Patient 1

A 42-year-old man from Cornwall sought care for severe low-back pain, which progressed to paresthesia in the legs, then the arms, and then weakness with normal sphincter control. The man had not traveled outside the United Kingdom and had had no contact with pigs. Physical examination found weakness of his entire upper limbs and proximal legs. Pinprick sensation was impaired in areas on the right side innervated from C2–4 and distally but asymmetrically in his legs; additionally, S2–5 were involved on the right. Reflexes were diminished or absent in all 4 limbs.

CSF analysis showed high protein levels with lymphocytic pleocytosis (protein 1.27 g/L [reference 0.15–0.45 g/L], glucose 3.5 mmol/L, and leukocytes 145 × 10⁹ cells/L [90% lymphocytes]). Magnetic resonance image (MRI) of the pelvis and lumbar spine showed no abnormalities. Nerve-conduction studies showed distal sensory and motor activity to be within normal limits for all limbs; however, substantial tibial F-wave responses after ankle stimulation were noted, with relative prolongation on the right (right 58.50 milliseconds [ms], left 47.00 ms [reference 52.3 ±4.3 ms, interleg latency difference <5.7 ms]).

Liver function tests showed serum bilirubin within reference range but elevated alanine aminotransferase (ALT) (623 IU/L [reference 3–35 IU/L]). Serologic testing was negative for Borrelia burgdorferi and Treponema pallidum. Anti-HEV IgM and IgG were detected in the serum, as was HEV RNA, confirming a diagnosis of acute HEV. Molecular characterization showed that the serum HEV was genotype 3e (GenBank accession no. FN869556). CSF was negative for HEV RNA, CMV DNA, EBV DNA, and varicella zoster virus (VZV) DNA.

The best explanation for the clinical and laboratory findings was acute inflammatory polyradiculoneuropathy. The patient was given no specific treatment; neurologic signs and symptoms resolved fully in 3 months, and laboratory parameters returned to reference range within 6 months.

Patient 2

A 38-year-old man from Cornwall, with type 1 diabetes had a 5-day history of diarrhea, followed by pain, paresthesia, and weakness in his upper arms. He had neither recently traveled outside the United Kingdom nor had contact with pigs. Sensation to pinprick over the C5–6 dermatomes was bilaterally reduced as was strength during elbow flexion, shoulder abduction, and external rotation (worse on the right). Electrophysiologic studies confirmed a diagnosis of bilateral brachial neuritis with denervation of the supraspinatus, infraspinatus, and triceps muscles, which was more severe on the right. CSF was not examined.

Liver function tests showed elevated total serum bilirubin (70 µmol/L [reference 3–17 µmol/L]) and ALT (1,160 IU/L [reference 3–35 IU/L]). Serum was positive for anti-HEV IgG, anti-HEV IgM, and HEV RNA. Molecular characterization showed that the HEV isolated from the serum was genotype 3e (GenBank accession no. FN869555).

The patient was given no specific treatment. Within 6 weeks, liver enzyme levels returned to reference range and HEV RNA became undetectable. Signs and symptoms of brachial neuritis and other neurologic deficits gradually improved over the next 18 months, but residual weakness in his upper right arm remained.

Patient 3

A 60-year-old woman from Toulouse, France, with type 1 diabetes, had a 1-week history of severe asthenia, jaundice, and progressive weakness in her legs. She had no history of recent travel outside France or contact with animals. She was bedridden with lower limb weakness and complete loss of deep-tendon reflexes but no paresthesia. She had no fever and no biological markers of inflammation, i.e., C-reactive protein was <1 mg/L. CSF protein was 2g/L, glucose 6.2 mmol/L, and leukocyte count 14 × 10⁹ cells/L. Liver function tests showed elevated total serum bilirubin (35 µmol/L [reference 2–21 µmol/L]) and elevated ALT (384 IU/L [reference 5–45 IU/L]). C-reactive protein and creatinine phosphokinase levels were within normal limits. Anti-HEV IgM and IgG were detected in the serum. HEV RNA was also detected in serum and fecal samples, confirming a diagnosis of acute HEV. Molecular characterization showed that the serum HEV was genotype 3f (GenBank accession no. EU 221001.1). CSF was negative for HEV RNA.

The patient’s clinical and laboratory findings are best explained by acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome) associated with HEV infection. She was given intravenous immunoglobulin at 0.4 g/kg 1×/d for 5 days. Neurologic signs and symptoms improved rapidly, and liver enzyme levels progressively returned to reference limits within 4 weeks. HEV RNA became undetectable 1 month after initial examination. Her neurologic condition gradually improved over the next 18 months, but residual weakness in her lower limbs remained.

