ARTICLES

Intrathecal Thyroid Autoantibody Synthesis in

a Subgroup of Patients With Schizophreniform
Syndromes
Dominique Endres, M.D., Rick Dersch, M.D., Benedikt Hochstuhl, Bernd Fiebich, Ph.D., Tilman Hottenrott, M.D.,
Evgeniy Perlov, M.D., Simon Maier, Ph.D., Benjamin Berger, M.D., Annette Baumgartner, M.D., Nils Venhoff, M.D.,
Oliver Stich, M.D., Ludger Tebartz van Elst, M.D.

Schizophreniform syndromes in combination with autoimmune thyroiditis and increased serum thyroid antibodies lead
healthcare practitioners to consider a diagnosis of Hashimoto’s encephalopathy. To detect specific biomarkers, the authors
analyzed whether intrathecal antithyroid antibody synthesis occurred in a subgroup of schizophreniform patients. In doing so,
the authors analyzed thyroid antibodies in paired cerebrospinal fluid and serum samples from 100 schizophreniform patients.
Increased antibody indices (AIs) for antithyroid peroxidase or antithyroglobulin autoantibodies in 13 schizophreniform pa-
tients were found. AIs were increased in 68% of the seropositive patients. These findings support the hypothesis that auto-
immune processes may contribute to the pathophysiology in these patients.
JNCN in Advance (doi: 10.1176/appi.neuropsych.16110296)

Schizophreniform syndromes are common phenomenolo- thyroid-stimulating hormone receptor antibodies) can be
gies in psychiatry. There are clinical phenotypes with dif- distinguished.3 Neuropsychiatric syndromes in combination
ferent combinations of delusional, hallucinatory, catatonic, with autoimmune thyroiditis should lead to the consideration
dysexecutive, amotivational, dysorganizational, or affective of a putative diagnosis of Hashimoto’s encephalitis (HE).3,10–13
symptoms. From a pathophysiological perspective, primary Several case reports supported the idea that HE can mimic
forms without and secondary forms with a recognizable schizophreniform syndromes.14–19 In patients with this con-
cause can be distinguished. Patients with primary forms of- dition, treatment with steroids can be very successful.3 In this
ten display familial liability probably as a result of a poly- case, HE is also called steroid responsive encephalopathy as-
genetic vulnerability. Secondary forms may be acquired sociated with autoimmune thyroiditis (SREAT).3,10–13
through substance abuse or a variety of brain disorders.1 Such
secondary brain disorders might be due to mild inflammatory
HOW TO DEAL WITH INCREASED ANTITHYROID
(e.g., immunological encephalopathies), neurodegenerative
AUTOANTIBODIES IN SCHIZOPHRENIFORM
(e.g., Huntington’s chorea), epileptic (e.g., paraepileptic psy-
DISORDERS
chosis, temporal lobe epilepsy), metabolic (e.g., porphyria),
vascular (e.g., vasculitis, strategic infarcts), or traumatic Increased serum thyroid autoantibodies were found in 13%
causes (traumatic brain injury).2 In the field of secondary of healthy individuals (more often in females and older
schizophreniform syndromes, immunological encephalop- patients).10,20 This observation complicates the question of
athies have received increased interest over the recent how we should deal with schizophreniform patients with
years due to the discovery that autoantibody-associated increased anti-TPO and/or anti-TG serum antibodies? Which
limbic and nonlimbic autoimmune encephalitis can mask additional findings should lead to corticosteroid treatment?
schizophrenia.3–9 In this context, antineuronal antibodies Should all such patients be diagnosed with HE and therefore
against intracellular synaptic antigens (GAD, amphiphysin), be treated with corticosteroids? The diagnostic criteria for
intracellular onconeural antigens (e.g., Yo, Hu, CV2/ CRMP5, HE do not fully answer these questions; they are inconsistent
Ri, Ma1/2, SOX1), neuronal cell surface antigens (e.g., and unspecific, and HE is still diagnosed by exclusion. Fol-
N-methyl-D-aspartate-R, AMPA-1/2-R, GABA-B-R, voltage lowing the German S1 guidelines (www.dgn.org), SREAT can
gated potassium channel-complex complex), and antithyroid be diagnosed if a patient presents encephalopathic symptoms
autoantibodies (thyroid peroxidase [TPO], thyroglobulin [TG], (i.e., subacute onset in addition to neuropsychiatric symptoms

