A 72-y-old nonsmoking man with a single episode of transient global amnesia 10 y previously presented with progressive diffuse arthralgia and a sore throat (day 0). Two days afterward, his general practitioner started josamycin for 4 d. On day 8, the patient exhibited an episode of fever (38°C–38.5°C) without rhinorrhea, cough, or dyspnea, leading to the prescription of azithromycin. He never experienced anosmia or ageusia. On day 12, chest CT showed peripheral bilateral ground-glass lesions and consolidative opacities suggestive of SARS-CoV-2 infection. The symptoms improved gradually. On day 17, he started to develop bilateral upper-limb action tremor. The next day, the tremor worsened, involving the lower limbs and trunk, making walking and sitting impossible and leading to his admission to the hospital.\nNeurologic examination showed a cerebellar syndrome (action tremor, ataxia, dysarthria, and upper-limb dysmetria) associated with spontaneous diffuse myoclonus, mostly affecting the proximal limbs and worsening with movement, also stimulus-sensitive. The remainder of the neurologic examination showed normal findings, including ocular motility and deep tendon reflexes. His body temperature, oxygen saturation, respiratory rate, and lung auscultation were normal. A moderate biologic inflammatory syndrome was present, with increased fibrinogen (7.07 g/L; reference level, 1.90–4.30 g/L) and C-reactive protein (14 mg/L; reference level, 0.0–5.0 mg/L).\nThe first nasopharyngeal swab test for SARS-CoV-2 was positive (day 18), as was the serology afterward (strongly positive for IgM and IgG). The next swab tests, quantitative reverse-transcription polymerase chain reaction testing of nasopharyngeal or oropharyngeal swabs, were negative (days 21, 22, 26, and 27).\nElectroencephalography showed symmetric diffuse background slowing, reactive to stimulation, without interictal paroxysm and, notably, no correlation of the myoclonus on back-averaging. Brain MRI with gadolinium contrast injection had normal results (). Brain PET with 18F-FDG showed putaminal and cerebellum hypermetabolism associated with diffuse cortical hypometabolism, confirmed by whole-brain voxel-based SPM quantification (). Slight lung and hilar lymph node hypermetabolism was noticed, matching postinfectious pseudonodular retractile consolidation on CT, without a straightforward argument for neoplasia.\nCerebrospinal fluid (CSF) testing showed normal cell counts (4 × 106/L), a mildly elevated protein level (49 mg/dL), negative reverse-transcription polymerase chain reaction, and no oligoclonal banding. Nerve tissue immunostaining with the serum and CSF revealed the presence of autoantibodies directed against the nuclei of Purkinje cells, striatal neurons, and hippocampal neurons, as illustrated with the CSF in . This immunostaining did not evoke any previously described targets for autoimmune encephalitis. The titer of the IgG isotype autoantibodies in the serum was extremely high (1/25,000) but was 1/96 in the CSF. The same intensity and reactivity in serum and CSF were observed at the same IgG concentration, ruling out intrathecal autoantibody synthesis in concordance with the absence of CSF-specific IgG oligoclonal banding. Dot blot assays against onconeural antigens and cell-based assays against membrane antigens had negative results. Finally, the patient was negative for antinuclear, antiphospholipid, and antipolynuclear autoantibodies and other tissue autoantibodies.\nBecause of the suspected autoimmune nature of the encephalitis, we promptly started immunomodulatory treatment: at first, beginning on day 23, we used intravenous immunoglobulins (0.4 g/kg/d for 5 d); tolerance was good, but there was no significant clinical improvement. We then decided to treat the patient with intravenous methylprednisolone (1 g/d for 5 d) beginning on day 30. To help reduce myoclonus, we introduced oral drops of clonazepam (0.3 mg 3 times a day), but the treatment was stopped because of drowsiness. Clinically, the patient improved considerably after the methylprednisolone treatment, leading to cessation of myoclonus and upper-limb dysmetria and allowing him to walk without assistance. He was discharged from the hospital on day 37. We did not observe any signs of SARS-CoV-2 reactivation.