Patient 4

In a 60-year-old man, acute autochthonous HEV (genotype 3f; GenBank accession no. EU221003) infection developed 27 months after a kidney–pancreas transplant. Acute polyradiculoneuropathy with moderate ataxia and severe proximal weakness of his lower limbs developed 30 months after HEV infection, occurring concomitantly with severe cognitive impairment and intermittent frontal dysfunction. CSF protein was 0.71 g/L, glucose 2.9 mmol/L, and leukocyte count 1 × 10⁹ cells/L. MRI of the cerebrum showed an old lenticular infarction and no acute changes. MRI of the spine showed no abnormalities.

Immunosuppressive therapy for transplantation was a combination of tacrolimus (trough level 6 ng/mL), mycophenolate mofetil, and low-dose prednisolone (5 mg/d). Liver function test results showed total bilirubin within normal limits (19 µmol/L [reference 2–21 µmol/L]) but elevated ALT (173 IU/L [reference 5–45 IU/L]). Liver biopsy sample showed features of chronic active hepatitis; Metavir score was A2F3. CD4 count was 219 × 10⁹ cells/L Serum HEV RNA concentration was 1,572 copies/mL. CSF was negative for anti-HEV IgG but positive for anti-HEV IgM. HEV RNA was detected in CSF obtained at the time of admission. CSF contained no detectable CMV DNA, EBV DNA, Herpes simplex viruses 1 and 2 DNA, VZV DNA, JC virus DNA, cryptococcal antigen, Toxoplasma gondii DNA, or Candida spp.

Because the patient was aphasic, confused, and drowsy, tacrolimus was replaced by low-dose sirolimus. After 10 days, neurologic signs and symptoms improved. However, 10 months later, despite rehabilitation and physiotherapy, motor deficit in the lower limbs remained and he was still unable to walk. Four months after conversion from tacrolimus to sirolimus, HEV RNA became undetectable in the serum and remains so as of September 2010. The patient declined follow-up lumbar puncture.

Patient 5

In a 35-year-old man, acute autochthonous HEV (genotype 3f; GenBank accession no. EU220999) infection developed 48 months after kidney transplantation. Three years later, drowsiness and fever (38°C) developed, and neurologic assessment revealed signs and signs and symptoms of encephalitis characterized by confusion and drowsiness without focal signs. CSF protein was 0.8 g/L, glucose 2.5 mmol/L, and leukocyte count 8 × 10⁹cells/L. Initial computed tomographic scan of the brain showed no abnormalities. However, a few hours later, his level consciousness deteriorated and he required mechanical ventilation. Cerebral MRI, performed 24 hours later, showed features of encephalitis with diffuse white matter signal abnormalities in the supratentorial and infratentorial regions.

Immunosuppressive therapy was a combination of tacrolimus (trough level 3 ng/mL), mycophenolate mofetil, and low-dose prednisolone (5 mg/d). Liver function tests showed total bilirubin level within reference range (12 µmol/L [reference 2–21µmol/L]) and an elevated ALT level of 110 IU/L (reference 5–45 IU/L). A liver biopsy sample showed features of chronic active hepatitis; Metavir score was A2F2. CD4 count was 149 × 10⁹ cells/L Serum EBV DNA concentration remained unchanged from 6 months earlier, at 4.24 log₁₀ copies/mL. Serum was positive for anti-HEV IgM but negative for anti-HEV IgG. Serum HEV RNA concentration was 2,154,000 copies/mL. CSF was negative for anti-HEV IgG and IgM. HEV RNA and EBV DNA were detected in CSF obtained at the time of admission. CMV DNA, Herpes simplex 1 and 2 DNA, VZV DNA, JC virus DNA, cryptococcal antigen, Toxoplasma gondii DNA, and Candida spp. were absent in the CSF.

Immunosuppressive therapy was stopped, and Foscavir (6 g/d) and intravenous immunoglobulins (total dose 2 g/kg) were added to the broad spectrum antimicrobial drugs given since admission. MRI showed improvement by day 10, and the patient was extubated. Two months later, despite the absence of neurologic signs and symptoms, CSF protein was 1 g/L, glucose 4.9 mmol/L and leukocyte count 16 × 10⁹ cells/L (96% lymphocytes). HEV RNA and EBV DNA were still detected in the serum and CSF. One year later, HEV spontaneously cleared from serum, but the patient declined a third lumbar puncture.

