Follow-up and prognosis of the anti-LGI1 encephalitis with and
without teratoma and anti-NMDAR encephalitis with teratoma
We followed the anti-LGI1 encephalitis patient with teratoma for five
months; one patient in the NT group was lost to follow up after
discharge, but the other eight were followed for an average of 26.1±12.0
months; and the three anti-NMDAR encephalitis patients
for average 27.0±17.8 months.
Teratoma was all asymptomatic in the four AE cases, which was diagnosed
through routine gynecologic examination before admission in one patient
and diagnosed because of aetiological screening for AE in the other
three. After immunotherapy and removal of the teratoma, the teratoma
associated anti-LGI1 and anti-NMDAR encephalitis patients recovered,
becoming seizure-free and living independently, especially 67% of
anti-NMDAR encephalitis recovered fully (mRS=0) without symptom.
Similarly, immune therapy (MPT, IVIG, plasma exchange and/or
immunosuppressant) was effective in 78% of the NT group; one patient
died of pneumonia because of comorbid myasthenia gravis and one patient
died of hepatic failure due to chronic schistosomiasis liver disease and
hepatitis B, deteriorated after MPT followed by oral azathioprine. None
of the patients relapsed within the follow-up period.
Discussion
Unlike anti-NMDAR encephalitis, anti-LGI1 encephalitis is a subtype of
AE with heterogenous clinical manifestations, rarely comorbid with
tumor[12, 14]. To our knowledge, ours is the first reported case of
anti-LGI1 encephalitis with teratoma. By comparing this case with other
cases of anti-LGl1 encephalitis without teratoma in our center, we have
derived several possible diagnostic biomarkers of anti-LGI1 encephalitis
in hopes of promoting its early diagnosis.
The mechanism of anti-LGI1 encephalitis is mediated by pathogenic
auto-antibodies, which directly attack presynaptic and postsynaptic
protein complexes[2]. Although limited data indicates the
correlation of tumor and anti-LGI1 encephalitis, one study showed that
less than 10% of patients have tumors, including thymoma, thyroid, lung
and renal cell tumors[13, 14]. We think that anti-LGI1 encephalitis
was associated with the teratoma in our case for several reasons: 1) IHC
staining confirmed that partial or focal positive nuclear staining of
LGI1 was appreciated in some tumor cells. Although by Karen Head et al’s
work, LGI1 did not express in normal mice thyroid[17], we think the
positive expression of LGI1 in the tumor cells of teratoma in our case
is still reasonable, based on reasons below: a) considering the nature
of benign germ cell tumor of struma-ovarii in this case, the neoplastic
thyroidal follicular cells were different from cells in normal thyroid
and may acquire the abnormal expression of LGI1 protein during the
development of teratoma; b) based on the reported immunohistochemical
images from the article by Karen Head et al[17], Fig3 B showed
positive staining of LGI1 within the ovarian follicle-like structure,
suggesting its possible expression in the germ cells. Although normal
thyroid tissue derived from the endodermal layer typically showed
negative LGI1 expression, the possibility of positive expression of LGI1
in some neoplastic thyroidal follicular cells within the struma-ovarii
cannot be totally excluded. 2) pathological results indicated that
teratoma tissue mainly consisted of thyroid gland, which is susceptible
to immunological attack and easily promotes the generation of various
antibodies as antigen[18] (additionally, thyroid cancer can be
comorbid with anti-LGI1 encephalitis [13, 14]); 3) after removal of
the teratoma, her cognitive function recovered greatly; and 4) many
reports about AE or PLE associated with ovarian teratoma have been
published since 1998, including Yang Y.W. et al ’s case of
episodic dystonia highly consistent with characteristic FBDS described
in anti-LGI1 encephalitis today[19-25].
The most representative and high-incidence subtype of AE associated with
teratoma was anti-NMDAR encephalitis; NMDA receptor-expressing neurons
have been described in the neural tissue within teratoma, which was
pathogenetic of anti-NMDAR encephalitis [26]. Unlike NMDA receptors,
which are the extracellular domain of the GluN1 subunit[27], LGI1 is
not a structural component of a receptor or ion channel, but is rather
secreted by neurons, perhaps explaining why the incidence of tumor is
much lower in anti-LGI1 encephalitis compared with anti-NMDAR
encephalitis. Nevertheless, LGI1 forms a trans-synaptic complex with
presynaptic proteins and is involved in synaptic transmission of
neuronal excitability[28], so anti-LGI1 encephalitis may still be
comorbid with tumors such as teratoma.
