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Opsoclonus Persisting During Sleep in West Nile Encephalitis FREE

Amer Alshekhlee, MD; Badr Sultan, MD; Krishan Chandar, MD
[+] Author Affiliations

Author Affiliations: Department of Neurology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio.


Arch Neurol. 2006;63(9):1324-1326. doi:10.1001/archneur.63.9.1324.
Text Size: A A A
Published online

ABSTRACT

Background  Recent outbreaks of West Nile virus infection have alerted the public to disabling paralysis as an outcome. Ocular motor involvement with West Nile virus is rare.

Objective  To describe a patient with West Nile virus encephalitis that resulted in opsoclonus-myoclonus syndrome with persistent ocular oscillation on electroencephalography during stage 2 sleep.

Patient  A 53-year-old man who presented with viral prodrome followed by intense vertigo and encephalopathy. In addition to multifocal myoclonic jerks in the extremities, his eye movements were disrupted by bursts of high-frequency, conjugate ocular oscillations that occurred in random directions.

Results  Electroencephalography showed eye movement artifacts during the awake state and stage 2 sleep. Opsoclonus-myoclonus syndrome remained disabling 3 months after onset but markedly improved 8 months after onset.

Conclusions  West Nile virus is another cause of opsoclonus-myoclonus syndrome that can occur in conjunction with encephalitis. The presence of an eye movement artifact on results of electroencephalography during stage 2 sleep should raise suspicion for opsoclonus.

Figures in this Article

Although 80% of West Nile virus (WNV) infections are asymptomatic, infected patients may present with a variety of clinical neurological manifestations.1 In this report, we describe a serologically confirmed case of WNV encephalitis with opsoclonus-myoclonus syndrome (OMS) in which the patient showed persistent ocular oscillations during stage 2 sleep, remained disabled 3 months after the onset of his illness, and markedly improved 5 months thereafter.

REPORT OF A CASE

A 53-year-old man with chronic hypertension, coronary artery disease, and left leg traumatic amputation presented with malaise and irritability of 2 weeks' duration followed by high fever (temperature, 40.5°C), dysuria, and severe frontal and cervical pain. A urinary tract infection was diagnosed and gatifloxacin (Tequin) was administered, but the patient showed no improvement. A few days prior to hospitalization, he had developed involuntary eye movements and jerking of the muscles in his upper limbs, along with intense, brief attacks of vertigo. On examination, the patient was an ill-looking, tremulous man with neck stiffness. He was hemodynamically stable and had no rash or lymphadenopathy. He had a fluctuating clouding of consciousness with confusion. There were no signs of meningeal irritation. His language was normal but he exhibited scanning speech. Muscle strength and tendon reflexes were normal and symmetrical, with a flexor right plantar response. There were prominent, involuntary, myoclonic muscle jerks, with intermittent action tremor in the upper extremities. When asked to look at a target, the patient's visual fixation was disrupted by bursts of high-frequency, conjugate ocular oscillations that had horizontal, vertical, and torsional components, all of which indicated opsoclonus (a video is available online at http://www.archneurol.com). Opsoclonus, but not myoclonus, was present during sleep (see the online video). The rest of the cranial nerve examination results were normal. He was unable to walk. Findings of a computed tomographic scan of the head were normal (a magnetic resonance image could not be obtained because of the patient's cardiac pacemaker). An analysis of cerebrospinal fluid showed lymphocytic pleocytosis (white blood cell count, 81/μL; 87% lymphocytes, 12% monocytes, and 1% neutrophils), with a total protein level of 0.11 g/dL and a glucose level of 52 mg/dL (3.1 mmol/L). Gram stain and cultures yielded negative results, including stains and cultures for fungi and Toxoplasma gondii. Polymerase chain reactions did not amplify any of the following viruses: herpes simplex, varicella-zoster, Epstein-Barr, Cytomegalovirus, or Enterovirus. Possible cross-reaction to encephalitis viruses (California, La Crosse, eastern equine, western equine, and St Louis) was eliminated by negative results of viral serology to both IgG and IgM antibodies. The patient had no recent history of travel or prior vaccination to yellow fever or Japanese B encephalitis viruses; thus, no further evaluation of these viruses was sought. Human immunodeficiency serology results were nonreactive. Paraneoplastic autoantibodies (anti-Ri, anti-Hu, anti-Yo, and anti–Ma-2) were undetectable in the serum. Electroencephalography (EEG) while the patients was in the awake state showed a mild slowing of the posterior dominant rhythm, with frequent prolonged runs of eye movements (Figure, B) corresponding to opsoclonus. The eye movements on EEG and the opsoclonus persisted during stage 2 sleep (note the sleep spindles in the Figure, A), although they were less frequent. The patient was initially treated with intravenous ceftriaxone sodium, vancomycin, ampicillin, and acyclovir. The use of these agents was discontinued after the detection of WNV on serologic analysis and after negative polymerase chain reaction results for herpes simplex and varicella-zoster viruses. Enzyme-linked immunosorbent assay results were positive for the presence of IgM antibodies to WNV and negative for the presence of IgG antibodies to WNV in the cerebrospinal fluid (ViroMed Laboratory, Minnetonka, Minn). Titers were not obtained on initial testing. The patient was discharged to a rehabilitation facility.

