# Presentation: 081663

## Emerging Clinical Syndromes of West Nile Virus Infection

**James J. Sejvar, MD**
**Division of Viral and Rickettsial Diseases**
**National Center for Infectious Diseases**
**Centers for Disease Control and Prevention**

## West Nile Virus—Clinical Disease

**Historically infrequent outbreaks of mild febrile illness**
**Since 1996:**
**More frequent outbreaks**
**More reports of severe CNS disease, fatalities**
**Understanding of clinical picture based mainly on recent outbreaks**

## WNV Human Infection “Iceberg” 

**~80****%**
**Asymptomatic**

**~****20%**
**“****West Nile Fever”**

**<1%**
**CNS**
**disease**

**~****10% fatal**
**(<0.1% of total infections)**

**WNV Human Infection “Iceberg” **

**1 CNS disease case**
**=**
**~150 total infections**

_***Very***_** crude estimates**

**Notes:**
The crows remain an important part of the avian mortality surveillance

## West Nile Virus—”Classical” Clinical Description

**Incubation period of 2-15 days**
**Most illness: “West Nile fever”**
**Self-limited dengue-like illness**
**Fever, headache **
**Rash, lymphadenopathy**
**Nausea, vomiting**
**Rarely pancreatitis, hepatitis, myocarditis**

## West Nile Virus—”Classical” Clinical Description

**Severe neurologic illness categories**
**-- ****Meningitis**
**Fever, nuchal rigidity, CSF pleocytosis**
**-- ****Encephalitis**
**Altered mental status**
**-- ****“Meningoencephalitis”**
**-- ****Acute flaccid paralysis**

## WNV—Clinical Questions

**Limitations of previous analyses**
**Retrospective chart reviews**
**Multiple observers**
**Incomplete and inconsistent studies**
**Long-term outcome data virtually nonexistent**
**True spectrum of disease unclear**

**Notes:**
However, most of what we know about the clinical manifestations of WNV in humans has been based on retrospective chart reviews and anecdotal reporting.  There has been a great deal of contradiction in the literature regarding human clinical disease.
For instance, though it seems clear that recent outbreaks have been associated with more frequent and more severe neurologic involvement, the true incidence of such manifestations remains unclear.  For instance, severe neurologic disease was felt to be relatively infreqent during the NYC outbreaks of 1999 and 2000, while outbreaks in Romania, Russia, and Israel have reported high rates of neurologic illness and death.  
Case fatality rates have ranged anywhere from 4% in Romania in 1996 to 12% in NYC in 1999 to nearly 50% in Russia in 1999
In addition, the particular clinical features have never really been accurately described.  Neurologic features have varied widely in published reports, due to the retrospective nature and multiple observers involved in previous assessments.
There are many unanswered questions regarding the progression of disease.  For instance, it is largely unknown  how often those presenting initially with febrile illness will go on to develop neurologic involvement.
And, although various predictors of poor outcome have been suggested, no single underlying condition has been significantly associated with neurologic illness or death.
Finally, data on long-term sequellae from WNV is essentially nonexistent

## WNV Clinical Investigations--2002

**Prospective clinical case series**
**Detailed serial neurologic exams**
**16 patients identified**
**WNV Fever Study**
**Detailed neurodiagnostic studies on large numbers of patients**
**House-to-house serosurvey**

## Clinical Syndromes—Understanding the Scope of Illness

**West Nile fever**
**Emerging clinical syndromes**
**Movement disorders**
**Parkinsonism**
**Flaccid paralysis**
**Rhabdomyolysis**
**Outcomes / prognosis**
**Future directions**

## West Nile Fever

**Felt to represent the majority of symptomatic infections**
**Determination of proportion with WNF in WNV outbreak setting**
**Subacute progression to severe CNS disease unlikely**
**Increased detection—fewer cases truly asymptomatic??**

## WNV and Movement Disorders

**Tremor**
**Sometimes associated with other viruses**
**Documented in 15 (94%) of prospective series patients**
**Static / kinetic; sometimes with movement**
**Occasionally disabling**

## Slide 11

## WNV and Movement Disorders

**Myoclonus**
**Observed in 10 (63%); described in 12 overall**
**Upper extremity, facial involvement most frequent**
**Nocturnal myoclonus**
**Both tremor and myoclonus—onset generally > 5 days following initial symptoms**