Summary data from our case series indicates similar clinical
manifestations as seen in many larger series. These specific
manifestations are probably early diagnostic clues to anti-LGI1
encephalitis, including, 1) acute or sub-acute onset of RPD in
relatively older aged population[3, 29, 30], 2) FBDS[3, 29, 31],
3) hyponatremia[3, 30] and 4) hyperintensity of bilateral
hippocampus on T2 and T2-FLAIR MRI[3, 29].
More importantly, our anti-LGI1 encephalitis case with teratoma
presented several specific features that might differentiate it from
other subtypes of AE, but perhaps even other cases of anti-LGI1
encephalitis without teratoma, and might therefore be clues. First of
all, her chronic onset of anxiety has never been reported in other
subtypes of AE by our best knowledge. For anti-NMDAR encephalitis, 86%
of 100 cases presented headache, fever of a non-specific viral-like
illness as prodromal symptom in one case series report[32], and in
another study anti-NMDAR encephalitis patients developed psychiatric
symptom and short term memory loss in less than two weeks[33]. 77%
of 22 anti-GABABR encephalitis patients presented
isolated recurrent seizure at onset[34].
In 76 LGI1 antibody positive
patients, only 2.6% presented isolated anxiety as initial symptom and
the median duration time for isolated initial symptoms was 2
months[35].
Secondly, seizure is one of the most common symptoms of AE, but the
clinical manifestation varies among different subtypes. The incidence of
seizure in anti-NMDAR encephalitis and anti-GABABR
encephalitis is the highest, followed by anti-LGI1 and anti-AMPA
encephalitis. Whereas the most typical seizure type with diagnostic
specificity is FBDS in anti-LGI1 encephalitis, seen in almost half of 39
confirmed cases, FBDS were not seen in our case with teratoma[3].
Anti-NMDAR encephalitis has more seizure types at onset; a study of
seven cases found that 43% had GTCS, 43% had focal seizures and 14%
had both simultaneously [36]. Seizure was relatively uncommon in
anti-AMPA encephalitis (20% of patients), typically GTCS[37]. SE is
seen more often in anti-GABA encephalitis, based on the limited
literature: seen in 58% of one series of 12 anti-GABAAR
encephalitis cases[38] and 27% in another series of 11 confirmed
GABABR encephalitis subjects[39], compared with only
6% of 100 anti-NMDAR encephalitis patients[40] and 5% of 19
anti-LGI1 encephalitis patients[41]). Interestingly, our case with
teratoma developed SE on her 8th day of admission. We
think there are two interpretations, 1) SE may be more typical in
anti-LGI1 encephalitis with teratoma and 2) the patient’s immunotherapy
started relatively late, one month after onset of RPD, facilitating the
development of SE.
Thirdly, the persistent short term memory impairment until 5 months
following the acute disease stage in our patient was highly consistent
with reported anti-LGI1 encephalitis. One study found 62% of 85
LGI1/CASPR2-IgG-positive patients with central involvement had residual
cognitive and personality disturbances[15]. Another study revealed
that 23% of 76 patients with LGI1 antibody positive had moderate or
severe cognitive impairment at two years follow-up[35]. Recovery
from cognitive and neuropsychological symptoms is quicker and more
complete in other forms of AE. 75% of 100 confirmed patients with
ani-NMDAR encephalitis showed full recovery (mRS 0, MMSE 29-30) or very
mild functional deficits (mRS 1-2, MMSE 25-28) at median 17 months
(range 1-194 months) follow-up[32]. This is consistent with our
three anti-NMDAR encephalitis, which presented fully recovery in 67% of
cases. Serial observation of patients with anti-GABABR
encephalitis indicated that 35% recovered fully and 40% improved
markedly, except for recurrent seizures in 50% of 20 cases comorbid
with SCLC[42]. Our case suggested that the cognitive deficits in
anti-LGI1 encephalitis might need longer time to recover than those in
anti-NMDAR or GABABR encephalitis.
Overall, given our experience with our small anti-LGI1 encephalitis
cohort, we suggest that physicians should consider the diagnosis of
anti-LGI1 encephalitis, and screen for the existence of teratomas, in
patients with chronic onset of mood disorders followed by RPD, SE and
psychiatric symptoms. Early diagnosis is vital because immunotherapy was
effective in anti-LGI1 encephalitis and if instituted early might avoid
deterioration and need for ICU management. Further illumination of
specific clinical biomarkers of anti-LGI1 encephalitis with teratoma
will require collection of more cases.