Powassan Virus Encephalitis: Unveiling the Unforeseen

1 / 10

Introduction

Case Study from NEJM

This presentation explores a case of Powassan virus encephalitis, a rare but serious tick-borne infection that presented unique diagnostic challenges in an immunocompromised patient.

Blacklegged tick (Ixodes scapularis)

Blacklegged tick (Ixodes scapularis), the primary vector for Powassan virus

この発表では、免疫不全患者におけるユニークな診断課題を示した、稀ですが深刻なマダニ媒介感染症であるPowassanウイルス脳炎の症例について探ります。

Case Introduction

Patient: 57-year-old woman

Presentation: Hospitalized in late November with a 3-day history of altered mental status

Symptoms Timeline:

  • Three weeks before admission: Fever, generalized weakness, decreased appetite, intermittent cough, and diarrhea
  • Progression: Cough and diarrhea resolved, but fever and weakness worsened
  • Subsequently: Developed intermittent visual hallucinations, tremors in arms and legs, and unsteadiness leading to recurrent falls

57歳女性が11月下旬に、3日間の精神状態変化の既往で入院しました。入院3週間前に発熱、全身倦怠感、食欲低下、間欠的な咳、下痢が発症。咳と下痢は治まりましたが、発熱と脱力感は進行し、その後、断続的な幻視、手足の振戦、不安定さが現れ、転倒を繰り返すようになりました。

Patient Medical History

Medical Background

  • Type 1 diabetes with complications:
    • Retinopathy
    • Neuropathy
    • Nephropathy
  • Four months before admission: Underwent simultaneous kidney and pancreas transplantation

Medications

  • Immunosuppressive therapy:
    • Tacrolimus
    • Mycophenolate mofetil
    • Prednisone
  • Prophylactic medications:
    • Valganciclovir (anti-herpesvirus)
    • Trimethoprim-sulfamethoxazole (anti-Pneumocystis)

Epidemiological Information

  • Lived in a small, rural community in the upper midwestern United States
  • Owned a cat, and family raised chickens
  • Stayed mostly indoors after transplantation
  • Reported no tick, flea, or mosquito bites

患者は1型糖尿病（網膜症、神経障害、腎症の合併症あり）を持ち、入院4ヶ月前に腎臓と膵臓の同時移植を受けていました。免疫抑制薬（タクロリムス、ミコフェノール酸モフェチル、プレドニゾン）と予防薬（バルガンシクロビルとST合剤）を服用。米国中西部の小さな田舎町に住み、猫を飼い、家族は鶏を飼育していましたが、マダニ、ノミ、蚊に刺された記録はありませんでした。

Initial Examination and Laboratory Findings

Physical Examination

  • Drowsy and disoriented to time
  • Oral temperature: 38°C
  • Heart, lungs, abdomen, skin: Unremarkable
  • Neurological:
    • Diffuse tremulousness
    • Midline gaze
    • Equal and reactive pupils
    • Symmetric face
    • Able to move extremities against gravity
    • No neck stiffness

Laboratory Findings

  • Hemoglobin: 10.6 g/dL
  • White blood cell count: 2,200/μL
    • Neutrophils: 1,550/μL
    • Lymphocytes: 290/μL (low)
  • Platelet count: Decreased from 201,000 to 109,000/μL
  • Serum electrolytes, kidney, liver, thyroid function: Normal
  • Nasopharyngeal swab: Positive for rhinovirus/enterovirus
  • Tacrolimus level: 6.7 ng/mL (normal range)

CSF Analysis

  • Opening pressure: 230 mm H₂O
  • Red blood cells: 10,000/μL
  • Nucleated cells: 125/μL
    • 67% lymphocytes
    • 29% monocytes
    • 4% neutrophils
  • Protein: 279 mg/dL (elevated)
  • Glucose: 44 mg/dL (CSF:serum ratio 0.47)

Imaging Studies

  • CT chest, abdomen, pelvis: Unremarkable
  • MRI head (initial):
    • No acute abnormalities on FLAIR
    • Some signal hyperintensity suggestive of chronic small-vessel disease

