A 68-year-old male patient was transferred to our neurological department after he had been admitted to another hospital twice before. The first admission had taken place 3 months before in July 2018 due to visual impairments (hemianopsia to the right) and uncommon behavior. The MRI had shown a T2-weighted (T2w)-FLAIR hyperintensity in the left temporooccipital lobe that had been interpreted as an ischemic stroke. The results of cardiovascular investigations had been normal and the patient had been discharged. In August 2018 he had been admitted again with a progression of symptoms consisting of severe sensory aphasia, psychomotoric deficits and progressive visual impairments. The MRI had displayed a massive enlargement of parietooccipital lesions in both hemispheres predominantly affecting the left white matter (Figure 1). The polymerase chain reaction (PCR) for JCV in the cerebrospinal fluid (CSF) had been positive whereas routine analysis of the CSF had shown normal results (cell count and distribution, lactate, protein). PCR for Varizella zoster virus had been negative. Serologic tests for Borrelia burgdorferi, Treponema pallidum, Herpes simplex virus, measles, Varizella zoster virus, HIV and hepatitis B and C had also been negative.
The patient was then transferred to our department for further diagnostics. His general physician and relatives revealed that the medical history contained no record of frequent or severe infections. He had never received any kind of immunosuppressive treatment. In 1999 the patient had suffered from a myocardial infarction. The medical history was unremarkable apart from arterial hypertension and a helicobacter-positive gastritis. In 2017 he had got a viral infection with mild influenza-like-symptoms. Neither the patient nor his family knew of any recent vaccinations.
Upon admission to our neurologic department he had developed a right sided homonymous hemianopsia, severe sensory aphasia and disorientation. Our CSF analysis showed a pleocytosis (22 cells/mul) and an elevated protein concentration (0.72 g/l). The cell-distribution was mostly lymphocytic, but monocytes and granulocytes were found as well. CSF specific oligoclonal bands (type 2) were present and there was an intrathecal production of IgG and IgM. The JCV-PCR (1E3 c/ml) from CSF and the JCV-antibody-index (24.000 AU/ml serum) were positive. All additional tests were negative (HSV, VZV, and Ebstein-barr-virus (EBV) in the CSF by PCR, as well as tickborn encephalitis (TBE), enterovirus, and cytomegalovirus serologically; CSF-antibody-indices for HSV, EBV, VZV and CMV). All investigated autoimmune encephalitis antibodies (anti-NMDAR, -AMPAR1/2, -CASPR2, -LGI1, -GABAR-b1/b2, -Yu, -Hu, -Ri, -Amphiphysin, -CV2/CRMP-5, -Ma1/2, -GAD, -SOX1, -Tr(DNER), -Zic4) were negative in serum and CSF.
Further investigations concerning an immunodeficiency were inconspicuous. An HIV-test was negative. The blood tests including peripheral blood cell count and inflammatory parameters showed mild eosinophilia (10,3%), elevated rheumatoid factor (60.5 IU/ml), Cardiolipin-IgM-antibodies (14 MPL-U/ml), and antinuclear antibodies (ANA, 1:320) of unspecific speckled pattern in the immunofluorescence and without specificity against ds-DNA or extractable nuclear antigens. An abdominal sonography showed a splenomegaly and prominent lymph nodes but no sign of neoplasia. We performed a whole-body PET/CT (including the brain) with 296 MBq 18F-Fluorodeoxyglucose (18F-FDG) 60 min p.i. to search for a malignancy or an inflammatory disease. The PET scan showed prominent mediastinal lymph nodes with moderately high metabolism, however, it did not reveal any profound hypermetabolic lesions. 18F-FDG uptake in the brain was further evaluated using statistical parametric mapping (SPM) for comparison with a reference group. The cerebral glucose metabolism was lowered bilaterally in parietotemporal and occipital areas with a clear predominance on the left side. The metabolism in the frontal cortex, basal ganglia, and cerebellar regions appeared to be normal (Figure 2).
A biopsy of the prominent mediastinal lymph nodes identified in the PET investigation showed no signs of malignancy or granuloma. Additionally ACE and the soluble IL-2-receptor in the blood were normal, so sarcoidosis seemed unlikely. The HLA-DR-expression and phenotyping of lymphocytes showed normal results [amount and distribution of CD3+, CD4+, CD8+, B-cells (CD20+), and natural killer cells (CD16+)]. In addition to extensive phenotyping of peripheral blood mononuclear cells (PBMC) even the functional analyses by proliferation assays of PBMC by plant lectins (PHA, Con A, PWM), tuberculin (PPD) and anti-CD3, spontaneous and antibody-dependent NK-cell activity (ADCC) were within normal range.
During inpatient treatment the patient developed a cough and had impaired breathing. The tracheal exudate was positive for HSV using PCR so we started a therapy with intravenous aciclovir which improved the respiratory symptoms markedly. In September 2018 a progression of the patient's symptoms with focal and generalized seizures occurred. We started a medication with levetiracetam and had to add valproate and lacosamide to the antiepileptic treatment due to recurring seizures. The MRI showed a further expansion of the lesions with a new peripheral contrast enhancement (Figure 3) as a sign of a PML-related immune reconstitution inflammatory syndrome (PML-IRIS). We treated the patient with a high dose of corticosteroids (1 g/d methylprednisolone for 5 days intravenously). After this therapy the seizures decreased and the anticonvulsive treatment could be reduced to levetiracetam and valproate. Finally, we applied a treatment with mirtazapine to our patient, which is able to block the specific serotonin-receptors used by JCV, since this was beneficial in a previous report of a PML in an immunocompetent patient. Mefloquine, another drug with potentially antiviral effects against JCV, was not included to the treatment as seizures are a strict contraindication.
After nearly 2 months the patient was transferred to a rehabilitation facility. Visual impairments, disorientation and a sensory aphasia were still persistent. During the following weeks the patient developed severe dysphagia until oral intake of food and fluids was no longer possible. The patient died 2 months after the transfer to a nursery home due to a respiratory infection and pulmonary insufficiency.