Table 3.
Diagnostic findings
| # | CT/MRI | EEG | CSF cells /µl | Oligoclonal bands CSF/serum | Reibergram | CSF glucose mg/dl |
CSF lactate mg/dl |
CSF total protein mg/l | Qalb | IgG % | IgA% | IgM% | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | MRI: thickened meninges, white matter lesions | Alpha, intermittent theta rhythm | 2 | Type 4 | Normal | 85 | 16.7 | 294.6 | 6.9 | 0 | 0 | 0 | |
| 2 | CT: chronic lacunar infarctions, massive leukoaraiosis | Alpha, intermittent theta rhythm | 2 | Type 1 | Barrier dysfunction | 55 | 16.7 | 792.1 | 14.4 | 0 | 0 | 0 | |
| 3 | CT: mild leukoaraiosis | Theta, intermittent delta rhythm | 1 | Type 4 | Normal | 127 | 17.3 | 217.8 | 4.8 | 0 | 0 | 0 | |
| 4 | MRI: small SAH, several microbleeds, small chronic infarction | Mixed theta-delta rhythm | 7 | Type 1 | Barrier dysfunction | 82 | 13.2 | 717.4 | 13.8 | 0 | 13 | 45 | |
| 5 | MRI: two small acute infarctions | Theta, intermittent delta rhythm | 1 | Type 4 | Borderline barrier dysfunction | 136 | 25.1 | 354.6 | 9.3 | 0 | 0 | 0 | |
| 6 | CT: leukoaraiosis | Theta, intermittent delta rhythm | 2 | Type 3 | Barrier dysfunction | 127 | 17.8 | 678.9 | 11.7 | 0 | 0 | 0 | |
| 7 | CT: mild leukoaraiosis | Mixed theta-delta rhythm | 0 | Type 4 | Barrier dysfunction | 59 | 16.8 | 379 | 8.4 | 0 | 0 | 0 | |
| 8 | CT: normal | nd | nd | nd | nd | nd | nd | nd | nd | nd | nd | nd | |
| 9 | CT: partially empty sella | nd | 0 | Type 1 | Barrier dysfunction | 97 | 17 | 864 | 21.5 | 0 | 0 | 0 | |
| 10 |
MRI: normal PET-CT: limbic encephalitis |
nd | nd | Type 1 | Barrier dysfunction | nd | nd | nd | 26.8 | 0 | 35 | 51 | |
| 11 | CT: leukoaraiosis | nd | 2 | Type 4 | normal | 70 | 17 | 239 | 7.7 | 0 | 0 | 0 | |
| 12 | MRI: multiple chronic small infarctions, global atrophy, leukoaraiosis | Mixed theta–delta rhythm | 1 | Type 4 | Borderline barrier dysfunction | 101 | 16.1 | 556 | 25.8 | 0 | nd | 0 |
| # | Antineuronal antibodies serum | Antineuronal antibodies CSF | IIFT binding pattern serum | IIFT binding pattern CSF | NfL serum (pg/ml) | NfL CSF (pg/ml) | NfL Ratio | IL-6 before IVIg (ng/l) | IL-6 after IVIg (ng/l) | IL-6 at discharge/death (ng/l) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Myelin Ab 1:100 | None | Panneuronal | Panneuronal | 435 | 2112 | 4 | 56 | 59 | 83 |
| 2 | nd | None | Negative | Negative | 31 | 6359 | 205 | 252 | 26 | 27 |
| 3 | Myelin Ab 1:100 | None | Medium sized vessels, myelin | Medium sized vessels, Myelin | 616 | 1181 | 1 | 19 | 23 | 7 |
| 4 | None | None | Negative | negative | 256 | 2445 | 9 | 24 | 30 | nd |
| 5 | CASPR2&NMDAR IgG Ab 1:10 | None | Antinuclear | Antinuclear | 914 | 1683 | 1 | 105 | 116 | 99 |
| 6 | None | None | Antinuclear, perinuclear | Negative | 125 | 2264 | 18 | 37 | nd | 16 |
| 7 | nd | None | Antinuclear, Perinuclear | Antinuclear, perinuclear | 185 | 981 | 5 | 66 | 16 | 39 |
| 8 | None | nd | Panneuronal | nd | 733 | nd | nd | 238 | 107 | 13 |
| 9 | nd | None | Negative | Negative | 232 | 2223 | 9 | 89 | 40 | 24 |
| 10 | Yo Ab | Yo Ab | nd | Antinuclear | nd | 2215 | nd | 1087 | nd | 61 |
| 11 | Myelin Ab 1:100 | None | Negative | Negative | 4153 | 12,500 | 3 | 121 | 133 | 5905 |