A 62-year old male patient was referred to our center with subacute onset of a cerebellar syndrome manifesting in writing disability and severe gait instability. Sixteen days earlier, he had developed acute-onset cough and high fever for 7 days, and 4 days after onset of upper airway symptoms, he experienced acute ageusia and anosmia for eleven days. Medical history was unremarkable. Clinical, imaging and laboratory findings are summarized in Table .\nThe patient presented with a cerebellar syndrome with slightly scanning speech and limb-, truncal- and gait ataxia at admission, i.e. 16 days after onset of COVID-19 respiratory illness and 1 day after resolution of symptoms of COVID-19 affecting the upper respiratory tract. Examination of the eye movements including vertical and horizontal saccades, saccadic pursuit and vestibulo-ocular reflex, was normal. No pathological nystagmus was observed. No opsoclonus or myoclonus was observed. Sensory functions including vibration sense, joint position sense, light touch, pin prick and temperature sensation, were normal; muscle tone, shape, strength and deep tendon reflexes were also normal. His vital signs on admission were normal. Lung auscultation was regular, but CT of the chest showed bipulmonary opacities. He tested positive for SARS-CoV-2 RNA via reverse-transcription polymerase chain reaction (RT-PCR) of nasopharyngeal swab using the Roche Cobas SARS-CoV-2 test (Roche, Basel, Switzerland) on day 2, but tested negative again on day 6 of hospital admission. Cerebral MRI imaging (Fig. a-d) showed a mild cerebellar atrophy of unclear etiology, in particular, the patient did not have a history or signs of pre-existing cerebellar disease such as alcohol abuse or gluten hypersensitivity. We ruled out paraneoplasia by whole-body FDG-PET and screening for anti-neuronal antibodies including anti-CASPR2, −LGI1, −Glut, −GlyR, −Hu, −Ri, −Yo, −Amphiphysin, −CV2 (CRMP5), −Ta/Ma2, −Ma1, −SOX1, −GAD65, −ZIC4, −Tr antibodies in cerebrospinal fluid (CSF) and serum, and anti-MOG antibodies in serum. FDG-PET was performed 13 days after onset of cerebellar symptoms and showed normal cerebellar and cerebral metabolism (Fig. e). Laboratory results showed no increase in inflammatory markers in peripheral blood, in particular CRP and white blood cell count were normal. CSF testing including cell count, protein, CSF/serum albumin ratio and Reibergram was normal. Isoelectric focusing revealed identical oligoclonal bands in CSF and serum (type 4, see Table ), indicating systemic inflammation of various etiology but no intrathecal IgG production. Notably, SARS-CoV-2 RT-PCR [] from CSF was negative. In addition, no viral nucleic acid was detected in metagenomic virus sequencing [] from CSF. An in-house developed, bead-based antibody assay (ABCORA, Luminex technology) for detection of IgG antibodies against subunit 1 (S1) and subunit 2 (S2) of the spike protein and nucleoprotein (NP) of SARS-CoV-2 was used to screen for SARS-CoV-2-specific antibodies in serum and CSF. We calculated CSF/serum-antibody index according to Reiber [], and CSF/serum-antibody index > 1.5 indicated intrathecal antigen-specific antibody production. SARS-CoV-2-specific antibodies were positive in serum, but there was no intrathecal SARS-CoV-2-specific antibody production. PCR testing of CSF for DNA of herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), JC polyomavirus (JCV) and varicella zoster virus (VZV) were also negative. No intrathecal antibody production reactive to HSV-1, HSV-2, VZV or Borrelia burgdorferi was detectable.\nEmpirical treatment with systemic acyclovir 3x10mg/kg body weight/day was given over 6 days, as herpes viral cerebellitis could not be excluded until day 33. The possibility of cerebellar infection with SARS-CoV-2 was discarded because of the normal CSF cell count and the absence of SARS-CoV-2 RNA and intrathecal SARS-CoV-2-specific antibody production. Other causes such as infections with other viruses, other autoimmune and/or paraneoplastic diseases or intoxication were excluded by details of the past medical history, results of the CSF analysis, auto-antibody screening and FDG-PET. In order to treat a possible post-infectious etiology, namely a post-infectious cerebellar ataxia, we additionally started high-dose methylprednisolone 500 mg/day i.v. over 5 days without subsequent tapering. The cerebellar syndrome improved slowly and slightly over a course of 20 days before acyclovir and corticosteroid treatment, and improved more rapidly with the steroid treatment, which was initiated 14 days after resolution of COVID-19-related respiratory symptoms, i.e. 13 days after onset of ataxia and 7 days after negative SARS-CoV-2 nasopharyngeal swab. The Scale for the Assessment and Rating of Ataxia (SARA ataxia score) improved from SARA 14 points on admission (onset of ataxia, i.e. day 16 after onset of COVID-19) to SARA 5 points 6 days after beginning of steroid treatment (i.e. day 35 after onset of COVID-19), and SARA 1 point nearly 4 months after beginning of steroid treatment (i.e. day 119 after onset of COVID-19). Steroid treatment was well tolerated without re-occurrence of COVID-19 symptoms.