Three months after disease onset, the patient continued to be debilitated with severe myoclonic jerks and fluctuating alertness due to encephalopathy. Thereafter, he started to improve, and 8 months after disease onset his cognition returned to normal and he was able to walk with the use of a cane. Saccadic intrusions and myoclonic jerks were absent, although mild action tremor was present. Follow-up serology results 8 months after disease onset showed an elevated IgG level of 4.3 (index value, <1.3), elevated IgM level of 1.9 (index value, <0.9), and a markedly elevated WNV neutralizing antibodies level of 1:160 (index value, <1:5) (Focus Diagnostics, Inc, Cypress, Calif).

COMMENT

West Nile virus is a single-stranded RNA flavivirus and a member of the Japanese encephalitis virus serocomplex. Rare neuro-ocular invasions cause a variety of ocular syndromes. The ocular findings include multifocal chorioretinitis and optic neuritis.2 The report of a similar experience during a North African outbreak of WNV suggested that the occurrence of multifocal iritis, chorioretinitis, vitritis, and retinal hemorrhages following acute WNV infection may be rather common.3

Opsoclonus consists of back-to-back saccades without an intersaccadic interval. Opsoclonus-myoclonus syndrome is encountered in patients with encephalitis, in association with certain neoplasms (notably, neuroblastoma in children and gynecological cancers in adults) and certain toxins. The onconeuronal antibodies associated with OMS are anti-Ri antibodies (gynecologic cancers) and, less frequently, anti-Hu, anti-Yo, and anti–Ma-2 antibodies.4 Epstein-Barr virus, Coxsackie virus, and enterovirus have been incriminated in OMS.57

The pathophysiology of opsoclonus is debated. Horizontal saccades are generated by burst neurons lying in the paramedian pons, and vertical saccades are generated by burst neurons lying in the rostral midbrain. The activity of both populations of burst neurons is gated by omnipause neurons, which are glycinergic and lie in the pontine raphe.4 One current hypothesis for opsoclonus is that it arises from an inherent instability of the brainstem burst neuron network, which becomes evident when omnipause neurons fail to hold burst neurons in check.8 Opsoclonus is often precipitated or exacerbated by blinking or eyelid closure, both of which may suppress omnipause neurons.9 Although opsoclonus may persist during sleep, our documentation of eye movements during stage 2 sleep could be evidence that omnipause neurons were affected by brainstem encephalitis in our patient. During drowsiness, slow roving eye movements are frequently present on EEG, but no rapid, conjugate eye movements are recorded during non–rapid eye movement sleep. The persistence of opsoclonus and eye movements on the EEG during stage 2 sleep, as seen in our patient, suggested probable instability of the brainstem burst neuron network, with intact thalamocortical circuits generating sleep spindles. The published description10 of 2 patients with spinocerebellar atrophy who had slow saccades and abnormal sleep architecture suggested the involvement of neural circuitry in the brainstem. A subsequent study11 identified a possible switch mechanism, thought to be coordinated by 2 sets of pontine neurons. An alternative hypothesis is that opsoclonus arises because of impaired control of the brainstem saccade-generating network by the cerebellum12; thus, our patient showed prominent ataxia. However, viral cerebellitis per se would not be expected to cause impaired consciousness, which was a feature of his illness. In any case, our demonstration of rapid eye movement during stage 2 sleep provides another detail of OMS that any hypothesis for this disorder must address.