JNCN in Advance neuro.psychiatryonline.org 1

INTRATHECAL THYROID AUTOANTIBODY SYNTHESIS

or other neurological symptoms) and increased thyroid auto- diagnostics. Only patients who gave their written consent
antibody levels plus positive response to corticosteroids (after were investigated.
exclusion of alternative causes with laboratory and cerebral
magnetic resonance imaging [cMRI] measurements).13 How- Study Sample
ever, following a recent position paper by Graus et al.,10 a We included 100 patients at our tertiary care hospital with
positive response to corticosteroids is no longer required. In- schizophreniform syndrome. Patients diagnosed with
stead, the authors use the term HE leaving the SREAT schizophreniform syndrome included those with schizo-
concept. They suggest considering corticosteroids for all phrenia (N=56), schizoaffective disorder (N=29), acute
patients with thyroid disease, elevated antithyroid anti- polymorphic psychotic disorder (N=14), and substance-
bodies, and nonspecific encephalopathy that cannot be induced psychosis (N=1). Only CSF/serum samples from
explained by another condition.10 However, in clinical patients with complete thyroid hormone status (thyroid-
practice it is difficult to decide whether to treat thyroid stimulating hormone [TSH], triiodothyronine [t3], and thy-
autoantibody positive schizophreniform patients with an- roxine [t4]) were included. For pragmatic reasons, we
tipsychotics, in accordance with the guidelines for schizo- selected the first 100 patients since 2006. The study included
phrenia (e.g., Nice guidelines [http://www.nice.org.uk]; 13 patients who underwent lumbar puncture between
German S3-Praxisleitlinie [www.dgppn.de]), or with off- 2006 and 2009 (i.e., CSF analysis was performed if there
label corticosteroids even after taking EEG and cMRI were signs of possible neuroinflammatory features). The
alterations into account. High-dose corticosteroid pulse other 87 patients underwent lumbar puncture since June
treatment may result in complete recovery, but it is not free 2009, when CSF analysis was offered as a routine procedure.
of side effects. Obviously, there is a need for more neurobi- The subgroups for the schizophreniform patient cohort
ological markers to guide the decision when to try immu- as well as number of instrument-based diagnostics are pre-
nomodulatory treatment. sented in Table 1. The diagnostic classification was per-
Given this problem, in the present study we analyzed in- formed by a board-certified psychiatrist following the ICD-10
trathecal thyroid autoantibody synthesis in order to identify a criteria.
possibly more specific biomarker for HE.
ELISA
Rationale of Our Study Paired CSF and serum samples were analyzed using an
In the Department of Psychiatry and Psychotherapy at the ELISA to identify anti-TPO and anti-TG antibodies. We used
University Medical Center Freiburg, we have traditionally commercially available Medizym anti-TPO and Medizym
analyzed cerebrospinal fluid (CSF) in patients with schizo- anti-TG ELISA kits (Medipan GmbH, 15827 Dahlewitz/
phreniform syndrome if they showed any signs of neuro- Berlin, Germany). We performed the ELISA according to the
inflammation (e.g., sudden onset, atypical clinical presentation, order of manufacturer’s instructions; however, since this
neurological symptoms, altered EEG and cMRI findings). assay is not validated for analyzing CSF samples, and we
Based on our experience with psychiatric patients suffering expected the titers of the thyroid antibodies to be very low,
from autoimmune encephalitis, we have offered CSF analy- we used undiluted CSF samples. The results of the mea-
sis as part of routine diagnostics since June 2009 for all surements in the CSF were adjusted to match the serum
patients with schizophreniform syndrome. Therefore, all dilution. Those serum samples exceeding the value limits
patients who consented were investigated since 2009. were controlled in a second assay to confirm the first positive
Moreover, we performed broad serum analyses (including finding. The AIs were only calculated if the second test was
thyroid hormone status), EEGs, and cMRI measurements in also positive.
our routine work-up for these patients.4,21 Based on these
experiences, we retrospectively performed paired antithy- Specific Antibody Index
roid antibody testing of CSF and serum samples and calcu- Measuring AIs allows the detection of intrathecal antibody
lated specific autoantibody indices (AIs) for the anti-TPO synthesis by distinguishing brain-derived fraction thyroid
and anti-TG antibodies.22,23 We hypothesized that we would antibodies from antibodies passively diffused out of the
find increased AIs in a subgroup of antithyroid antibody se- serum into the CSF. 22,23 The calculation of specific AIs
ropositive patients. For these patients, we planned to describe depends on parallel antibody testing of CSF and serum
our clinical, laboratory, and instrument-based findings in samples and the reference to the relevant quotient of total
detail. We also wanted to compare these findings between CSF/serum IgG in relation to blood-brain barrier (BBB)
patients with and without increased AIs. function (the albumin quotient is used as a reference
standard).22 AIs were calculated in the case of increased
antithyroid autoantibodies in the serum. The calculation of
METHODS
AIs was described in earlier papers.22–25 The normal range
The study received approval from the local ethics com- for AIs is 0.7–1.3.22 AI values .1.4 were assessed as in-
mittee of the University of Freiburg (EK-Fr 609/14). dicating intrathecal-specific antithyroid autoantibody syn-
Lumbar punctures were offered as part of patients’ routine thesis in our study.23

2 neuro.psychiatryonline.org JNCN in Advance

 ENDRES ET AL.

