Eurosurveillance remains in the updated list of the Directory of Open Access Journals (DOAJ). Citation style for this article: Santos L, Mesquita JR, Rocha Pereira N, Lima-Alves C, Serrao R, Figueiredo P, Reis J, Simoes J, Nascimento MS, Sarmento A. Autochthonous hepatitis E virus (HEV) infection has been increasingly reported in Europe and the United States, mostly arising from genotype 3 and less frequently  genotype 4.
We report on a patient in Portugal with autochthonous acute hepatitis E complicated by Guillain–Barre syndrome (GBS). At the end of November 2012, a man in his late 50s was hospitalised, having presented with signs and symptoms of acute hepatitis. During the three days after admission, he began to complain of muscle weakness and was then admitted to an intermediate care unit (three days after admission).
The day before admission to the ICU, magnetic resonance imaging of the spinal cord was normal.
Serum samples (taken on admission to the referring hospital and on admission to the ICU) and CSF (taken on admission to the ICU) were tested by serology and polymerase chain reaction to detect the presence of various pathogens (Table 2).
Serological analysis to detect hepatitis viruses was negative for all except HEV, being positive for anti-HEV IgM and negative for anti-HEV IgG, suggesting an acute infection with HEV.
In a routine visit to the hospital two months after being discharged, analysis of a blood sample collected at that time showed that HEV RNA was undetectable, anti-HEV IgM was negative and anti-HEV IgG was positive. In recent years, an increasing number of autochthonous infections with HEV have been reported in Europe and in United States [2]. Autochthonous HEV infection is usually subclinical or runs a mild course and is self-limiting, but chronic autochthonous infection has been identified among immunocompromised persons, including organ transplant recipients, patients receiving cancer chemotherapy and persons infected with human immunodeficiency virus (HIV) [6]. A broad set of symptoms of autochthonous HEV disease has been seen as well as increasing recognition of its extra-hepatic manifestations [7].
Exhaustive tests to detect the agents mostly frequently associated with GBS, other than Campylobacter, gave negative results in samples from our patient. The actual incidence of GBS associated with HEV infection is unknown because autochthonous hepatitis E is still underdiagnosed in many industrialised countries [11]. Since the patient reported no travel history, it seems likely that the HEV infection was locally acquired.
To our knowledge, this is the first report of a neurological disorder associated with an autochthonous HEV3 infection in a Portuguese patient. We thank the medical and nursing staff of the Infectious Diseases Intensive Care Unit for their contributions to the patient management.
Disclaimer: The opinions expressed by authors contributing to Eurosurveillance do not necessarily reflect the opinions of the European Centre for Disease Prevention and Control (ECDC) or the editorial team or the institutions with which the authors are affiliated. Pulsed Erlotinib as Sole Treatment of Leptomeningeal Carcinomatosis: Can We Avoid the Use of Intrathecal Therapy?
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We describe a case of bilateral retrobulbar optic neuritis associated with varicella-zoster virus (VZV) infection in a patient with advanced HIV infection with profound immunosuppression. CASE REPORT A 38-year-old woman was transferred to our hospital because of decreased visual acuity, with inability to perceive light in both eyes. The expansion of HIV testing to all adults leaves many primary care physicians in a tight spot, having no experience or training in how to deliver the news to patients who may have no idea they were even at risk. Hemolytic uremic syndrome is characterized by the triad of microangiopathy, haemolytic anemia, thrombocytopenia and acute renal failure. This suggests that age-related antigen-antibody reaction may contribute to the tendency for the development of S pneumoniae associated HUS in very young children [ 5]. Acute hepatitis E complicated by Guillain-Barre syndrome in Portugal, December 2012 – a case report. We report here on a patient with HEV genotype 3a infection complicated by Guillain-Barre syndrome in Portugal in December 2012. He had not travelled outside Portugal and had no history of risky sexual behaviour or drug addiction. Electromyography nerve conduction studies of peripheral motor and sensory nerves in upper and lower limbs the day following ICU admission revealed a severe acquired demyelinating sensory and motor polyneuropathy. The patient began a rehabilitation programme; he was fully able to breathe spontaneously at day 26. Although Toxoplasma and Mycoplasma infections were initially suspected, based on the presence of specific IgM in the patient’s serum, polymerase chain reaction (PCR) of CSF and blood samples did not confirm the presence of these agents. Most of these autochthonous cases have been caused by HEV genotype 3 (HEV3) and less frequently by genotype 4 [2]. Both acute and chronic HEV infections have been reported to be associated with muscular weakness, neurological disorders including polyradiculopathy, GBS, bilateral brachial neuritis, encephalitis or proximal myopathy [8]. This is in part due to the fact that frequently HEV infection is subclinical and because the neurological findings surpass the liver injuries and hepatitis is not suspected.
