• modified Rankin-Score (mRS) [ Time Frame: 3, 6, 9 and 13 weeks after first administration of the study drug; GCS Score also 17 weeks after first administration of the study drug ]
  modified Rankin-Score from 0 = no symptoms to 6 = death
• Length of in-hospital stay / length of ICU stay [ Time Frame: until 17 weeks after first administration of the study drug ]
  Number of days in hospital or on ICU for each patient from first administration of the study drug until 17 weeks after first administration of the study drug
• Immune response [ Time Frame: at study start and 17 weeks after first administration of the study drug ]
  Antibody titer (in serum and liquor) and cellular immune response (FACS analysis of liquor)
• neurocognitive function assessed by Montreal Cognitive Assessment [ Time Frame: at study start and 17 weeks after first administration of the study medication ]
  total score of the Montreal Cognitive Assessment (MoCA) (0 to max. 30 points = best possible result)
• neurocognitive function assessed by Mini-Mental Status Test [ Time Frame: at study start and 17 weeks after first administration of the study medication ]
  total score of the Mini-Mental Status Test (MMST) (0 to max 30 points = best possible result)
• neurocognitive function assessed by Rey Auditory Verbal Learning Test [ Time Frame: at study start and 17 weeks after first administration of the study medication ]
  total score of the Rey Auditory Verbal Learning Test (RAVLT) (memory performance assessed by 3 word lists which are read to the patient and should be recalled and repeated by the patient; different proceeding for the 3 word lists)
• neurocognitive function assessed by Neuropsychiatric Inventory Questionnaire [ Time Frame: at study start and 17 weeks after first administration of the study medication ]
  total score of the Neuropsychiatric Inventory Questionnaire (NPI) (0 = best score to max 36 (patient) or 60 (caregiver)
• safety of Bortezomib regarding polyneuropathy, increase of liver enzymes and secondary infections [ Time Frame: until 17 weeks after first administration of the study drug ]
  number of polyneuropathy cases, number of increased liver enzymes, number of secondary infections
• safety of Bortezomib regarding polyneuropathy [ Time Frame: until 17 weeks after first administration of the study drug ]
  number of polyneuropathy cases
• safety of Bortezomib regarding increase of liver enzymes [ Time Frame: until 17 weeks after first administration of the study drug ]
  number of increased liver enzyme values
• Secondary infections due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]
  number of secondary infections
• Hematotoxicity events due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]
  number of hematotoxicity events
• Gastrointestinal toxicity due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]
  number of gastrointestinal toxicity events
• total Glasgow Coma Scale (GCS) [ Time Frame: 3, 6, 9, 13 and 17 weeks after first administration of the study drug ]
  GCS from 3 to 15 points (sum of 3 subscores eye response (1 to 4 points), motor response (1 to 6 points), verbal response (1 to 5 points); highest score = best score; 1= worst score)
• Destruction marker UCH-L1 (Ubiquitin carboxy-terminal hydrolase L1) in serum and liquor [ Time Frame: at baseline visit and 17 weeks after first administration of the study drug ]
  Analysis of destruction marker UCH-L1 in serum and liquor
• Destruction marker Neurofilament light chain (in serum and liquor) [ Time Frame: at baseline visit and 17 weeks after first administration of the study drug ]
  Analysis of destruction marker Neurofilament light chain in serum and liquor
• Destruction markers GFAP (glial fibrillary acidic protein) in serum and liquor [ Time Frame: at baseline visit and 17 weeks after first administration of the study drug ]
  Analysis of destruction marker GFAP in serum and liquor
• Destruction marker TAU proteins in serum and liquor [ Time Frame: at baseline visit and 17 weeks after first administration of the study drug ]
  Analysis of destruction marker TAU in serum and liquor