TABLE 1. Schizophreniform Subgroups and Instrument-Based two patients showed an increased AI for anti-TG-antibodies
Diagnostics (50%; AI: 1.84). Overall, we found increased thyroid autoan-
Schizophreniform Patient Cohort tibodies in 19 of 100 (19%) of the patients. One patient showed
(N=100) Number of Patients both increased anti-TPO and anti-TG antibodies in the serum
Schizophrenia 56 and increased AI only for anti-TPO antibodies (patient 3)
Schizoaffective disorder 29 (Table 4). Thirteen patients showed increased AIs. Increased
Acute polymorphic psychotic disorder 14
AIs were found in 68% of the seropositive patients.
Substance-induced psychosis 1
Diagnostic Measurements Number of Samples Clinical Characteristics of Schizophreniform Patients
Antithyroid peroxidase and anti- 100a With Increased AIs
thyroglobulin antibodies The age range of the sample with increased AIs varied from
CSF basis diagnostics (white blood cell 100
19 to 61 years, and mostly women were affected (11/13 pa-
count, protein concentration,
albumin quotient, and intrathecal tients [84.6%]). Increased AIs were found in one of 13 (7.7%)
immunoglobulin synthesis) patients in the nonscreened cohort (before June 2009) and
Electroencephalography data sets 100 in 12 of the 87 (13.8%) that underwent routine lumbar
Magnetic resonance imaging data sets 93 puncture (x2=0.263, p=0.608). Most patients with increased
a
Retrospectively analyzed in this study. AIs suffered from paranoid-hallucinatory schizophrenia
(6/13 [46%]) or schizoaffective disorder (6/13 [46%]). One
Data Handling and Statistical Analysis patient with an increased AI presented with an acute poly-
In earlier projects,4,26 we established a CSF database in- morphic psychotic disorder (1/13 patients [8%]). Six of
cluding all CSF findings since 2006, socio-demographic in- the 56 patients with schizophrenia showed increased AIs
formation, diagnoses, laboratory results, and cMRI and EEG (10.7%), while the other 51 patients had normal thyroid an-
ratings. The procedures we used to obtain CSF-based diag- tibodies or normal AIs (91.1%). In the schizoaffective group,
nostics and cMRI and EEG ratings were described earlier.4,26 increased AIs were found in six out of 29 patients (20.7%),
In our CSF-database, antithyroid-autoantibody findings from while 22 patients (75.9%) had normal thyroid antibodies or
serum and CSF were added. Statistical analyses were per- normal AIs. Of the 14 patients with acute polymorphic
formed using Statistical Package for the Social Sciences, psychotic disorder, only one showed increased AIs (7.1%),
version 22 (SPSS 22 [www-01.ibm.com/software/analytics/ while 13 had normal thyroid antibodies or normal AIs
spss]). The AIs of both groups were described in detail. Group (92.9%). The single patient with drug-induced psychosis was
comparisons for continuous variables (age, protein concen- antibody-negative. The chi-square test showed no significant
tration, etc.) were performed using two-sided independent differences in increased AIs between the diagnostic cate-
sample t tests. Group comparisons for categorical variables gories (x2 =2.349, p=0.503). Thyroid hormone status was
(gender, general cMRI alterations, AIs, etc.) were carried out normal in 10 of the 13 AI-positive cases (76.9%). Further CSF
using Pearson’s chi-squared test. Correlation analyses were analyzes showed BBB dysfunction in three samples (23%)
performed using the Pearson correlation coefficient. For all and displayed unspecific (identical pattern in CSF and se-
statistical analyses, a p value ,0.05 served as the criterion of rum) oligoclonal bands in two of 13 cases (15%). The cMRI
significance. For the correlation analyses, we did not perform showed alterations in nine of 13 cases (69%). The alterations
a Bonferroni correction for multiple tests because our analy- were most likely unspecific white matter lesions (in 38%)
ses were exploratory. (Table 5). EEGs were abnormal with intermittent slowing in
five of 13 cases (38%). One patient with slowing had addi-
tional spike waves in the EEG (8%) (Table 5).
RESULTS
Demographic Data Characteristics of Patients With Normal and
The patients’ mean age was 33.32 years (612.35 years) (ranging Increased AIs
from 18 to 66 years), and more were female than male (females, Females were significantly more likely to have increased an-
N=59; males, N=41). tithyroid AIs (p=0.044). Patients with and without increased
antithyroid AIs cannot be distinguished by the thyroid hor-
Thyroid Hormones and Antithyroid Antibody Findings mone status, CSF, and EEG findings separately. The cMRI
The patients’ thyroid hormone statuses are presented in alterations tended to be more frequent in the group with in-
detail in Table 2, and the autoantibody findings are pre- creased AIs (p=0.060) (Table 5).
sented in Table 3. In our cohort of schizophreniform pa-
tients, we found increased anti-TPO antibodies in the sera of
DISCUSSION
18 of the 100 patients (18%). Twelve of these 18 seropositive
patients (67%) showed increased AIs for anti-TPO anti- We found increased AIs for anti-TPO and anti-TG autoan-
bodies (ranging from 1.54 to 8.16). Anti-TG antibodies were tibodies in 13 schizophreniform patients. AIs were increased
found in the sera of two of 100 patients (2%). One of these in 68% of the seropositive patients. Therefore, we were able

