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Table e-1 . Clinical features of previous reported cases of thymoma-associated paraneoplastic encephalitis.

Patients Author Sex, age in years

Presentation and main

symptoms

History of autoimmunity

MRI CSF EEG Anti-Neuronal

Abs

Treatment Outcomes

1 Mcardle (1988)(1)

M, 41 Confusion, memory deficits

ANA (serum) Not available oligoclonal IgG bands

Not Available

No Partial, thymectomy, radiation, corticosteroids

Death (1 month)

2 Ingenito (1990)(2)

M, 59 Confusion, memory deficit, hyper somnolence, axial cerebellar ataxia

No Not reported 13 WBC Slow activity with frontal intermittent rhythmic delta activity

No Corticosteroids Death (51 days after admission, symptoms onset were 7 months before admission

3 Cunningham (1994)(3)

F, 56 Confusion, memory deficit, emotional lability

No Left temporallobe corticaland subcorti-cal lesionsnoted onT2 (no figures available)

Elevated protein level

Not reported

No(Negative anti-Hu)

Thymectomy, radiation, chemotherapy (three cycles of cisplatinandetoposide)

Significant improvement

4 Antoine (1995)(4)

F, 58 Confusion, visual and auditory hallucinations, short term memory loss

No Before treatment: increased signals on T2 weighted sequences in right hippocampusAfter treatment

36 lymphocytes/m3

Protein 0,3 g/l

Epileptic discharges in the right temporal lobe

Anti-neuronal Cytoplasmatic (serum 1/1500 and CSF 1/100)

Thymectomy and radiation

No residual symptoms

–normal(No figures available)

5 Antoine (1995)(4)

F, 67 Confusion, agitation, hallucination, short memory loss

Anti-striated muscle antibody (1/10)

Before treatment: mild increased signals in the right hippocampus on T2 weighted sequences

Normal after treatment (no figures available)

Normal Epileptic discharges in the left temporal lobe

Anti-neuronal Nuclear (serum and CSF)

ThymectomyRadiotherapy

Mild memory deficits (necessity of noting her shopping requirements)

6 Evoli (1999)(5,6)

M,32 New onset generalized tonic-clonic seizures and confusion, memory deficits

Myasthenia GravisNeuromyotonia

Before treatment: increased signal and swelling of both hippocampi on T2-weighted images

25 cells/mm3Normal protein and glucose

Theta background activity with sharp waves on both temporal lobes

No(negative anti-Hu)

Thymectomy, radiation, chemotherapy (cyclophosphamide, doxorubicin, vincristine and metilprednisolone), corticosteroids, PLEX

Mild memory deficits, (“good condition and has returned to work”)Dependent on corticosteroids

7 Rickman (2000)(7)

M,55 Malaise, fever, cough, dysarthria, intermittent twitching of right hand. One week after short-term memory, word finding difficulty.

AchR andStriational antibodies

MRI1: Patchy T2 hyperintensity in the gray matter of both cerebral hemisphere with no gadolinium enhancementMRI 2 (D35):

CSF 1: protein 69 mg/dLCSF 2: protein 63 mg/dl

Multifocal, independent, periodic, lateralizing epileptiform discharges (PLEDs)Fig 2)

Anti-CRMP-5 Partial thymectomy, pulse therapy (methylpredinisolone), PLEX

Initial responseRecurrence of symptomsDied (9 months)

Nystagmus, vertical gaze impairment, jerking movements of face, neck and arms, and left lower extremity. Intractable seizures

multiples areas of cortical signal abnormalities most prominent in the temporal lobes and spare subcortical and posterior fossa structuresMRI 3 (D105): cortical atrophy and reduced number of lesions, temporal lobe are still prominent

8 D’Avino (2001)(8)

M, 61 Short term memory loss, confusion, irritability, hallucinations, feeding disorders, loss of weight, generalized tonic clonic seizures (not described if it was refractoryMMSE: 23/30

No Normal(No available figures)

