually shows pleocytosis with lymphocyte predominance and a normal glucose level.

c. Treatment is supportive and clinical trials with alpha-interferon are currently in progress.

d. Persistent respiratory symptoms, including orthopnea and dyspnea on exertion, are found in most patients who are successfully extubated.

3. Which of the following is false regarding the prognosis of a patient diagnosed with WNV- associated AFP?a. At the one-year follow-up, all patient showed some

improvements in their functional status. b. Electrodiagnostic studies such as EMG and NCS

can be used to assess prognosis.c. Peak gains in functional status, cognitive status and

strength are usually made from 4 to 6 months after illness.

d. Those patients diagnosed with WNV- associated AFP and respiratory compromise who endure mechanical ventilation for more than four months have a worse prognosis.

4. Which of the following is not seen in the acute setting of WNV- associated AFP?

Patients may present with fever and flu like symptoms, altered level of consciences, headache, eye pain and other neurological signs/symptoms suspicious for meningitis or encephalitis. A m u c h s h o r t e r i n c u b a t i o n p e r i o d i n immunocompromised patients compared to young healthy individuals.Presence of WNV-specific serum and CSF IgM.Neuromuscular symptoms including asterixis, twitching, flaccid asymmetrical paralysis, seizures, diaphragmatic paralysis.

a.

b.

c.d.

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