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INTRATHECAL THYROID AUTOANTIBODY SYNTHESIS

TABLE 2. Thyroid Hormones and Autoantibody Findingsa autoantibodies to reach the

Hormones and Mean6SD Number of Frequency of CSF compartment in patients
Autoantibodies (N=100) Alterations Alterations Reference Values with normal BBB function.
Thyroid-stimulating 2.3962.24 ↔: 88 12% 0.27–4.20 mU/ml However, it remains unclear
hormone ↑: 9 whether intrathecal antibody
↓: 3 synthesis or only passive
Triiodothyronine 4.7360.90 ↔: 92 8% 3.4–6.8 pmol/l
transfer of blood-derived anti-
↑: 2
↓: 6 bodies to CSF is the origin
Thyroxine 16.6063.23 ↔: 94 6% 10.6–22.7 pmol/l of elevated antithyroid anti-
↑: 4 bodies in CSF. Therefore, it
↓: 2 might be necessary to calcu-
Antithyroid peroxidase 50.156104.96 ↔: 82 18% ,50 IU/ml
late patients’ AIs to investigate
antibodies in serum ↑: 18
Antithyroglobulin 14.87623.79 ↔: 98 2% ,100 IU/ml an intrathecal synthesis in-
antibodies in serum ↑: 2 dicating presence of antithy-
a
Abbreviations: ↑, increased; ↔, normal; ↓, decreased; SD, standard deviation.
roid specific autochthonous
B-cell clones within the cen-
tral nervous system (CNS). In
to confirm our working hypothesis that specific intrathecal a second study conducted by the Ferracci et al. group, they
antibody synthesis occurs in a subgroup of schizophreniform found increased specific antithyroid autoantibodies indices in
patients but also in a subgroup of patients with serum anti- nine antibody-seropositive patients with neurological mani-
bodies. Thus, the AI might be a more specific signal for sus- festations (e.g., confusion, impaired consciousness, ataxia,
pected HE than the presence or absence of serum antibodies paresis, paresthesias) of HE.31 However, the authors did not
alone. Significantly more female patients showed increased systematically compare their findings to the albumin quotient.
AIs, similar to previous HE cohorts.10 In patients with increased polyspecific intrathecal total
IgG synthesis, these procedures would lead to overestimation
Our Findings in the Context of Earlier Findings of the disruption of BBB function and underestimation of
Today, serum thyroid antibodies are the main indicator for AIs,23 although the authors still found unexpectedly high AI
considering the diagnosis of HE. However, elevated serum levels (varying from 5.8 to 314.5).31 It remains unclear whether
antithyroid antibodies are not disease-specific and are also these results can be applied to purely psychiatric (e.g.,
present in healthy subjects, as well as in patients with other schizophreniform) cohorts. In our cohort of schizophreniform
autoimmune diseases.10,28 In a large sample of U.S. citizens patients, we found increased AIs (varying from 1.54 to 8.16)
(17,353 people), serum thyroid antibodies were increased in in a relevant subgroup of 68% of antithyroid antibody se-
13% of healthy individuals (more often in females and older ropositive patients. The increased AIs we found were lower
patients).10,20 Therefore, they are unreliable as the sole cri- than those reported by Ferracci et al.31 Patients with in-
terion for detecting HE. CSF antibody synthesis (represented creased AIs were mostly female and showed more frequent
by AI) might be a better diagnostic marker. In a previous study cMRI alterations. EEGs did not help to distinguish patients
including six patients with HE and neurological manifesta- with and without increased AIs. Although this finding is
tions (e.g., confusion, paresis, ataxia, falls, myoclonic jerks), remarkable given the frequent EEG alterations reported in
the authors detected antithyroid autoantibodies in the CSF of earlier publications,11,32we recently published a case report
six patients with HE (independent of BBB function), but not of a female patient with a normal EEG that suffered from a
in a control group of 21 patients with different neurological purely psychiatric (i.e., affective) syndrome that turned out
conditions.29 High levels of CSF antithyroid autoantibodies to be caused by SREAT. We speculated that the normal
were also detected in the HE group of another study with EEG might be the consequence of a less severe variant of
10 neurological HE patients and 33 controls.30 From these SREAT without neurological deficits. The rate of increased
observations, one might conclude that it is possible for CSF protein concentration in only 23.1% of patients is also
lower, compared with a large
literature review on SREAT
TABLE 3. Thyroid Autoantibody Findings in the Entire Schizophreniform Syndrome Cohorta characteristics, in which in-
Serum creased protein levels were
Autoantibodies Specific Frequency of Increased
Antibody Type (N=100) Antibody Index Specific Antibody Indices
found in 82%.33 However, if
increased AIs are a marker
Antithyroid peroxidase ↑: 18 ↑: 12 In the entire cohort: 12%
antibodies ↔: 82 ↔: 88 b
In seropositive patients: 66.7%
for corticosteroid responsive-
Antithyroglobulin ↑: 2 ↑: 1 In the entire cohort: 1% ness in schizophreniform HE
antibodies ↔: 98 ↔: 99b In seropositive patients: 50% patients, they would be more
a
Abbreviations: ↑, increased; ↔, not increased. specific than serum autoanti-
b
Antibody indices were only calculated in the case of increased antithyroid antibodies in the serum. body levels. Our patients were