Positive OB

Theta backaground activity with sharp waves in both fronto-temporal lobes

Antibody reactivity to Purkinje cells (serum and CSF)

Thymectomy, radiation

Mild memory deficitsMMSE: 29

9 Fujii (2001)(9) M,55 Confusion, memory deficit, irritability, mania,3 generalized

Myastenia Gravis 15-years previoulsyAChR

Bilateral highIntensity (no available figures)

Normal No epileptic discharges

Hippocampus showing human IgG at autopsy

Thymectomy Death (4months)

tonic clonic seizures

antibodies

10 Vernino (2002)(10)

F, 66 Hoarseness, unilateral loss of hearing, vertigo, arreflexia

No Not reported Not reported

Not reported

ANNA-1 (anti-Hu), VGCC (serum)

Partial thymectomy, chemotherapy (two cycles of cisplatinandetoposide

Death (7 months)

11 Vernino (2002)(10)

M, 34 Presented with dysphagia and dysarthria being diagnosed as myasthenia gravis. After 1 month presented with confusion, auditory hallucination, and tonic clonic seizures

Myastenia GravisAChR antibodies

Normal (no available figures)

10 WBC with normal protein concentration

Diffuse slowing over the left temporal lobe

ANNA-1 (anti-Hu),

PLEX, thymectomy, corticosteroids

“Three months later, he was noted to be intermittently withdrawn and confused; no seizures were observed”

12 Vernino (2002)(10)

F, 34 Recurrent vertigo, tinnitus, and vomitingClonic activity of the tongue and jaw (seizures?)

Dysautonomia MRI 1: normalMRI 2:Non-enhancing left temporal lesionMRI 3 (11 days after):Four new enhancing cortical lesions (figure 1)

Elevated protein 78 mg/dL

Not reported

ANNA-1, VGKC

Thymectomy Residual symptoms, constipation, fixed right pupil

13 Vernino (2002)(10)

F, 39 Dysphagia, generalized

Myasthenia Gravis

Normal (no available

Not reported

Not reported

ANNA-1, CRMP-5,

Partial Thymectomy,

Not reported

weakness (attributed to Myasthenia Gravis)Personality changes

AChR andStriational antibodies

figures) radiation, chemotherapy (etoposide, cysplatin), corticosteroid, PLEX

14 a Ances (2005) – patient 5(11) corresponds to Lai (2009) patient 2(12)

F, 44 Hippocampal syndrome; pure short-term memory loss. Evolved to extensive LE, focal motor seizures

Not reported MRI(1) : normalMRI (2, after 5 days): mild temporal lobe FLAIR abnormalities (right>left), no contraste enhancement

0 WBC, protein 63 mg/dL, glucose 64 mg/dL

Not reported

Neuropil antibodies Later prove to be AMPAR Abs (12)

Thymectomy, corticosteroids, IVIg

Returned to baseline

15 Ances (2005) – patient 6(11) corresponds to Lai (2009) - patient 3(12)

M,38 Confusion, agitation, short-term memory loss, generalized tonic-clonic seizures (prior episode of Limbic Encephalitis 5 years earlier). Evolved to hippocampal and multifocal encephalitis, and stiff person syndrome

Stiff person FLAIR abnormalities in right medial and lateral temporal lobe, right frontal, left insular and left occipital regions. No contrast enhancement.

7 WBC, protein 50 mg/dL, glucose 92 mg/dL, positive OB. Positive ISAb, IgG index not examined

Not reported

Neuropil antibodies Later prove to be AMPAR Abs (12)

Thymectomy, corticosteroids, plasmapheresis, IVIg

Mild residual memory deficits and steroid-dependent muscle spasms and rigidity

16 Ohshita (2006)(13,14)

F, 59 3 years earlier years, invasive thymoma had been diagnosed

Positive single-stranded DNA antibodies

T2/FLAIR images demonstrated bilateral

Mild elevation of the protein

Normal VGKC (LGI1) andAnti-GABAaR(14)