入院時、患者は傾眠状態で時間に対する見当識障害があり、全身的な振戦を呈していました。臨床検査では、貧血、白血球減少症、リンパ球減少症、血小板減少が見られました。脳脊髄液検査では、リンパ球優位の細胞増加、タンパク質上昇、正常ブドウ糖を示しました。初期頭部MRIでは明らかな急性異常は認められませんでした。

Disease Progression and Final Diagnosis

Clinical Deterioration

  • Progressive decrease in responsiveness and increased confusion
  • Transfer to ICU and initiation of mechanical ventilation
  • Development of coma with preserved brainstem reflexes
  • Flaccid paralysis of arms with reduced tendon reflexes
  • Triple flexion response to pain in legs and feet

Follow-up MRI Findings (Day 5)

  • New signal hyperintensity with mass effect in cerebellum
  • Microhemorrhages throughout cerebral and cerebellar hemispheres
  • Involvement of:
    • Right hippocampus
    • Right occipital pole
    • Both thalami
  • Spinal MRI: Diffuse hyperintense signal with enhancement of anterior horn cells (myelitis)

Final Diagnosis

Powassan virus lineage II infection

Confirmed by positive CSF PCR for Powassan virus

Serum Powassan virus IgM: Negative

Note: Negative serology despite active infection highlights the importance of direct pathogen detection in immunocompromised patients.

Complications

  • Development of brain edema
  • Placement of external ventricular drain
  • Decompressive craniectomy
  • Hemorrhagic fluid collection at the posterior fossa
  • Evacuation of suboccipital epidural hematoma

次の2日間で患者の症状は悪化し、ICUへ転送され人工呼吸器管理となりました。脳幹反射は保たれているものの昏睡状態となり、上肢の弛緩性麻痺と腱反射減弱が進行。5日後のMRIでは小脳の信号増強、脳出血、視床両側の異常、脊髄炎所見を認めました。最終的にCSF PCRによりPowassanウイルス（系統II）感染と診断されました。血清IgMは陰性でした。

Treatment and Outcome

Treatment Approach

  • Antimicrobial management:
    • Most antimicrobials discontinued after diagnosis
    • Doxycycline continued for 21 days (prophylaxis against possible coinfection with Borrelia or Anaplasma)
  • Immunotherapy:
    • Intravenous immune globulin daily for 5 days
  • Immunosuppression adjustment:
    • Tacrolimus and mycophenolate mofetil discontinued
    • Prednisone continued for essential immunosuppression
  • Supportive care:
    • Mechanical ventilation
    • Management of increased intracranial pressure
    • Tracheostomy
    • Percutaneous gastrostomy

Surgical Interventions

  • External ventricular drain placement
  • Decompressive craniectomy
  • Evacuation of suboccipital epidural hematoma
  • Tracheostomy
  • Percutaneous gastrostomy placement

Clinical Outcome

  • Hospitalization duration: 26 days
  • Discharged to rehabilitation facility
  • Neurological status at discharge:
    • Intermittently opened eyes without consistently following commands
    • No movement of extremities
  • Follow-up at 2 months:
    • Kidney and pancreas allografts functioning well
    • No significant improvement in neurologic status

Powassanウイルス脳炎の診断後、多くの抗菌薬は中止されましたが、可能性のある共感染予防のためにドキシサイクリンは21日間継続されました。免疫グロブリン静注を5日間実施し、タクロリムスとミコフェノール酸モフェチル治療は中止され、プレドニゾンのみ継続されました。患者は26日間の入院後、リハビリ施設へ転院。退院時、時折目を開くものの一貫して指示に従えず、四肢の動きもありませんでした。2ヶ月後のフォローアップでは、移植臓器の機能は良好でしたが、神経学的状態の改善は見られませんでした。