4 neuro.psychiatryonline.org JNCN in Advance

 TABLE 4. Clinical Characteristics of the Schizophreniform Patients With Increased Specific Antibody Indices (AIs)a
Age (Years), Gender, Serum AI Serum AI Overall
Item Syndrome Anti-TPO Anti-TPO Anti-TG Anti-TG Thyroid Status CSF cMRI EEG Alterations
1 19 years, female, 213.24 (↑) 2.11 (↑) ↔ ↔ TSH: ↔ Normal Asymmetry of ventricles; Interm. gen. slow AI TPO ↑

JNCN in Advance
schizoaffective T3: ↔ one isolated WM activity cMRI
disorder T4: ↔ lesion EEG
2 25 years; female, 66.60 (↑) 4.39 (↑) ↔ ↔ TSH: ↔ Normal Enlarged Virchow- Normal AI TPO ↑
paranoid- T3: ↔ Robin’s space cMRI
hallucinatory T4: ↔
schizophrenia
3 37 years; female, 216.87 (↑) 6.17 (↑) 126.23 (↑) ↔ TSH: ↔ Slight BBB-dysfunction Asymmetry of ventricles Interm. bitemporal AI TPO ↑
paranoid- T3: ↔ (protein concentration: with enlarged right theta/delta slowing CSF
hallucinatory T4: ↔ 532 mg/L; albumin lateral ventricle cMRI
schizophrenia quotient: 6.6b) EEG
4 49 years, female, 153.29 (↑) 1.84 (↑) ↔ ↔ TSH: 0,03 (↓) Normal Isolated unspecific white Normal AI TPO ↑
acute polymorph T3: ↔ matter lesions TH
psychotic T4: ↔ cMRI
disorder with
schizophreniform
symptoms
5 31 years, female, 62.96 (↑) 5.17 (↑) ↔ ↔ TSH: ↔ Normal Isolated unspecific Normal AI TPO ↑
paranoid- T3: ↔ frontal white matter cMRI
hallucinatory T4: ↔ lesions; asymmetry of
schizophrenia ventricles with
enlarged left lateral
ventricle
6 25 years, male, 88.25 (↑) 2.32 (↑) ↔ ↔ TSH: ↔ Normal Normal Interm. frontal AI TPO ↑
schizoaffective T3: ↔ slowing EEG
disorder T4: ↔
7 30 years, female, 697.28 (↑) 8.16 (↑) ↔ ↔ TSH: ↔ Normal Posttraumatic changes Normal AI TPO ↑
schizoaffective T3: ↔ with a right frontal cMRI
disorder T4: ↔ contusion lesion: right
side accentuated
gliosis of WM
8 24 years, male, 183.83 (↑) 2.38 (↑) ↔ ↔ TSH: ↔ Distinct BBB-dysfunction Normal Interm. general. AI TPO ↑
paranoid-hallucinatory T3: ↔ (protein concentration: theta/delta CSF
schizophrenia T4: ↔ 1510 mg/L; albumin slowing; rare EEG
quotient: 20.8) epileptic activity
9 49 years, female, 54.24 (↑) 3.76 (↑) ↔ ↔ TSH: 0.25 (↓) One isolated band in Isolated unspecific white Intermitt. general. AI TPO ↑
schizoaffective T3: ↔ CSF and serum matter lesions theta slowing TH
disorder T4: 23.40 (↑) CSF
cMRI
EEG
10 52 years, female, 319.53 (↑) 7.65 (↑) ↔ ↔ TSH: 6.83 (↑) Identical oligoclonal Normal Normal AI TPO ↑
schizoaffective T3: ↔ bands in CSF and TH
disorder T4: ↔ serum CSF

neuro.psychiatryonline.org
continued

5
ENDRES ET AL.
INTRATHECAL THYROID AUTOANTIBODY SYNTHESIS

not treated with corticosteroids; therefore, this question cannot

Abbreviations: ↑, increased; ↔, normal; ↓, decreased; AI, antibody index; CSF, cerebrospinal fluid; cMRI, cerebral magnetic resonance imaging; EEG, electroencephalography; TSH, thyroid-stimulating hormone;
Alterations
AI TPO ↑ be answered at present.