We consider it most probably resulted from consumption of pork or pork products, as there is a strong tradition of pork consumption among Portuguese people and HEV3 has been detected in domestic pigs from several farms in Portugal [13].
It is known that middle-aged and elderly men are more vulnerable to severe HEV3 infection, which can ultimately lead to hospitalisation and possibly death [6].
Considering the GBS-HEV cases reported, we recommend that testing for HEV should be included routinely in the diagnostic algorithm of GBS when liver function is altered.
CLA, RS, PF, JR, AS took part in the clinical management of the patient and reviewed the manuscript.
Detection of a novel hepatitis E-like virus in faeces of wild rats using a nested broad-spectrum RT-PCR. High prevalence of anti-hepatitis E virus antibodies in blood donors from South West France. Guillain-Barre syndrome associated with autochthonous infection by hepatitis E virus subgenotype 3c. Detection and characterization of hepatitis E virus in domestic pigs of different ages in Portugal.
Neither ECDC nor any person acting on behalf of ECDC is responsible for the use that might be made of the information in this journal. She had presented to another hospital complaining of mild to moderate headache for 1 week and of ocular pain and blurred vision in both eyes for 2 days, which rapidly progressed to inability to see light on the day of admission. Detection of red cell T-antigen activation was not performed in the patients because the tests were not available in Tunisia.
Children with pneumococcal disease and severe haematological or renal abnormalities should be investigated for evidence of HUS.
We draw attention to the diagnosis of autochthonous HEV infection and to its rare, but important, neurological complications.
Two weeks before hospitalisation, he complained of malaise, nausea, vomiting and right upper quadrant abdominal pain: these symptoms were followed by onset of jaundice some days after. During that day and the following day, a rapid ascending weakness and sensitivity loss with a non-impaired mental status was observed. His clinical evolution was favourable: he had progressive recovery of muscle strength, with efficacious cough and no need for oxygen supplementation. The diagnosis of HEV infection was confirmed by the presence of HEV RNA in the serum sample taken the day the patient was admitted to the referring hospital.

Seroprevalence studies also show that HEV infection in the population of industrialised countries is higher than previously thought [3]. Although neurological disorders associated with HEV3 are rare, some data are emerging in literature [8].
Although rare, the increasing number of reports of neurological disorders associated with autochthonous HEV infections in Europe drew our attention to a possible HEV diagnosis. Hence, HEV infection should be considered in neurological diseases associated with abnormal levels of liver enzymes [7,12]. FisheraaVince Lombardi Cancer Clinic, Aurora Cancer Care, Aurora Health Care, Sheboygan, WI, USAbCorresponding Author: Cheruppolil R. Neurological complications of varicella-zoster virus infection in adults with human immunodeficiency virus infection. Unilateral retrobulbar optic neuritis due to varicella zoster virus in a patient with AIDS: a case report and review of the literature. Varicella zoster virus retrobulbar optic neuritis preceding retinitis in patients with acquired immune deficiency syndrome. Optic neuropathy preceding acute retinal necrosis in acquired immunodeficiency syndrome [published correction appears in Arch Ophthalmol. S pneumonia associated HUS patients commonly had a presentation of pneumococcal pneumonia or meningitis [2]. Most patients died during the early phase of the disease from severe infection and neurological complications. Eurosurveillance is listed there as a ‘green’ journal, which means that authors can archive pre-print (i.e. At admission (day 1), besides jaundice, he had right upper quadrant tenderness and an enlarged liver. HEV3 infections have been associated with the consumption of raw or insufficiently cooked pork, deer and wild boar [2,4] and to direct contact with infected swine [5]. In recent years, a number of GBS cases associated with HEV infections have been described [8,9].