About Powassan Virus

Virus Characteristics

  • Tick-borne orthoflavivirus
  • Two lineages:
    • Lineage I: Transmitted by Ixodes cookei and I. marxi
    • Lineage II: Known as deer tick virus, transmitted primarily by Ixodes scapularis
  • Rapid transmission: Can be transmitted within 15 minutes after tick attachment (unlike other tick-borne pathogens)

Epidemiology

  • Geographic distribution in U.S.:
    • Northeastern states
    • Great Lakes region
  • Seasonal patterns:
    • Most cases occur from late spring to mid-fall
    • Cases can occur in colder months (as in this patient)
  • Increasing incidence:
    • Rising number of reported cases
    • Climate change associated with longer tick activity seasons
    • Expanding geographic distribution

Transmission Cycle

  • Main vector: Ixodes scapularis (blacklegged tick)
  • Ticks become infected by feeding on:
    • Small mammals (mice, voles)
    • Medium-sized mammals (skunks, groundhogs)
  • Humans are incidental hosts
  • Reported cases increasing in North America
  • Often patients may be unaware of tick bites
Blacklegged tick

Powassanウイルスはマダニが媒介するオルソフラビウイルスです。2つの系統があり、系統IはIxodes cookeiとI. marxiによって媒介され、系統II（シカダニウイルス）は主にIxodes scapularisによって媒介されます。他のマダニ媒介病原体と異なり、わずか15分のマダニ付着で感染することがあります。米国では北東部と五大湖地域に多く、通常は春から秋に発生しますが、気候変動により活動シーズンが長くなっています。

Clinical Features and Diagnosis

Clinical Manifestations

  • Incubation period: 1-6 weeks
  • Clinical spectrum:
    • Asymptomatic infection
    • Mild febrile illness
    • Severe necrotizing encephalitis
  • Common presenting symptoms:
    • Fever
    • Altered mental status
  • Neurologic manifestations:
    • Rhombencephalitis (brain stem and cerebellum inflammation)
    • Meningoencephalitis
    • Isolated meningitis
    • Rarely myelitis (as in this case)

Laboratory Findings

  • Hematologic abnormalities:
    • Thrombocytopenia
    • Lymphopenia
  • CSF characteristics:
    • Lymphocytic pleocytosis
    • Elevated protein
    • Normal glucose
  • Imaging findings:
    • Leptomeningeal enhancement
    • Cerebellar involvement
    • Basal ganglia involvement
    • May be normal early in disease course

Diagnostic Methods

Method Specimen Considerations
Serology (IgM by ELISA) Serum or CSF May be negative in immunocompromised patients
Neutralizing antibodies (PRNT) Serum Confirmatory test for serological results
PCR CSF Direct detection, especially valuable in immunocompromised patients
Metagenomic next-generation sequencing CSF Emerging method for direct pathogen detection

Note: In immunocompromised patients, direct detection methods (PCR, sequencing) may be necessary as serologic testing can be negative despite active infection.

Powassanウイルスの潜伏期間は1〜6週間で、無症状から重度の壊死性脳炎まで様々です。一般的な症状は発熱と精神状態変化で、菱脳炎（脳幹・小脳の炎症）、髄膜脳炎、髄膜炎などの神経症状を呈します。検査では血小板減少、リンパ球減少、髄液のリンパ球優位の細胞増加などが特徴的です。診断は血清や髄液のIgM抗体検出や中和抗体検査、PCR法などで行いますが、免疫不全患者では抗体検査が陰性になることがあり、PCRなどの直接検出法が重要です。

Treatment, Prognosis, and Prevention

Treatment Approach

No specific antiviral therapy available

  • Supportive care:
    • Respiratory support
    • Management of increased intracranial pressure
    • Prevention of secondary complications
  • Adjunctive therapies (limited evidence):
    • Intravenous corticosteroids
    • Intravenous immune globulin
  • In transplant recipients:
    • Consider reducing immunosuppression
    • Balance between allowing immune response and preventing allograft rejection