AI TPO ↑

AI TG ↑
Overall

cMRI

cMRI
CSF
Pathophysiological Meaning of Increased AIs
Increased AIs can be found in inflammatory neurological
conditions (e.g., herpes zoster, Lyme neuroborreliosis).22,27
For antibodies against intracellular synaptic antigens
(e.g., anti-GAD antibodies) and intracellular onconeural
EEG

antigens (e.g., anti-Yo antibodies), AIs have also been

shown to be effective in the detection of intrathecal anti-
Normal

Normal

Normal

body synthesis.24,25 Increased AIs allow semi-quantitative

evaluation of the intrathecal antigen-specific humoral im-
perivascular spaces in

mune reaction. Intrathecal antibody synthesis occurs as a

Slight increased protein Unspecific white matter
the basal ganglia on

consequence of activated plasma cell clones within the

CNS. Therefore, our results support the idea of central
Slightly enlarged
cMRI

autoimmunity in the pathophysiology of schizophreniform

both sides

patients with thyroid autoantibodies. However, it is still

lesions

unclear whether the thyroid anti-TPO and anti-TG anti-

Normal

bodies play an etiopathogenic role (i.e., cytopathic or func-

tional effects) or whether they are only an epiphenomenon
of underlying autoimmune processes, comparable with the
“MRZ reaction” in patients with multiple sclerosis.34,35 The
hypothesis of a direct etiopathogenic role of antithyroid au-
concentration
CSF

(556 mg/L)

toantibodies could be supported by cross-reactivity between

t3, triiodothyronine; t4, thyroxine; TG, thyroglobulin; TH, thyroid hormones; TPO, thyroid peroxidase; WM, white matter.

the thyroid gland and CNS epitopes.35 Findings in line with

Normal

Normal

this were provided by Blanchin et al.,30 who demonstrated

that anti-TPO antibodies in patients with HE can bind to
cerebellar astrocytes. In contrast, serum antibodies from
Anti-TG Thyroid Status

patients with only Hashimoto’s thyroiditis did not bind to

TSH: ↔

TSH: ↔

TSH: ↔

cerebellar tissue.30 In turn, astrocytes are important for

T4: ↔

T4: ↔

T4: ↔
T3: ↔

T3: ↔

T3: ↔

immunomodulation via cytokines and for glutamatergic

signaling, which might be associated with neuronal dys-
function and schizophreniform symptoms in a subgroup of
1.84 (↑)

patients with HE.35,36 To our knowledge, similar results

↔

↔
AI

have not been found for anti-TG antibodies. Clearly, further

Age-dependent reference value was 6,5310–3 in this case (see reference 27).

research is necessary. In particular, it would be interesting

112.67 (↑)

to clarify whether passive transfer of anti-TPO antibodies

Anti-TG
Serum

(from HE patients) produces the same symptoms in ani-

mal studies, which would contradict the hypothesis that
such antibodies are a pure epiphenomenon. Moreover, re-
Anti-TPO Anti-TPO
1.54 (↑)

1.67 (↑)

searchers should analyze the binding sites of antithyroid

↔
AI

autoantibodies on brain slices and whether immunization

with putative antigens allows the development of an animal
model for HE.30
96.02 (↑)
166.91 (↑)
Serum

The Role of Antithyroid AI Measurement in Diagnostic

Procedures
paranoid-hallucinatory

paranoid-hallucinatory
Age (Years), Gender,

Thyroid antibodies should be measured independently of

thyroid hormone status, as we found normal thyroid hormone
schizoaffective
61 years, female,
Syndrome
21 years, female,

21 years, female,
schizophrenia

schizophrenia

levels in 10 of 13 patients with thyroid autoantibodies. Based

on the results of this study and earlier studies by our group,4,21
TABLE 4, continued

disorder

we suggest a broad routine work-up for schizophreniform

patients with increased thyroid antibodies. The routine
work-up should include a cMRI (to detect white matter
Item

lesions or other nonspecific alterations), an EEG (to detect

12

13
11

frequent slowing or epileptic activity), neuropsychological

b
a

6 neuro.psychiatryonline.org JNCN in Advance

 TABLE 5. Laboratory and Instrument-Based Findings in Patients With and Without Increased Antithyroid Antibody Indices (AIs)a
Patients With Increased AIs (N=13) Patients With Normal AIs (N=87)
p
Frequency Frequency
Measurement Mean6SD Number of Cases of Alterations Mean6SD Number of Cases of Alterations Statistics