MSJN and JRM did the molecular diagnosis tests and the sequence of the HEV and wrote the lab section. The physical examination findings were remarkable for dilated pupils with no light perception in either eye.
This patient presented seizures which were controlled with treatment by Phenobarbital and Clonazepam. This worsening of neurological symptoms led to the patient being transferred to our hospital on day 5, where he was admitted to the intensive-care unit (ICU). Two months later, he continued to have a favourable outcome and was already able to walk if assisted.
HEV RNA in serum was detected using a nested broad-spectrum reverse transcription PCR with amplification within the open reading frame (ORF) 1 region of HEV genome [1].
GBS is an acute, acquired, autoimmune disorder of peripheral nerves that develops in susceptible individuals after infection and, in rare cases, after vaccination [10].
Except where otherwise stated, all manuscripts published after 1 January 2016 will be published under the Creative Commons Attribution (CC BY) licence.
She required peritoneal dialysis for four months without any improvement of  her renal function and died. A smear of the peripheral blood demonstrated fragmented red blood cells and schistocytes consistent with microangiopathic hemolytic anemia. The pneumococcal organism produces a neuramidase enzyme, which can expose an antigen (T-antigen) present on erythrocytes, platelets, and glomeruli.
This can be attributed to early recognition of the disease, advances in the intensive care and dialysis intervention. Due to hypoventilation, decreased reflex cough and hoarseness, the patient needed intubation, ventilation support and sedation.
In about 60% of cases, GBS is preceded by an infection, most frequently by Campylobacter jejuni, but other pathogens,  such as viruses from Herpesviridae family (cytomegalovirus, varicella zoster virus, Epstein–Barr virus) or bacterial agents (Haemophilus influenzae, Mycoplasma pneumoniae) can be responsible [10].
You are free to share and adapt the material, but you must give appropriate credit, provide a link to the licence, and indicate if changes were made. The advent of targeted therapy may have positively impacted the prognosis of such patients recently. Antibodies to the Tantigen , normally found in human serum, bird the exposed Tantigen , and the resultant antigen-antibody reaction ( Tactivation) can lead to HUS and anemia [3,4 ].
In the first case, the infant had impairment of renal function after three months of peritoneal dialysis. Besides the tetraparesis and areflexia, the patient also had autonomic instability with bradycardia and hypertension.
Standard approaches to treatment of leptomeningeal metastasis include intrathecal chemotherapy with or without cranial or craniospinal radiation and additional systemic therapy. Findings on a CT scan of the brain and from cerebrospinal fluid (CSF) analysis also were normal. This patient required peritoneal dialysis, platelets and packed red blood cell transfusions. After being transferred to our hospital for further evaluation, the patient continued to have moderate to severe headache. Generally, LC is associated with poor prognosis, and median survival is reported in case series as weeks to months [2-5]. One day later, a vesicular rash was noted on the left side of her face (lips, bridge of the nose, and eyelids), and treatment with high-dose acyclovir was started.
However, his clinical course was further complicated by subdural hematoma which was evacuated and by hydrocephaly which was derived. However, the advent of targeted therapy may have positively impacted the prognosis of such patients recently [4].
At 4 months of follow up, this patient had a normal renal function, haemoglobin level and platelets count; however he had right hemiparesia. Results of a VDRL test, a Cryptococcus antigen test, an acid-fast stain, a Mycobacterium tuberculosis polymerase chain reaction (PCR) assay, and all cultures (viruses, fungi, bacteria, and mycobacteria) were negative. A CT scan of the brain with contrast showed mild atrophy, but an MRI scan showed diffuse enhancement of the bilateral optic nerves (Figure). Three months prior, she had been diagnosed with an unprovoked deep venous thrombosis of the left leg and thigh and initiated on warfarin for anticoagulation.