In a 2003 outbreak of WNV infection in North America, 2 cases with OMS were reported. One of these occurred in a potentially immunocompromised subject with non–small cell lung cancer, which was the cause of death13; thus, there is some doubt as to whether WNV was primarily responsible for the OMS. The second case14 mimicked the symptoms of our patient (except for the prompt improvement upon hospital discharge) but without a recognized EEG or sleep abnormality.

In summary, we document a case of OMS due to WNV infection in which ocular oscillations persisted during stage 2 sleep. For electroencephalographers, the presence of rapid eye movement artifact during stage 2 sleep should raise the suspicion for opsoclonus.

Place holder to copy figure label and caption
Figure.

Electroencephalogram obtained during the sleep (A) and awake (B) states showing stage 2 sleep (spindles indicated by dotted arrows), with persistent eye movements evident on the frontal channels (solid arrows).

Graphic Jump Location

ARTICLE INFORMATION

Correspondence: Amer Alshekhlee, MD, Department of Neurology, University Hospitals Health System, Case Western Reserve University, Westlake Medical Building, 960 Clague Rd, Suite 2667, Westlake, OH 44145 (amer.alshekhlee@uhhs.com).

Accepted for Publication: May 1, 2006.

Author Contributions:Study concept and design: Alshekhlee. Acquisition of data: Alshekhlee, Sultan, and Chandar. Analysis and interpretation of data: Alshekhlee and Chandar. Drafting of the manuscript: Alshekhlee. Critical revision of the manuscript for important intellectual content: Sultan and Chandar. Administrative, technical, and material support: Alshekhlee.

Additional Information: The video is available online at http://www.archneurol.com.

Acknowledgment: We thank John R. Leigh, MD, for his critical review and helpful comments in the preparation of the manuscript.

REFERENCES

Burton  JMKern  RZHalliday  W  et al.  Neurological manifestations of West Nile virus infection. Can J Neurol Sci 2004;31185- 193
PubMed
Bakri  SJKaiser  PK Ocular manifestations of West Nile Virus. Curr Opin Ophthalmol 2004;15537- 540
PubMed Link to Article
Khairallah  MBen Yahia  SLadjimi  A  et al.  Chorioretinal involvement in patients with West Nile virus infection. Ophthalmology 2004;1112065- 2070
PubMed Link to Article
Leigh  RJZee  DS The Neurology of Eye Movements. 4th ed. New York, NY: Oxford University Press; 2006
Sheth  RDHorwitz  SJAronoff  SGingold  MBodensteiner  JB Opsoclonus myoclonus syndrome secondary to Epstein-Barr virus infection. J Child Neurol 1995;10297- 299
PubMed Link to Article
Kuban  KCEphros  MAFreeman  RLLaffell  LBBresnan  MJ Syndrome of opsoclonus-myoclonus caused by Coxsackie B3 infection. Ann Neurol 1983;1369- 71
PubMed Link to Article
Tabarki  BPalmer  PLebon  PSebire  G Spontaneous recovery of opsoclonus-myoclonus syndrome caused by enterovirus infection. J Neurol Neurosurg Psychiatry 1998;64406- 407
PubMed Link to Article
Ramat  SLeigh  RJZee  DSOptican  LM Ocular oscillations generated by coupling of brainstem excitatory and inhibitory saccadic burst neurons. Exp Brain Res 2005;16089- 106
PubMed Link to Article
Hepp  KHenn  VVilis  TCohen  B Brainstem regions related to saccade generation.  In: Wurtz RH, Goldberg ME, eds. The Neurobiology of Saccadic Eye Movements. Amsterdam, the Netherlands: Elsevier Science Publishers; 1989:105-212
Osorio  IDaroff  RB Absence of REM and altered NREM sleep in patients with spinocerebellar degeneration and slow saccades. Ann Neurol 1980;7277- 280
PubMed Link to Article
Sinton  CMMcCareley  RW Neurophysiological mechanisms of sleep and wakefulness: a question of balance. Semin Neurol 2004;24211- 223
PubMed Link to Article
Wong  AMMusallam  STomlinson  RDShannon  PSharpe  JA Opsoclonus in three dimensions: oculographic, neuropathologic and modelling correlates. J Neurol Sci 2001;18971- 81
PubMed Link to Article
Khosla  JSEdelman  MJKennedy  NReich  SG West Nile virus presenting as opsoclonus-myoclonus cerebellar ataxia. Neurology 2005;641095
PubMed Link to Article
Sayao  ALSuchowersky  OAl-Khathaami  A  et al.  Calgary experience with West Nile virus neurological syndrome during the late summer of 2003. Can J Neurol Sci 2004;31194- 203
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Electroencephalogram obtained during the sleep (A) and awake (B) states showing stage 2 sleep (spindles indicated by dotted arrows), with persistent eye movements evident on the frontal channels (solid arrows).