Chemotherapy (carboplatin and etoposide)

Mental state partially improved

and treated with thymectomy and radiotherapySubacute onset of amnesia (short-term memory impairment), disorientation, and; 10 months later, progressive memory impairment and recurrence of thymoma

hyperintense areas in the medial part of the temporal lobe. High intensity lesions were also seen in the right insular cortex, as well as bilaterally in the frontobasal cortex and cingulate gyrus

content (60 mg/dl)

17 Chaudhry (2007)(15)

F, 67 Memory deficits, cognitive impairment. MMSE: 23

No Bilateral increased signal on FLAIR in both hippocampi. More extensive similar changes were on the left side extending to trigone and up to the level of the corpus callosum.

Protein: 67 mg/ 100 ml Positive OB

Not reported

Negative for anti-Hu, anti-Ri, anti-Yo and VKGC

Thymectomy, chemotherapy (cyclophosphamide, doxorubicin, cisplatin), rituximabe, PLEX

Progressive cognitive deficits

18 Khella (2007)(16)

F, 41 Headache, diplopia, nausea, dizziness. After

Myasthenia GravisAchR antibodies

Bright signal on T2 weighted and FLAIR in the right globus

43 WBC (66% of lymphocytes)

Not reported

Unknown antigen.in Serum and CSF,

Prednisone 1mg per kg for 90 days, IVIg (350 g), PLEX

Initial partial responseDeath with 31 days

9 weeks: recent memory loss, neck weakness on flexion and extension, horizontal and down beating.14 weeks from symptoms onset: sudden worsening of true vertigo and dysphagia, hyper somnolence and gait ataxia

palidus and substantia nigra and both thalami (no available figure)

Negative OB

Probably not exposed on cell surface

and cyclophosphamide

19 Gesundheit (2008)(17)

M, 28 Hallucinations, incoherent speech,“bizarre” disorganized movements of the limbs

No Showed subtle mesial temporal hyperintensity on FLAIR

Not reported

Unremarkable

Not reported Thymectomy

IVIg

No residual symptoms

20 Graus (2008) - patient 4 (18) correspond to Lai (2009) - patient 5 (12)

F, 41 Behavior change, confusion

Not reported Not performed (diagnosis if limbic encephalitis performed on autopsy)

15 WBC Not reported

CRMP-5 (CV-2) and NSA antibodies, later proved to be AMPAR Abs (12)

No Death (2 weeks)

21 Monstad (2009)(19)

F,49 Progressive loss of memory for recent events

MGAchR antibodies

Bilateral hippocampal lesions on

10 WBCNegative OB

Epileptic discharges in both

CRMP5 Thymectomy, PLEX

Short memory deficits

FLAIR(after treatment)

temporal lobes

22 Hammound (2009)(20)

F, 43 Seizures (not refractory), confusion and rapidly progressive mutism

MGAchR antibodies

Numerous cortically based signal abnormalities on FLAIR as well as extensive left mesial temporal lobe abnormality with minimal enhancement

70 WBCprotein: 101 mg/dL with normal glucose level

Intermittent periodic lateralized epileptiform discharges in the left temporal region

VGKC Thymectomy, radiation, chemotherapy, corticosteroids, IVIg

Death (2 months)

23 Rizzardi (2009)(21)

F, 55 Seizure and aphasia

No T2/FLAIR multiple lesions located in insular, parietal and

temporal lobes (in cortical and sub-cortical area) including limbic and extra limbic system

Normal Focal epileptic discharges in temporal-parietal left region

No Thymectomy, Radiation

No residual symptoms and disease free

24 Werry (2009)(22)

M, 32 Vertigo, diplopia and nystagmus, clumsiness of the left hand, olfactory disturbances, progressive gait ataxia, myoclonic

MG developed after encephalitis

MRI1: normal

MRI 2(4 weeks later): spots of cortical hyperintensity of the insula bilaterally, the medial right

CSF (1): 4 WBCProtein 58 mg/dL Negative OBCSF (2): 25WBC

Showed epileptic changes

CRMP-5 Corticosteroids, Thymectomy, PLEX, IVIg

Almost complete recovery except for complaints of headache, fatigue. After on year developed diplopia and ptosis and was diagnosed as MG

jerking temporal lobe and in the left parieto-occipital region on T2-weighted images. No contrast enhancement.

