Table 1.
Basic demographic and clinical features
| Case # | Stage | Sex | Age at onset | Age at death | Disease duration (months) | Cause of death | Presentation | Clinical subtype at presentation | Concurrent AI disorder |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 1 | Male | 81 | 82 | 6 | Pneumonia, sepsis | Subacute | Bulbar syndrome, sleep syndrome | No |
| 2 | 1 | Male | 81 | 82 | 11 | Respiratory insufficiency (unknown cause) | Subacute | Movement disorder, cognitive impairment, epilepsy | Yes, asthma |
| 3 | 1 | Male | 71 | 73 | 24 | Sudden death (unknown cause) | Chronic | Sleep disorder, PSP-like syndrome | Unknown |
| 4 | 1 | Male | 85 | 86 | 9 | Urinary infection and sepsis | Subacute | Sleep disorder | No |
| 5 | 1 + mild TDP | Female | 69 | 70 | 15 | Autonomic dysfunction, bradycardia | Subacute | Sleep disorder, cognitive impairment | No |
| 6 | 1 + TDP | Male | 77 | 77 | 9 | Pneumonia | Subacute | Bulbar symptoms, PSP-like syndrome | No |
| 7 | 1 | Male | 76 | 78 | 26 | Probable sepsis (palliative setting) | Subacute | Bulbar syndrome, sleep syndrome | No |
| 8 | 2 | Male | 62 | 75 | 156 | Pneumonia, status epilepticus | Chronic | PSP-like syndrome | No |
| 9 | 2 | Male | 75 | 76 | 6 | Unknown, found dead at home | Subacute | PSP-like syndrome, cognitive impairment | No |
| 10 | 2 + TDP | Male | 66 | 72 | 96 | Respiratory failure | Chronic | PSP-like syndrome | No |
| 11 | 2 | Male | Likely 69 | 73 | 48 | Respiratory failure | Subacute/chronic | Bulbar syndrome, ALS-like syndrome | No |
| 12 | 3 | Male | 53 | 59 | 72 | Sudden while asleep | Chronic | Sleep disorder | No |
| 13 | 3 | Male | 48 | 60 | 144 | Respiratory arrest | Chronic | Movement disorder | Unknown |
| 14 | 3 | Male | 49 | 59 | 120 | Respiratory failure | Chronic | Bulbar syndrome | No |
| 15 | 3 | Female | 54 | 66 | 156 | Aspiration pneumonia | Chronic | Sleep disorder, bulbar syndrome | No |
| 16 | 3 | Female | 77 | 87 | 120 | Sudden while asleep | Chronic | Bulbar syndrome | No |
| 17 | 3 | Female | 61 | 70 | 108 | Pneumonia | Chronic | PSP-like syndrome | Yes, rheumatoid arthritis |
| 18 | 3 | Male | 50 | 65 | 180 | Respiratory failures | Chronic | Bulbar syndrome, sleep disorder | No |
| 19 | 3 (PSP) | Male | 67 | 76 | 108 | Subdural hematoma | Chronic | PSP-like syndrome, bulbar syndrome | No |
| 20 | 3 + TDP | Female | 76 | 76 | 6 | Sudden while asleep | Subacute | Bulbar syndrome | No |
| 21 | 3 + TDP | Female | 66 | 71 | 60 | Infection of unknown origin | Chronic | Bulbar syndrome, possible sleep disorder | No |
| 22 | 3 + TDP | Female | 70 | 76 | 72 | Respiratory failure | Chronic | Bulbar syndrome, sleep disorder | Unknown |
| Case # | Concurrent cancer disorder | Co-pathologies | Antibody testing | Immunotherapy | CSF analysis | Brain MRI | Video-PSG | HLA type | MAPT haplotype |
|---|---|---|---|---|---|---|---|---|---|
| 1 | No | ADNC intermediate severity (A3, B2, C2), ARTAG, olfactory alpha-synuclein Lewy body pathology | In-house (TBA/CBA), positive, titer: serum 1:12,800; CSF 1:256 | IVIg w/ short time response, RTX | n/a | Generalized atrophy | Severe central sleep apnea with hypoxemic episodes | DRB1*10:01, DQB1*05:01, DRB1*15:01, DQB1*06:02 | n/a |
| 2 | Yes, multifocal urothelial carcinoma, first diagnosis 2 years before IgLON, relapse 1 year before diagnosis | PART stage III, no ßA4, no alpha-synuclein | In-house (TBA), Euroimmune (CBA), positive (no titer) | Steroids 3 × 500 mg, improvement (mainly cognitive) | 8 cells /µl, increased protein (104.5 mg/dl), lactate 3 mmol/l, OCB neg | Global atrophy, microangiopathy | n/a | n/a | n/a |