• modified Rankin-Score (mRS) [ Time Frame: 3, 6, 9 and 13 weeks after first administration of the study drug; GCS Score also 17 weeks after first administration of the study drug ]
  modified Rankin-Score from 0 = no symptoms to 6 = death
• Length of in-hospital stay / length of ICU stay [ Time Frame: until 17 weeks after first administration of the study drug ]
  Number of days in hospital or on ICU for each patient from first administration of the study drug until 17 weeks after first administration of the study drug
• Immune response [ Time Frame: at study start and 17 weeks after first administration of the study drug ]
  Antibody titer (in serum and liquor) and cellular immune response (FACS analysis of liquor)
• neurocognitive function assessed by Montreal Cognitive Assessment [ Time Frame: at study start and 17 weeks after first administration of the study medication ]
  total score of the Montreal Cognitive Assessment (MoCA) (0 to max. 30 points = best possible result)
• neurocognitive function assessed by Mini-Mental Status Test [ Time Frame: at study start and 17 weeks after first administration of the study medication ]
  total score of the Mini-Mental Status Test (MMST) (0 to max 30 points = best possible result)
• neurocognitive function assessed by Rey Auditory Verbal Learning Test [ Time Frame: at study start and 17 weeks after first administration of the study medication ]
  total score of the Rey Auditory Verbal Learning Test (RAVLT) (memory performance assessed by 3 word lists which are read to the patient and should be recalled and repeated by the patient; different proceeding for the 3 word lists)
• neurocognitive function assessed by Neuropsychiatric Inventory Questionnaire [ Time Frame: at study start and 17 weeks after first administration of the study medication ]
  total score of the Neuropsychiatric Inventory Questionnaire (NPI) (0 = best score to max 36 (patient) or 60 (caregiver)
• safety of Bortezomib regarding polyneuropathy, increase of liver enzymes and secondary infections [ Time Frame: until 17 weeks after first administration of the study drug ]
  number of polyneuropathy cases, number of increased liver enzymes, number of secondary infections
• safety of Bortezomib regarding polyneuropathy [ Time Frame: until 17 weeks after first administration of the study drug ]
  number of polyneuropathy cases
• safety of Bortezomib regarding increase of liver enzymes [ Time Frame: until 17 weeks after first administration of the study drug ]
  number of increased liver enzyme values
• safety of Bortezomib regarding secondary infections [ Time Frame: until 17 weeks after first administration of the study drug ]
  number of secondary infections
• total Glasgow Coma Scale (GCS) [ Time Frame: 3, 6, 9, 13 and 17 weeks after first administration of the study drug ]
  GCS from 3 to 15 points (sum of 3 subscores eye response (1 to 4 points), motor response (1 to 6 points), verbal response (1 to 5 points); highest score = best score; 1= worst score)
• Destruction markers (in serum and liquor) [ Time Frame: at study start and 17 weeks after first administration of the study drug ]
  Analysis of destruction markers (Neurofilament light chain, GFAP, TAU, UCH-L1) in serum and liquor

Autoimmune Encephalitis is a disorder of the central nervous system caused by bodily substances, called antibodies. Antibodies normally help the body to prevent infections. However, in this disorder, the antibodies turn against the body itself and especially against cells in the brain and disturb the normal brain function. They are therefore called autoantibodies.

There is no specific therapy for patients with autoimmune encephalitis so far. At the moment, the symptoms are treated with approved medications such as cortisone and immunotherapies also used in oncology. These therapies are unspecified and aim to reduce the number of autoantibodies and to contain the autoimmune process. In this trial we aim to test a new therapy option: in this therapy the body cells producing autoantibodies will be specifically targeted by a substance called bortezomib.

The trial addresses patients with severe autoimmune encephalitis. The aim of the trial is to evaluate the efficacy and safety of bortezomib in patients with severe autoimmune encephalitis.

Autoimmune encephalitis is characterized by autoantibodies against neuronal surface antigens like the NMDA (N-methyl-D-aspartate) receptor or LGI1 (Leucin-rich glioma inactivated protein 1). So far, no specific therapy exists for this disease. Actual treatment includes combination therapies aiming for a reduction of pathogenic antibodies and containing the autoimmune process. In first line, patients are treated with plasmapheresis and cortisone. In second line, Rituximab and/or cyclophosphamide are administered. The response to these treatments are, however, often delayed and insufficient.

Therefore, we need a specific therapy aiming at the antibody-producing plasma cells.

Bortezomib is a proteasome inhibitor which interferes with NF-kB (nuclear factor kB) and the ubiquitin proteasome signaling pathway. Bortezomib acts preferably on cells with high protein synthesis - like plasma cells - and induces cell death in these cells. Bortezomib is used since more than a decade in chemotherapy of the multiple myeloma. Additionally, it is reported for systemic autoimmune diseases like lupus erythematodes that bortezomib leads to a depletion of plasma cells and therefore reduces the number of pathogenic antibodies and improves clinical outcome. The therapeutic potential of bortezomib for NMDAR encephalitis is described in a first case series with 5 patients.

• Drug: Bortezomib
  1 to 3 cycles Bortezomib with 1,3mg/m2 body surface s.c. + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)
• Drug: Placebo
  1 to 3 cycles placebo (NaCl solution) s.c. + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)
  Other Name: isotonic NaCl solution

• Experimental: Interventional
  1 to 3 cycles Bortezomib with 1,3mg/m2 body surface s.c. + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)
  Intervention: Drug: Bortezomib
• Placebo Comparator: Placebo
  1 to 3 cycles placebo (NaCl solution) s.c. + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)
  Intervention: Drug: Placebo

Inclusion Criteria:

• Clinically diagnosed severe autoimmune encephalitis (defined as mRS ≥ 3) with autoantibodies to neuronal surface proteins in cerebrospinal fluid and / or serum
• Pretreatment with rituximab
• Age ≥18 years
• signed informed consent
• Women of childbearing potential (up to 2 years after menopause): negative pregnancy test

Exclusion Criteria:

• pregnancy/breast-feeding
• acute infiltrative pulmonary and pericardial disease
• malignant tumor under current chemotherapy
• Simultaneous participation in another intervention study
• Previous participation in this study
• Known hypersensitivity to an ingredient of the investigational product
• Continued therapy with glucocorticoids / rituximab during the study duration (last dose must be administered before the first dose of the investigational product)