Prognosis

  • Mortality:
    • 10-18% reported case fatality rate
  • Long-term sequelae:
    • Majority of survivors experience neurologic sequelae
    • Persistent cognitive impairment
    • Gait disturbances
    • Motor deficits
    • Postencephalitic parkinsonism
  • Poor prognostic factors:
    • Immunosuppression
    • Seizures
    • Cerebellitis

Prevention Strategies

  • Tick bite prevention:
    • Use insect repellents containing DEET
    • Wear protective clothing
    • Perform regular tick checks
    • Shower shortly after being outdoors
    • Treat clothing with permethrin
  • Environmental management:
    • Remove leaf litter
    • Clear tall grasses and brush
    • Create a barrier between wooded areas and lawn
    • Discourage tick-carrying wildlife
  • Additional precautions for immunocompromised patients
  • No vaccine available currently

CDC Tick Prevention Measures

  • Use EPA-registered insect repellents
  • Treat clothing and gear with products containing 0.5% permethrin
  • Avoid wooded and brushy areas with high grass
  • Walk in the center of trails
  • Check body and clothing for ticks after being outdoors
  • Shower within 2 hours after coming indoors

Powassanウイルス感染症に対する特異的な抗ウイルス療法はなく、支持療法が中心となります。ステロイドや免疫グロブリン静注が使用されることもありますが、有効性のエビデンスは限られています。移植患者では免疫抑制を減らすことも検討されます。予後は不良で、死亡率は10-18%、生存者の多くは神経学的後遺症を残します。予防は主にマダニ咬傷の予防に焦点を当て、DEETを含む忌避剤の使用、防護服の着用、定期的なダニチェックなどが推奨されます。

Key Lessons and Title Explanation

Key Clinical Lessons

1. Expanded Differential Diagnosis

Consider Powassan virus in patients with encephalitis in endemic regions, even outside typical seasons

2. Diagnostic Approach in Immunocompromised

Direct detection methods (PCR, sequencing) may be necessary as serologic testing can be negative despite active infection

3. Immunosuppression Management

Early reduction of immunosuppression while maintaining essential therapy may be beneficial in transplant recipients

4. Multidisciplinary Approach

Collaboration between infectious disease specialists, neurologists, and transplant physicians is crucial for optimal management

Title Explanation: "Unveiling the Unforeseen"

The title aptly captures several aspects of this case:

  • The unexpected diagnosis of a rare tick-borne infection
  • The occurrence outside the typical season (November)
  • The absence of known tick exposure in the patient's history
  • The atypical presentation in an immunocompromised host
  • The negative serology despite active infection
  • The importance of considering uncommon pathogens in the appropriate epidemiological context

This case highlights how physicians must maintain vigilance for rare but serious infections, especially in immunocompromised patients, and use appropriate diagnostic methods that account for the patient's immune status.

Key References

  • 1. Piantadosi A, Rubin DB, McQuillen DP, et al. Emerging cases of Powassan virus encephalitis in New England: clinical presentation, imaging, and review of the literature. Clin Infect Dis. 2016;62:707-13.
  • 2. Mendoza MA, Hass RM, Vaillant J, et al. Powassan virus encephalitis: A tertiary center experience. Clin Infect Dis. 2024;78:80-9.
  • 3. Kemenesi G, Bányai K. Tick-borne flaviviruses, with a focus on Powassan virus. Clinical Microbiology Reviews. 2018;31(1):e00106-17.

この症例から学ぶ重要なポイントは：1) 流行地域では非典型的な季節でもPowassanウイルスを考慮すること、2) 免疫不全患者では抗体検査が陰性でも直接病原体検出法が必要、3) 移植患者では免疫抑制の早期軽減が有益な可能性、4) 最適な管理には多職種協力が不可欠。論文タイトル「Unveiling the Unforeseen（予期せぬものの発見）」は、稀なマダニ媒介感染症の予想外の診断、非定型的な季節での発生、患者の既知のマダニ暴露がないこと、免疫不全宿主での非典型的な表現型を的確に表現しています。

Powassan Virus Encephalitis: Unveiling the Unforeseen - Case Study from NEJM