This axial T1-weighted MRI scan after intravenous injection of gadolinium shows marked signal enhancement of both optic nerves, indicating disruption of the blood-nerve barrier and optic neuritis.The patient’s vesicular rash evolved over the next few days and healed several days later.
She had quit her 30-year habit of smoking one pack a day in 1994.Medical history was significant for deep venous thrombosis and pulmonary embolism in the postpartum period of her fourth pregnancy in 1971. Her severe headache, which required high doses of narcotics, also improved about 1 week after admission. Family history was significant as both the patient’s mother and a daughter died of breast cancer, the latter with LC. There was ovarian cancer, brain cancer, lung cancer and non-Hodgkin lymphoma in her extended family.
Physical examination was remarkable only for mild edema of the left arm.A computed tomography (CT) scan of the neck and chest showed thrombosed right internal jugular and brachiocephalic veins.

A VDRL test, M tuberculosis PCR assay, Cryptococcus antigen test, and culture results were negative.
The results of PCR studies for viruses such as Epstein-Barr virus, herpes simplex virus (HSV) 1 and 2, Cytomegalovirus (CMV), and JC virus (a polyomavirus) were negative, but the test for VZV was positive.
Because of the lack of improvement with specific antiviral therapy, the patient received a short course of high-dose corticosteroids. Pleural fluid analysis and biopsy of the right scapular lesion showed malignant cells consistent with adenocarcinoma. She was discharged 2 weeks after admission with only modest improvement in vision in her left eye.
There was no evidence of a T790M or other mutation.A CT-positron emission tomography (PET) scan (Fig.
DISCUSSION We have described a woman with advanced HIV infection with profound immunosuppression in whom bilateral retrobulbar optic neuritis developed as a result of VZV infection. Multiple metabolically active lymph nodes were located in the mediastinum, left supraclavicular region and retroperitoneum.
Optic neuritis is defined as the retrobulbar inflammation of the optic nerve.1 This sudden inflammation of the optic nerve leads to edema and destruction of the myelin, although some authors suggest that the inflammation is most frequently caused by demyelination. Magnetic resonance imaging (MRI) of the brain did not show any evidence of parenchymal or leptomeningeal metastatic disease.Figure 1. The inflammation is commonly associated with autoimmune diseases, particularly multiple sclerosis; more than 50% of patients who have optic neuritis will eventually have multiple sclerosis.
However, the inflammation may occasionally be caused by infection, such as Lyme disease, tuberculosis, syphilis, hepatitis B virus infection, and infections with the Herpesviridae family (HSV, VZV, and CMV).2 The most common signs and symptoms are acute loss of vision, loss of color vision, pain on movement of the eye, and evidence of optic neuropathy (impaired visual acuity and color vision, visual field loss, and afferent pupillary defects). The vision typically improves over 3 to 8 weeks, and most visual recovery occurs within the first 6 months, but it can continue for up to 1 year after the acute event.
Three-fourths of patients have nearly complete return of central vision, as measured by reading the eye chart. The patient started oral erlotinib, 150 mg daily, and subcutaneous denosumab, 120 mg monthly, in addition to daily subcutaneous low molecular weight heparin. However, there is usually some permanent residual haziness, which patients describe as “looking through smoke” even though outlines of objects are sharp. The patient rapidly became asymptomatic and significant decrease in the lung mass, improvement of pleural effusion and resolution of pulmonary emboli were noted on chest CT 3 months after diagnosis.In July 2013, 18 months after diagnosis, the patient began experiencing episodes of confusion, headaches, bizarre sensations in the head and difficulties with short-term memory.
The diagnosis is established on clinical grounds and is complemented by MRI (demonstration of inflammation within the optic nerve).1,2 Varicella-Zoster Virus VZV, an exclusively human, highly neurotropic alphaherpesvirus, is a member of the Herpesviridae family.
A cerebrospinal fluid (CSF) study showed mild decrease in CSF glucose, normal protein level and the presence of multiple mononuclear cells consistent with adenocarcinoma. The initial infection, or varicella, causes an acute febrile illness, usually in childhood, characterized by a widespread vesicular exanthem (chickenpox). A CT-PET scan showed evidence of response to therapy with decrease in size of the lung mass to 6 mm without increased metabolic activity, resolution of pleural effusion and sclerosis of bone metastasis without increased metabolic activity.Figure 2.