## WNV and Parkinsonism

**Parkinsonism observed in 11 (68%)**
**Cogwheel rigidity**
**Bradykinesia**
**Postural instability**
**Rest tremor not observed**
**Seen both in encephalitis **_**and**_** meningitis cases**

## WNV and Movement Disorders

**Neuroimaging:  lesions in basal ganglia, thalamus, pons**
**Histopathology—virus detected in basal ganglia, thalamus, brainstem**

## WNV-Associated Flaccid Paralysis

**Previously described; not “new” syndrome**
**Relatively young; lack of premorbid conditions**
**May have absence of fever, headache**
**Clinical hallmarks:**
**Onset during acute infection**
**Asymmetry of weakness**
**Absence of sensory changes**
**Elevation of CSF protein **_and_** WBC**

## WNV-Associated Flaccid Paralysis

**Multiple alternative diagnoses (stroke, GBS, myopathy)—Rx with heparin, IVIG**
**Syndrome actually localized to spinal anterior horn cells*—resultant poliomyelitis**
**Recognition could limit unnecessary diagnostic procedures, treatment**
**Little or no improvement short-term**

*****Dr. A. Leis, Methodist Rehab. Center, Jackson, MS

## WNV and Rhabdomyolysis

***Rhabdomyolysis*****—acute destruction of skeletal muscle cells**
**Infrequent manifestation of viral infection**
**September 2002—rhabdomyolysis reported in Chicago WNV patients**
**14 total cases identified**
**Trauma, medication effect unlikely**
**Further studies to assess association**

## West Nile Virus--Other Clinical Syndromes (?)

**Flaccid paralysis with sensory symptoms**
**Neuropathic pain**
**Causalgia**
**Paresthesias**
**Peripheral neuropathy, polyradiculopathy**
**Optic neuritis**
**Acute demyelinating encephalomyelitis (ADEM)**
**Prenatal WNV infection with CNS developmental abnormalities**
**WNV as a teratogen?**

## West Nile Virus—Clinical Outcomes Data

**Current data limited**
**Fatality rates**
**10% fatality rate in CNS disease**
**Elderly, immunosuppressed**
**Independent risk factors unknown**
**Long-term outcomes in NYC: **
**>50% with continued impairment at 1 year**
**Only 37% considered fully recovered**

## West Nile Virus—Clinical Outcomes Data

**Short-term prospective data**
**No deaths**
**Most patients (14/16; 88%) eventually went home **
**Follow-up telephone query data**
**Persistent / chronic headache**
**Concentration, memory difficulties**
**Overwhelming fatigue**
**Persistence of tremor, parkinsonism**
**Paralysis—no short-term improvement**

## WNV Human Infection “Iceberg” 

**~80****%**
**Asymptomatic**

**~****20%**
**“****West Nile Fever”**

**<1%**
**CNS**
**disease**

**~****10% fatal**
**(<0.1% of total infections)**

**WNV Human Infection “Iceberg” **

**1 CNS disease case**
**=**
**~150 total infections**

_***Very***_** crude estimates**

**Notes:**
The crows remain an important part of the avian mortality surveillance

## WNV Human Infection “Iceberg” Revisited

**~80****%**
**Asymptomatic**

**~****10% fatal**
**(<0.1% of total infections)**

**WNV Human Infection “Iceberg” Revisited**

**1 CNS disease case**
**=**
**~****??**** total infections**

**Febrile illness alone less frequent?**

**~****?****%**
**“****West Nile Fever”**

**<****?****%**
**CNS**
**disease**

## WNV Clinical Syndromes—Future Directions

**Surveillance for meningitis, encephalitis as distinct entities**
**Enhanced surveillance for flaccid paralysis; incidence rates**
**Population-based assessment of movement disorders, parkinsonism**
**Long-term follow up studies **
**persistence of symptoms**
**psychosocial outcomes**
**development of sequelae**

** **

## WNV--Outcomes

**Short-term prospective data**
**Of 8 encephalitis patients, 6 went home, 1 to SNF, 1 on chronic ventilation**
**All meningitis patients discharged home**
**Follow-up call data**
**Persistent / chronic headache**
**Concentration, memory difficulties**
**Overwhelming fatigue**
**Persistence of tremor, parkinsonism**
**AFP—no short-term improvement**

## West Nile Fever (WNF)

**Subacute progression to severe CNS disease unlikely**
**Development of meningitis / encephalitis /paralysis within 24-48 hours of fever onset**
**No subsequent hospitalization among fever outpatients**