Graphic Jump Location

Tables

References

Burton  JMKern  RZHalliday  W  et al.  Neurological manifestations of West Nile virus infection. Can J Neurol Sci 2004;31185- 193
PubMed
Bakri  SJKaiser  PK Ocular manifestations of West Nile Virus. Curr Opin Ophthalmol 2004;15537- 540
PubMed Link to Article
Khairallah  MBen Yahia  SLadjimi  A  et al.  Chorioretinal involvement in patients with West Nile virus infection. Ophthalmology 2004;1112065- 2070
PubMed Link to Article
Leigh  RJZee  DS The Neurology of Eye Movements. 4th ed. New York, NY: Oxford University Press; 2006
Sheth  RDHorwitz  SJAronoff  SGingold  MBodensteiner  JB Opsoclonus myoclonus syndrome secondary to Epstein-Barr virus infection. J Child Neurol 1995;10297- 299
PubMed Link to Article
Kuban  KCEphros  MAFreeman  RLLaffell  LBBresnan  MJ Syndrome of opsoclonus-myoclonus caused by Coxsackie B3 infection. Ann Neurol 1983;1369- 71
PubMed Link to Article
Tabarki  BPalmer  PLebon  PSebire  G Spontaneous recovery of opsoclonus-myoclonus syndrome caused by enterovirus infection. J Neurol Neurosurg Psychiatry 1998;64406- 407
PubMed Link to Article
Ramat  SLeigh  RJZee  DSOptican  LM Ocular oscillations generated by coupling of brainstem excitatory and inhibitory saccadic burst neurons. Exp Brain Res 2005;16089- 106
PubMed Link to Article
Hepp  KHenn  VVilis  TCohen  B Brainstem regions related to saccade generation.  In: Wurtz RH, Goldberg ME, eds. The Neurobiology of Saccadic Eye Movements. Amsterdam, the Netherlands: Elsevier Science Publishers; 1989:105-212
Osorio  IDaroff  RB Absence of REM and altered NREM sleep in patients with spinocerebellar degeneration and slow saccades. Ann Neurol 1980;7277- 280
PubMed Link to Article
Sinton  CMMcCareley  RW Neurophysiological mechanisms of sleep and wakefulness: a question of balance. Semin Neurol 2004;24211- 223
PubMed Link to Article
Wong  AMMusallam  STomlinson  RDShannon  PSharpe  JA Opsoclonus in three dimensions: oculographic, neuropathologic and modelling correlates. J Neurol Sci 2001;18971- 81
PubMed Link to Article
Khosla  JSEdelman  MJKennedy  NReich  SG West Nile virus presenting as opsoclonus-myoclonus cerebellar ataxia. Neurology 2005;641095
PubMed Link to Article
Sayao  ALSuchowersky  OAl-Khathaami  A  et al.  Calgary experience with West Nile virus neurological syndrome during the late summer of 2003. Can J Neurol Sci 2004;31194- 203
PubMed

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