Supplementary table e-1



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Supplementary table e-1. Symptoms, diagnostic work-up, therapy and clinical outcome of patients treated with bortezomib. As outcome parameter, modified Rankin Scale (mRS) was measured in a post-hoc manner. Abbreviations: ICU = intensive care unit; CSF = cerebrospinal fluid; AI = antibody index; MTX = methotrexate; BTZ = bortezomib; mRS = modified Rankin Scale; i.v. = intravenous; i.t. = intrathecal; s.c. = subcutaneous; c.d. = cumulative dose

symptoms

patient 1, 22y ♀

patient 2, 28y ♀

patient 3, 19y ♀

patient 4, 22y ♀

patient 5, 61y ♂

prodromal symptoms

facial paresis, paraesthesia, aphasia

withdrawal tendencies, dysphagia

headaches

headaches, paresis, hypacusis, paraesthesia

aphasia, confusion

psychiatric symptoms

mutism, katatonia, psychosis, agitation, aggressive behaviour

mutism, anxiety, panic attacks, aggressive behaviour, hypersomnia

mutism, psychosis

desorientation, mutism, psychosis, dissociative behaviour

vegetative state

movement disorder

orofacial dyskinesias

orofacial dyskinesias, stereotype movements

orofacial dyskinesias

orofacial dyskinesias, chorea, hyperkinesias

orofacial dyskinesias

autonomic dysfunctions

sympathetic hyper-activity syndrome, hypersalivation

none

cardiac arrest (<1min), hypersalivation

tachycardia, hypersalivation

none

seizures

focal and generalized seizures

focal/generalized seizures, status epilepticus

focal and generalized seizures

focal/generalized seizures, status epilepticus

focal/generalized seizures, status epilepticus

ventilation

10 months

5 months

3 months

7 months

6 months

duration on ICU

11 months

5 months

4 months

7 months

6 months

diagnostic workup
















CSF at presentation

lymphocytic pleocytosis (13/µl), oligoclonal bands

normal

lymphocytic pleocytosis (14/µl), oligoclonal bands

lymphocytic pleocytosis (100/µl), i.t. Ig-synthesis IgA>IgG>IgM

lymphocytic pleocytosis (7/µl), i.t. Ig-synthesis IgA>IgG>IgM, HSV1-PCR negative, HSV1 IgG AI 11.1

cranial MRI

small unspecific gliosis; later brain volume atrophy

periventricular hyperintensities

bitemporal hyperintensities

mild unspecific gliosis

massive supratentorial malacic defects with laminar cortex necrosis

PET-CT

no malignancy

no malignancy

not done

no malignancy

no malignancy

EEG

focal/generalized rhythmic delta activity, delta brush

alpha rhythm with partial epileptic activity

theta/delta rhythm, delta brush

focal/generalized rhythmic delta activity, delta brush

theta/delta rhythm, epileptic activity

tumor

none, bilateral ovariectomy

none

teratoma  teratomectomy

teratoma  teratomectomy

none

remarks

none

febrile meningo-encephalitis of unknown origin at age of 3 years

none

none

brain biopsy: acute necrotising encephalitis with lymphocytic infiltrates (HSV1-PCR+)

treatment
















methylprednisolone

5x1g i.v.

no

5x1g i.v.

2x 5x1g i.v.

2x 5x1g i.v.

plasma exchange

17 cycles

10 cycles

7 cycles

24 cycles

8 cycles

immunoadsorption

no

no

no

3 cycles

no

immunoglobulins

no

3x2g/kg i.v.

no

1x2g/kg i.v.

1x2g/kg i.v., 1x1g/kg i.v.

rituximab

weekly 375mg/m2 i.v. and 25mg i.t. for 4 weeks

5x unknown dose and 5x1000mg i.v.

2x1000mg i.v.

2x1000mg i.v.

2x1000mg i.v.

cyclophosphamide

5 cycles (cumulative dose 4.4g)

3 cycles (cumulative dose 2.7g)

no

no

no

bortezomib

4 cycles (1-1.3mg/m2 i.v.)

2 cycles (1.3mg/m2 s.c.)

1 cycle (1.3mg/m2 s.c.)

6 cycles (1-1.3mg/m2 s.c.)