Protein: 65 mg/dL

25 Erkmen (2010)(23)

M, 61 Seizure, memory loss

No Bilateral foci of cortical and subcortical non-enhancing signal abnormalities on T2 weighted images

Lymphocytic pleocytosis

Not reported

LGI1 Thymectomy, radiation, methylprednisolone, IVIg

No residual symptoms and disease free

26 Miyasaki (2012)(14,24)

M, 46 Subacute onset of aphasia, visual hallucination,and generalized seizures with delirium; residual thymoma

MGAchR antibodies

Axial T2-weighted brain MR image showing multifocal signal abnormality

Protein: 60 mg/dL

Electroencephalogram showed diffuse slow wave back- ground and theta (h) waves with epileptic discharges dominant in the left temporal lobe

VGKC (LGI1)Anti-GABAaR (14)

Corticosteroids and IVIg; AED

Epileptic seizures disappeared; severe cognitive impairment and psychological symptoms remained

27 Shaulov F, 66 Short term MG Multiple T2 Normal Normal Negative Thymectomy, No residual symptoms

(2012)(25) memory loss, grand mal seizure

AchR antibodies

weighted high signal hiperintensities in the hippocampi bilaterally, with no enhancement with gadolinium

anti-HU AED developed MG 18 years after encephalitis.

28 Aysal (2013)(26)

M, 43 3 secondarily generalized tonic-clonic seizureRefractory complex partial seizures

MGAchR antibodies

Hyper intense lesions on T2/FLAIR on the left temporo-parietal, left insular, left frontal subcortical white matter, and the right hippocampus without contrast enhancement

Normal Background activity was disorganized (7-9 Hz)

Negative for VGKC

IVIg, thymectomy, DAE

No residual symptoms

29 Suh (2013)(27) F, 42 Short-term memory loss, personality changes and severe agitation

MGAchR antibodies

Multifocal high intensity signals in the cerebral cortex including the limbic area on T2 flare images

Not reported

Diffuse delta background activity and moderate diffuse cerebral dysfunction

Negative for anti-Hu, anti-Ri and anti-Yo

Thymectomy, radiotherapy

No residual symptoms

30 Alexopoulos (2014)(28)

M, 25 Recurrent episodes of vertigo,

Normal 10 WBC, protein

Normal Hu, CV2, GABAb

Thymectomy, oral prednisolone,

Slight dizziness and vertigo in the supine position

dizziness, hiccups, nausea, and vomiting, tongue myoclonus

85, normal glucosePositive OB

PLEX, corticosteroids, azathioprine

FootnotesAchR antibodies to acetylcholine receptors; AED, anti-epileptic drugs; ANNA-1, type-1 anti-neuronal nuclear antibody; anti-neuronal Ab, anti-neuronal antibodies; AMPAR Abs , α -amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antibodies; ANA, antinuclear antibody; CRMP5, collapsin response mediator; CSF, cerebrospinal fluid; EEG, electroencephalogram; FLAIR, fluid attenuated inversion recovery; GAD, glutamic acid decarboxylase;ISAb, intrathecal synthesis of antibodies, IVIg, intravenous immunoglobulin G; LGI1, Leucine-rich Glioma Inactivated 1; MMSE, Mini-Mental State Examination; MRI, magnetic ressonance imaging; NSA, novel surface antigens; OB, oligoclonal bands; PLEX, plasma exchange; VGKC, Voltage-gated potassium channel antibody; WBC, white blood cell count;

a This patient had thymic carcinoma

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[Internet]. 2014 Oct 29 [cited 2014 Dec 4];1(4). Available from:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215391/