| 12 | Myelin Ab 1:100, Glycin-R Ab 1:10 | None | Negative | Negative | 1348 | 28,099 | 20 | 106 | 237 | - |
| Mean | 821 | 5642 | 28 | 183 | 79 | 627 | ||||
| Responders | 392 | 2406 | 32 | 98 | 52 | 39 | ||||
| Non-responders | 2751 | 14,271 | 12 | 438 | 185 | 2983 | ||||
| P values | 0.0023 | 0.0216 | 0.711 | 0.0819 | 0.0056 | 0.0342 | ||||
All findings were measured after occurrence of acute encephalopathy and prior to IVIg administration except IL-6 levels, which were determined every second day throughout the ICU stay. Cerebral imaging only showed nonspecific pathologies including small ischemic strokes or intracerebral bleedings with no clinical correlation. Such imaging alterations are frequently seen in COVID-19 patients due to their higher risk of cerebral vasculopathy, especially in patients treated with vvECMO-therapy. But also activation of the coagulation system in COVID-19 patients predisposes them to thrombotic events of the brain and other organs. Patient #4 had a blood contamination in lumbar puncture with an increased CSF cell count of 7/µl and 1000 erythrocytes/µl. In all other patients CSF cell count and cytology were normal (< 5/µl, lymphocytes). Part of the CSF samples of patient #10 coagulated due to blood contamination, which is why some laboratory information is missing
Oligoclonal bands are reported as follows: type 1: Normal CSF, type 2: Oligoclonal IgG restricted to CSF, type 3: Oligoclonal IgG in CSF with additional identical bands in CSF and serum (combination of types 2 and 4), type 4: Identical oligoclonal bands in CSF and serum
Antineuronal antibodies in serum and CSF were tested according to a standard panel including IgG-antibodies against amphiphysin, PNMA2 (Ma2/Ta), Ri, Yo, Hu, CV2 (CRMP5), Tr (DNER), NMDAR, GABA-b-R, AMPA-R1/2 (GluA1/GluA2), mGluR5, Glycin-R, Dopamin2-R, DPPX, LGI1, CASPR2, Aquaporin-4, Myelin, GAD65. The upper limit for normal serum NfL levels is 9.9 pg/ml. The values for CSF NfL are age dependent, but values > 289 pg/ml are indicative of axonal damage of unknown specificity, whereas NfL values > 2.200 pg/ml can be found in patients with amyotrophic lateral sclerosis. NfL ratio is calculated by dividing CSF NfL by serum NfL. The increased NfL values in serum and CSF of all investigated patients reflect relevant axonal damage in affected individuals
P values show the comparison between responders and non-responders with a t-test and a standard α = 0.05. Due to the limited sample size (nine vs. three subjects), these should only be interpreted on an exploratory level. Responders: patients #1–9, non-responders: patients #10–12
↑ increased, Ab antibodies, CASPR2 contactin-associated protein 2, CSF cerebrospinal fluid, CT computed tomography, EEG electroencephalography, IgA% intrathecal fraction IgA, IgG% intrathecal fraction IgG, IgM% intrathecal fraction IgM, IIFT indirect immunofluorescence technique, IL-6 interleukin-6, MRI magnetic resonance imaging, nd not determined, NfL neurofilament light chain, NMDAR N-methyl-d-aspartate receptor, PET–CT Positron emission tomography–computed tomography, SAH subarachnoid hemorrhage