| 3 | Unknown | ADNC intermediate severity (A3, B2, C2) | In-house (TBA/CBA), positive (no titer) | IVIg, no response | Normal | Normal | Abnormal pseudo-rhythmic movements at 0.7 Hz, cramps, and complex movement automatisms during rapid eye movement and non-rapid eye movement phases | DRB1*10:01–DQB1*05:01 | H1/H2 |
| 4 | No | ADNC mild (A1, B1, C0) + mild CAA, microvascular lesions | In-house (TBA/CBA), positive (no titer) | Steroids iv, plasmapheresis, partial and transient improvement | 5 cells/µl, increased protein (49 mg/dl) | Non-specific mild small vessel cerebrovascular disease | NREM parasomnia, no REM sleep recorded, slow efficiency, obstructive hypopneas (AHI 27) | DRB1*10:01–DQB1*05:01 | n/a |
| 5 | No | PART stage III, no ßA4, no alpha-synuclein | Positive (post-mortem) | IVMP, no response | 5 cells/µl, normal protein | Normal | Flexion–extension movements throughout, severe central apnea | DRB1*03:01/DRB1*16:01 DQB1*05:02/DQB1*02:01 | H1/H1 |
| 6 | Unknown | ADNC intermediate severity (A2, B2, C1), mild CAA, no alpha-synuclein | Indirect immunofluorescence, positive, titer CSF 1:100, serum 1:1000 | No | Normal | Normal | Not performed | DRB1*08:01/DRB1*10:01, DQB1*04:02/DQB1*05:01, HLA-A*02:01/HLA-A*31:01, HLA-B*15:01/HLA-B*40:01, HLA-C*03:03/HLA-C*03:04, DQA1*01:05/DQA1*04:01, DPB1*02:01/DPB1*04:01, HLA-E*01:01/HLA-E*01:03, HLA-F*01:01/HLA-F*01:01, HLA-G*01:01/HLA-G*01:03 | H1/H1 |
| 7 | Yes, metastasized stomach cancer | AGD stage II-III with prominent septal and limbic involvement, NFT in LC | In-house (TBA), Euroimmune (CBA), positive, titer: serum 1:10,000, CSF 1:100 | IVMP, oral steroids, RTX | Normal | Global atrophy with emphasis on mesencephalon | No SOREM | n/a | n/a |
| 8 | No | AGD limbic, LATE with limbic TDP-43 and early HS, microvascular lesions | In-house (TBA, CBA), positive, titer: serum 1:400, CSF neg | No | Unknown | Atrophy of mesencephalon | Unknown | DRB1*03:01/DRB1*14:01 DQB1*05:03/DQB1*02:01 | H1/H1 |
| 9 | No | ADNC mild (A2, B1, C1), small vessel disease | In-house (TBA, CBA), positive, titer: serum 1:6400, CSF 1:128 | IVMP, oral steroids, MMF | Increased protein (77 mg/dl), rest normal | Vascular leukoencephalopathy, general atrophy | Not done | Unknown | n/a |
| 10 | No | ADNC mild (A2, B1, C2) + mild CAA, ARTAG, small vessel disease | Euroimmune Biomosaic (IFA, CBA), positive, titer: serum 1:100, CSF 1:10 | 5 × 1 g IVMP, oral steroid taper, RTX; improvement of consciousness | Normal | Iron accumulation in globus pallidus, dentate nuclei | n/a | DRB1*10:01; DQB1*05:01 | n/a |
| 11 | Yes,discovered at autopsy: colon carcinoma, silent prostate carcinoma | ADNC mild (A2, B2, C2) | In-house (TBA), positive, (no titer) | No | Normal | Perinatal encephalomalacia, chronic subcortical small vessel disease thalamus, midbrain | Not performed | n/a | n/a |
| 12 | No | No ßA4, no TDP-43, no alpha-synuclein | In-house (TBA/CBA), positive (no titer) | Three cycles of intravenous steroids and cyclophosphamide | Increased protein (55 mg/dl), rest normal | Normal | NREM-REM parasomnia | DRB1*10:01, DQB1*05:01 | H1/H1 |
| 13 | Unknown | No ßA4, no alpha-synuclein, LATE (TDP-43 dentate gyrus); PART II | Not done (archival case) | No | Unknown | Unknown | Unknown | Unknown | n/a |