Patient 6

In a 44-year-old man from Toulouse, France, acute autochthonous HEV (genotype 3f; GenBank accession no. FJ665423) infection developed 50 months after a kidney transplant (15). After 33 months of chronic HEV infection, the patient experienced progressive bilateral muscular weakness, difficulty walking, and palmar and plantar dysesthesia without fever. Neurologic examination revealed peripheral nerve involvement (with proximal muscular weakness that affected all limbs) and central nervous system involvement (bilateral pyramidal signs). Electrophysiologic studies showed signs of peripheral demyelinating polyradiculoneuropathy. MRI of the cerebrum showed no abnormalities. CSF protein was 0.76 g/L, glucose 3.9 mmol/L, and leukocyte count 7 × 10⁹ cells /L.

Immunosuppressive therapy consisted of tacrolimus (trough level 8 ng/mL), mycophenolate mofetil (1 g/d), and low-dose prednisolone (2.5 mg/d). Liver function tests showed total bilirubin level within normal limits (12 µmol/L [reference 2–21]) and elevated ALT level (105 IU/L [reference 5–45 IU/L]). Liver biopsy sample showed cirrhosis; Metavir score was A2F4. Serum CD4-positive count was 167 × 10⁹ cells/L. Serum, but not CSF, contained anti-HEV IgG and IgM. Serum HEV RNA was 260,000 copies/mL, and HEV RNA was detected in CSF. No signs of infection were detected in the serum and CSF, except for EBV DNA, which had remained detectable in the blood since transplantation and at an unchanged concentration of 4.4 log₁₀ copies/mL.

After 3 months, because the patient had severe ataxia and loss of sphincter control, neuromuscular biopsy was performed and showed nonspecific signs of neurogenic muscular atrophy but no signs of vasculitis in either muscule or nerve specimens. Consequently, the tacrolimus dosage was markedly reduced to target a trough level of 2.5 ng/mL, and intravenous immunoglobulins were administrated (0.4 g/kg/d for 5 days, total dose 2 g/kg). However, no substantial improvement was observed. After another month, decompensated cirrhosis developed and the patient died of bleeding esophageal varices.

Patient 7

A 48-year-old man from Cornwall was examined for persistently abnormal liver function that was complicating HIV disease. HIV-1 infection had been diagnosed in 2001 when the patient lived in Cambodia; he was subsequently treated for miliary tuberculosis in 2003.

When back in the United Kingdom, before receiving any antiretroviral medications, the patient had mildly elevated ALT (51 IU/L, reference 3–35 IU/L); other liver enzymes were within reference range. CD4 count was 30 × 10⁹ cells/L, and HIV-1 viral load was 8.3 × 10⁴ copies/mL. Accordingly, in January 2007, the patient was given tenofovir/emtricitabine and lopinavir/ritonavir. In February 2007, the regimen was changed to abacavir/lamivudine and efavirenz; after this time, because the patient had difficulty tolerating these drugs, the regimen was again changed to abacavir/lamivudine and lopinavir/ritoanvirfor, which led to serum HIV RNA clearance in June 2007. In March 2007, ALT had risen to 114 IU/L, but there was no serologic evidence of syphilis or acute hepatitis A, B, or C. From July 2007 through July 2009, ALT remained elevated (118–195 IU/mL). In July 2007, HEV IgM and IgG were detected by enzyme immunoassay. HEV infection was confirmed by detection of HEV RNA (genotype 3a; GenBank accession no. FN869554) in serum. Testing of stored plasma samples for HEV RNA showed that the patient had been viremic since July 2007 and had remained so for 30 months, confirming chronic HEV infection. Liver biopsy sample showed cirrhosis; Metavir score was A3F4. The time HEV infection was acquired and its geographic origin remain uncertain.

In 2005, soon after completing antituberculous chemotherapy, the patient experienced progressive and painful sensory peripheral neuropathy with decreased pinprick sensation and proprioception and weakness in the distal lower limbs. At the time, these neurologic signs and symptoms were thought to have resulted from either HIV-associated neuropathy or previous isoniazid-containing antituberculous chemotherapy. In May 2009, CSF contained 0.47 g protein/L, 3.2mmol glucose/L, 1 × 10⁹ leukocytes/L and HEV RNA.

In July 2009, because of chronic HEV liver infection, the patient was given pegylated interferon-α-2a and ribavirin. During the course of this treatment, the neurologic signs and symptoms improved, and by the time the virus cleared, they were virtually gone. One month after completion of therapy and symptom resolution, CSF levels of protein, glucose, erythrocytes, and leukocytes were within reference range; however, HEV RNA was still detected. An exact estimate of HEV viral load was not performed, but the semiquantitative technique used showed substantial reduction of HEV (barely detectable) in a follow-up CSF sample.