JNCN in Advance
Serumb
TSH 2.2961.90 ↔: 10 23.1% 2.4062.29 ↔: 78 10.3% p=0.865
↑: 1 ↑: 8
↓: 2 ↓: 1
(range: 0.03–6.83) (range: 0.06–19.32)
T3 4.6660.81 0% 4.7460.92 ↔: 79 9.2% p=0.784
↔: 13 ↑: 2
↑↓: 0 ↓: 6
(range: 3.84–6.52) (range: 2.43–7.20)
T4 17.2962.67 7.7% 16.5063.31 ↔: 82 5.7% p=0.410
↔: 12 ↑: 3
↑: 1 ↓: 2
(range: 12.50–23.40) (range: 9.20–26.30)
CSFb
White blood cell count 1.4660.66/ml 1–4 cells: 0% 2.2966.32/ml 1–4 cells: 2.3% p=0.639
13 84
$5 cells: $5 cells: 2
0 (range: 1–59 cells/ml)
(range: 1–3 cells/ml)
Protein concentration 432.626341.72 mg/l ↔: 10 23.1% 450.396303.39 mg/l ↔: 51 41.4% p=0.847
↑: 3 (range: ↑: 36 (range:
206–1510 mg/l) 165–2890 mg/l)
Albumin quotient 5.5864.78 ↔: 11 15.4% 5.8064.17 19.54% p=0.867
↑: 2 ↔: 70
(range: 2.50–20.8) ↑: 17 (range:
2.00–38.70)
Immunoglobulin-G-index 0.4860.05 mg/l ↔: 13 0% 0.5060.08 mg/l ↔: 85 2.3% p=0.558
↑: 0 ↑: 2
(range: 0.41–0.61 mg/l) (range: 0.42–0.95 mg/l)
Oligoclonal bands No: 11 15.4% restricted to No: 80 8% restricted to
Yes: 2 (restricted to CSF: 7.7% mirror Yes: 7 (restricted to CSF: 2.3% mirror pattern:
CSF: 1; OCBs mirror pattern: 7.7% CSF: 2; OCBs mirror 5.7%
pattern: 1) pattern: 5)
Number of Cases Frequency Number of Cases Frequency Statistics
c
cMRI
White matter lesions/ 5/13 38.5% 19/80 23.8%
cerebral microangiopathy
Generalized cortical 0/13 0% 3/80 3.8%
atrophy
Localized cortical atrophy 0/13 0% 1/80 1.3%
Other alterations 1/13 7.7% 5/80 6.3%
continued
ENDRES ET AL.

neuro.psychiatryonline.org 7
INTRATHECAL THYROID AUTOANTIBODY SYNTHESIS

testing (to identify frequent cognitive impairments and as a

Abbreviations: ↑, increased; ↔, normal; ↓, decreased; cMRI, cerebral magnetic resonance imaging; CSF, cerebrospinal fluid; EEG, electroencephalography; t3, triiodothyronine; t4, thyroxine; TSH, thyroid-
Statistics

p=0.060

p=0.533
follow-up parameter during corticosteroid treatment), CSF
diagnostics (to detect BBB dysfunction, increased white
blood cell count, or oligoclonal bands), and autoantibody
measurements (onconeural/synaptic and cell surface anti-
gens). In cases where SREAT is suspected, an analysis of
anti-TPO and anti-TG antibodies in CSF with additional
calculation of respective AIs could produce additional in-
Frequency

formation in the diagnostic process. Earlier studies showed

23.0%

3.4%
6.3%

2.3%

1.1%
that a specific AI seems to be a marker for HE.29,31 We also
0%

found increased AIs in a subgroup of schizophreniform pa-

tients. However, further research is needed to determine
whether an elevated AI is a prognostic marker for steroid
responsiveness and/or long-term prognosis of the disease
course in such patients.

Limitations
The main limitation of our study is that it was uncontrolled,
as we did not analyze a healthy control group for compari-
Number of Cases

son. However, it would not be ethically justifiable to perform

Only the predominant EEG/cMRI alteration was depicted, EEG and cMRI alterations were compared using Pearson’s chi-squared tests.
Yes: 26
Yes: 33
No: 47

No: 61

lumbar punctures on healthy controls due to potential

5/80

2/87

3/87
20/87
0/87

1/87

complications. Since we included patients since 2006 (be-

fore we introduced CSF analyses as a standard procedure),
the cohort is not representative of all schizophreniform
patients. There was a potential selection bias, as we included
only patients at a tertiary care hospital for whom CSF and
serum material, as well as full thyroid hormone status, were
available. Another limitation is that we focused on thyroid
antibodies; however, patients with autoimmune disorders
may harbor a panoply of antibodies that might also play a
Frequency

pathophysiological role. Future studies should combine

7.7%

7.7%
23.1%

23.1%

measurements of different, potentially relevant antibodies.