2 cycles (1.3mg/m2 s.c.)

maintenance therapy

MTX 15mg/week

MTX 7.5mg/week

MTX 7.5mg/week

MTX 10mg/week

MTX 7.5mg/week

outcome
















relapses

none

3

none

first disease episode

none

physical dísabilities

none

spastic paraparesis

none

in rehabilitation, walking without assistance

tetraparesis, tracheostoma

cognitive impairment

mild, in vocational training

moderate-severe

none, back to work

mild, still remitting

minimal conscious state

mRS before BTZ

5

3

5

5

5

mRS after BTZ

0

3

0

1

5


Supplementary table e-2. Antiepileptic drug (AED) therapy before and after bortezomib




before bortezomib

after bortezomib

patient 1

midazolam 3mg/h

isoflurane 4ml/h

valproic acid 3300mg/d

primidone 1500mg/d



valproic acid 300mg/d

patient 2

lamotrigine 300mg/d

lacosamide 300mg/d



lamotrigine 300mg/d

lacosamide 300mg/d



patient 3

lacosamide 400mg/d

levetiracetam 3000mg/d

primidone 1500mg/d

diazepam 40mg/d



levetiracetam 1000mg/d

patient 4

propofol 300mg/h

midazolam 18mg/h

levetiracetam 4000mg/d

primidone 1250mg/d

clonazepame 8mg/d

lacosamide 400mg/d



levetiracetam 4000mg/d

primidone 875mg/d




patient 5

levetiracetam 3000mg/d

primidone 825mg/d

clonazepame 6mg/d

valproic acid 1500mg/d



levetiracetam 3500mg/d

primidone 250mg/d





Supplementary table e-3. The table presents the intervals from disease onset to initiation of first-line therapy, from end of first-line to beginning of second-line therapy and from end of second-line to beginning of third-line therapy. The time delay from disease onset to initiation of first-line therapy in some patients is the result of delayed diagnosis in referring hospitals. Abbreviations: MP = methylprednisolone, PE = plasma exchange, RTX = rituximab, CYC = cyclophosphamide, BTZ = bortezomib, IVIg = intravenous immunoglobulins




disease onset to first-line therapy

first-line to second-line therapy

second-line to third-line therapy




therapy

interval

therapy

interval

therapy

interval

patient 1

MP

PPH


4 weeks

4 weeks


CYC

RTX


5 weeks

15 weeks


BTZ

8 weeks

patient 2

IVIG

PE


5 months

6 months


RTX

CYC


3 months

16 months



BTZ

6 months

patient 3

PE

MP


3 weeks

4 weeks


RTX

2 weeks

BTZ

9 weeks

patient 4

MP

PPH


2 weeks

2 weeks


RTX

2 days

BTZ

1 day

patient 5

MP

IVIG


PE

4 weeks

14 weeks


16 weeks

RTX

5 weeks

BTZ

1 year


Supplementary table e-4. NMDAR antibody titers before and after rituximab and bortezomib treatment. Abbreviations: RTX = rituximab, BTZ = bortezomib, n.d. = not detectable, n.m. = not measured




serum

CSF

serum

CSF




before

RTX

after RTX

before RTX

after

RTX

before BTZ

after BTZ

before BTZ

after BTZ

patient 1

n.d.

n.d.

1:10

1:10

n.d.

n.d.

1:10

1:10

patient 2

1:100

1:1000

1:3.2

1:10

1:1000

1:100

1:10

1:10

patient 3

1:320

1:320

1:32

1:16

1:320

1:100

1:16

n.m.

patient 4

1:10000

1:10000

1:320

1:320

1:10000

1:100

1:320

1:10

patient 5

1:320

1:100

1:100

1:100

1:100

1:10

1:100

1:3.2


Supplementary table e-5. Serum IgG, CSF IgG index, CSF oligoclonal bands before and after bortezomib treatment. Abbreviations: BTZ = bortezomib, n.d. = not measured




serum IgG

CSF IgG index

CSF oligoclonal bands




before BTZ

after BTZ

before BTZ

after BTZ

before BTZ

after BTZ

patient 1

455mg/dl

633mg/dl

3.4

5.4

positive

negative

patient 2

1196mg/dl

1070mg/dl

2.4

2.7

negative

negative

patient 3

n.m.

n.m.

2.5

n.m.

negative

n.m.

patient 4

966mg/dl

434mg/dl

9.9

2.5

positive

positive

patient 5

207mg/dl

n.m.

10.1

5.4

positive

positive


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