| 14 | No | No ßA4, no TDP-43, no alpha-synuclein; PART II | Not done (archival case) | No | Unknown | Generalized atrophy | Unknown | Unknown | n/a |
| 15 | No | No ßA4, no TDP-43, no alpha-synuclein; PART II, microvascular lesions | In-house (TBA, CBA), positive, titer: serum 1:3200, CSF 1:32 | No | Unknown | Unknown | During episodes: low amplitude slow alpha activity, vertical more than horizontal rapid eye movements, and increased mental and submental muscle tone | DRB1*10:01; DQB1*05:01 | H1/H1 |
| 16 | No | ADNC mild (A1, B1, C1) + mild CAA | Not done (archival case) | No | Increased protein (57 mg/dl), rest normal | Unknown | Unknown | Unknown | n/a |
| 17 | Yes, adrenal cortical carcinoma, adenocarcinoma of the lung | No ßA4, no alpha-synuclein; PART II | Indirect immunofluorescence, positive, titer serum 1:3200; no CSF | IVIg with improvement | Unknown | Abnormal, slight parietal cortical atrophy | Unknown | DRB1*01:01/DRB1*04:04, DQB1*05:01/DQB1*03:02, HLA-A*02:01/HLA-A*03:01, HLA-B*07:02/HLA-B*18:01, HLA-C*03:04/HLA-C*07:01, DQA1*01:01/DQA1*03:01, DPB1*04:01/DPB1*04:01, DRB4*01:03, HLA-E*01:01/HLA-E*01:03, HLA-F*01:01/HLA-F*01:03, HLA-G*01:01/HLA-G*01:01 | H1/H2 |
| 18 | No | No ßA4, no alpha-synuclein | Euroimmun (CBA), positive, titer: serum 1:000, CSF 1:10 | IVMP, PLEX, RTX with improvement | Mild pleocytosis (15 cells/µL) | Unspecific white matter hyperintensities in the brainstem | Severe insomnia with overall 24 min of sleep, sleep efficiency of 4%, stridor, vocalizations and abnormal movements both during wakefulness and sleep; neither N3 sleep stages nor REM sleep present | DRB1*10:01; DQB1*05:01 | H2/H2 |
| 19 | No | no ßA4, no TDP-43, no alpha-synuclein | In-house (TBA/CBA), positive (no titer) | No | Mildly increased protein (44.7 mg/dl) | Atrophy of the corpus callosum and the midbrain during the course of disease | Unknown | DRB1*01:02, DRB1*03:01; DQB1*02:01, DQB1*05:01 | H1/H1 |
| 20 | No | ADNC mild (A1, B1, C1) + mild CAA | In-house (TBA/CBA), positive (no titer) | Three cycles of intravenous and oral steroids; two cycles of cyclophosphamide | Normal | Normal | NREM-REM sleep parasomnia, stridor | DRB1*10:01, DQB1*05:01 | H1/H1 |
| 21 | No | Intranuclear neuronal hyaline inclusion disease | Not done (postmortem) | No | n/a | Minor cerebellar atrophy, DAT-SPECT: abnormal uptake putamen | n/a | Unknown | n/a |
| 22 | Unknown | ADNC mild (A1, B1, C1), ARTAG, no ßA4, brainstem alpha-synuclein Lewy body pathology, small vessel disease | In-house (TBA/CBA), positive (no titer) | 2 × IVIg, RTX, IVMP, PLEX | Unknown | Unknown | Unknown |
DRB1*01:01, DRB1*11:01, DQB1*03:01 DQB1*05:01, DQA1*01:01, DQA1*05:05 |
H1/H1 |
The column “Co-pathologies” represents the summary of associated pathologies observed in the neuropathological examination
ADNC Alzheimer’s disease neuropathologic change, AGD argyrophilic grain disease, ARTAG aging-related tau astrogliopathy, CAA cerebral amyloid angiopathy, CBA cell based assay, CSF cerebrospinal fluid, HS hippocampal sclerosis, IFA indirect immunofluorescence assay, IVIg intravenous immunoglobulins, IVMP intravenous methylprednisolone, LATE limbic age-related TDP-43 encephalopathy, NFT neurofibrillary tangles, NREM non-rapid eye movement, OCB oligoclonal bands, PART primary age-related tauopathy, PLEX plasma exchange, PSG polysomnography, PSP progressive supranuclear palsy, REM rapid eye movement, RTX rituximab, SOREM sleep onset REM, TBA tissue based assay