CNS complications occur in fewer than 1% of cases and include mild meningitis and acute cerebellitis (the most common neurological abnormality associated with varicella in children and adolescents). Encephalitis and myelitis have been reported as well, but they are quite rare.4 After the acute attack of chickenpox resolves, VZV becomes latent, and the viral DNA may remain extrachromosomal but in a nonin-fectious state. VZV may later reactivate in a ganglion, causing a localized, usually dermatomal, eruption of zoster (shingles). Zoster is known to cause a wide spectrum of neurological conditions, including postherpetic neuralgia, segmental sensory loss or motor paresis from radicular involvement, meningoencephalitis, myelitis, ventriculitis, cerebral vascular occlusion arising from vasculitic involvement, zoster sine herpete (neurological disease without rash), necrotizing retinitis, progressive outer retinal necrosis, and optic neuritis. A diagnosis of LC was made and treatment options including intrathecal chemotherapy and cranial or craniospinal radiation were discussed.
Almost all cases of optic neuritis described in the literature have been in patients with advanced HIV infection.5-8 Several mechanisms could possibly lead to tissue injury, including cytotoxic or demyelinating effects of the virus itself, vasculitis leading to cord ischemia, or meningitis with release of inflammatory mediators or secondary involvement of penetrating vessels. The patient refused these treatments mainly because of the death of her daughter who had LC related to an Ommaya reservoir for treatment of breast cancer several years ago. Diagnosis The characteristic rash (either of primary varicella or zoster) usually leads to a clinical diagnosis without the need for additional testing.
The patient was placed on pulsed erlotinib therapy with dose adjustments depending on toxicity. The patient derived her own optimal dosage of 600 to 750 mg daily for 3 days on and 2 days off resulting in a total dose of 2,550 mg per week. The patient noticed complete resolution of neurological symptoms in about a week and has remained symptom free at the time of this report more than 12 months after diagnosis of LC.
The patient is symptomatic only in terms of grade 1 dermatologic toxicity and grade 1 diarrhea secondary to erlotinib. Rapid diagnosis by PCR amplification of VZV DNA in the CSF is very helpful in diagnosing VZV infection and can provide early support of the diagnosis.
There is, however, a diagnostic window for the PCR method in the early phase of the infection, after which viral DNA may disappear in the CSF. During the later stages of CNS infection, testing for VZV IgG antibodies in CSF seems to be the method of choice for diagnosis. Antiviral IgG antibody is not normally found in CSF, so its presence in the absence of red blood cells in the CSF is considered significant.
The diagnosis of a VZV infection in the CNS should not be ruled out in the appropriate clinical setting, even if no VZV DNA or specific IgG antibodies are detected, since it is recognized that none of the available assays have ideal sensitivity. Pharmacokinetic studies have shown that high doses of oral erlotinib can result in higher CSF penetration [6].
Treatment The patient’s age and immune status are the main factors to consider in deciding how to treat zoster, or shingles. It is possible that the higher weekly dose of 2,550 mg may have contributed to the prolonged response in our patient.Similar to non-small cell lung cancer, prolonged survival has been reported in patients with HER2-positive breast cancer and brain and leptomeningeal metastasis undergoing anti-HER2 therapy [7]. In general, the use of oral antivirals (acyclovir, famciclovir, or valacyclovir) is not required in immunocompetent patients younger than 50 years, but there may be some evidence that it will speed healing of the rash. High-dose intravenous methotrexate therapy has been found to be comparable to intrathecal methotrexate in patients with lymphomas and leukemias [8, 9]. Given evidence of vascular inflammation in many tissue specimens from patients with CNS sequelae of VZV infection, a rationale exists for combining immune suppression with antiviral therapy.
Corticosteroids used concomitantly with antivirals are suggested to be of benefit, but rigorous clinical trial evidence is lacking.
Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. Analysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non-small-cell lung cancer. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?
Complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases.

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