0%

0%

One patient with negative antibodies suffered from drug-

Serum and CSF values ware compared using two-sided independent sample t tests.

induced psychosis, and substance abuse could sufficiently

explain this patient’s symptoms. Future studies should an-
alyze more homogenous cohorts without obvious explana-
tions for their psychiatric symptoms. In addition, it could be
interesting to investigate whether drug consumption might
lead to BBB dysfunction, allowing thyroid antibodies to
transfer into the CNS. With regard to methodology, one
Number of Cases

criticism may be that the assays were not established for

CSF. However, since there are no established measure-
Yes: 9

Yes: 5
No: 4

No: 8
0/13
3/13

1/13

1/13
0/13

3/13

ments for thyroid antibody in CSF, no validated assays were

available. Future projects should close this gap. The patients
were treated primarily with antipsychotics, and sometimes
with anticonvulsants, following the guidelines for schizo-
phrenia. Only recently have we started to do treatment at-
tempts with intravenous steroids in such constellations.
Intermittent generalized

Therefore, none of the patients in our sample had received

Continuous generalized

Intermittent regional

such a steroid treatment, and thus we were unable to analyze

Continuous regional
Anatomic variations

stimulating hormone.
Overall alterations

Overall alterations
TABLE 5, continued

difference in response to steroids between patients with and

Epileptic activity
slow activity

slow activity

slow activity

slow activity

without abnormal AIs. Our results might be influenced by

the effects of antipsychotic/anticonvulsant medications, for
which no correction was performed. Additionally, the sta-
EEGc

tistical analysis of possible group effects between patients

with and without elevated AIs might have produced false
b
c
a

8 neuro.psychiatryonline.org JNCN in Advance

 ENDRES ET AL.

negative results because of the small size of the AI positive 4. Endres D, Perlov E, Baumgartner A, et al: Immunological findings
group (N=13). in psychotic syndromes: a tertiary care hospital’s CSF sample of
180 patients. Front Hum Neurosci 2015; 9:476
5. Endres D, Perlov E, Stich O, et al: Steroid responsive encepha-
lopathy associated with autoimmune thyroiditis (SREAT) pre-
CONCLUSIONS senting as major depression. BMC Psychiatry 2016; 16:184
In summary, we were able to detect increased antithyroid 6. Endres D, Perlov E, Stich O, et al: Hypoglutamatergic state is
associated with reduced cerebral glucose metabolism in anti-
specific AIs in a relevant subgroup of our cohort of schizo- NMDA receptor encephalitis: a case report. BMC Psychiatry
phreniform patients and also in the subgroup of those 2015; 15:186
schizophrenia patients with positive serum thyroid anti- 7. Endres D, Perlov E, Stich O, et al: Case report: low-titre anti-Yo
bodies. Therefore, the signal of intrathecal thyroid antibody reactivity in a female patient with psychotic syndrome and
detection might be more specific than the analysis of serum frontoparieto-cerebellar atrophy. BMC Psychiatry 2015; 15:112
8. van Elst LT, Klöppel S, Rauer S: Voltage-gated potassium channel/
antibodies alone. The fact that we found increased AIs
LGI1 antibody-associated encephalopathy may cause brief psy-
supports the hypotheses that intrathecal synthesis of anti- chotic disorder. J Clin Psychiatry 2011; 72:722–723
thyroid autoantibodies occurs in schizophreniform patients 9. Normann C, Frase L, Berger M, et al: Steroid-responsive de-
and that autoimmune processes might play a pathophysio- pression. BMJ Case Rep 2013; 2013:bcr2013009101
logical role in these patients. Further research is needed to 10. Graus F, Titulaer MJ, Balu R, et al: A clinical approach to diagnosis
of autoimmune encephalitis. Lancet Neurol 2016; 15:391–404
determine whether increased AIs are a prognostic marker
11. Castillo P, Woodruff B, Caselli R, et al: Steroid-responsive en-
for corticosteroid response and disease course. cephalopathy associated with autoimmune thyroiditis. Arch Neurol
2006; 63:197–202
AUTHOR AND ARTICLE INFORMATION 12. Degner D, Haust M, Meller J, et al: Association between autoim-
From the Section for Experimental Neuropsychiatry, Department for
mune thyroiditis and depressive disorder in psychiatric outpa-
Psychiatry & Psychotherapy, University Medical Center Freiburg, Freiburg,
tients. Eur Arch Psychiatry Clin Neurosci 2015; 265:67–72
Germany (DE, BH, BF, EP, SM, LTvE); the Department for Neurology,
13. Bien C: Immunvermittelte Erkrankungen der grauen ZNS-Substanz
University Medical Center Freiburg, Freiburg, Germany (RD, TH, BB, AB,
sowie Neurosarkoidose: S1-Leitlinie. Leitlinien für Diagnostik und
OS); and the Department of Rheumatology and Clinical Immunology,
Therapie in der Neurologie. http://www.dgn.org/leitlinien-online-2012/
University Medical Center Freiburg, Freiburg, Germany (NV).
inhalte-nach-kapitel/2396-ll-32-2012-immunvermittelte-erkrankungen-
der-grauen-zns-substanz-sowie-neurosarkoidose.html
Send correspondence to Dr. Endres; e-mail: dominique.endres@uniklinik- 14. Guirgis H, Amar C: A case of Hashimoto’s encephalopathy pre-
freiburg.de senting with acute psychosis. J Neuropsychiatry Clin Neurosci 2014;
Drs. Endres and Dersch share first authorship and contributed equally to 26:E1–E2
this study. 15. Lee MJ, Lee HS, Hwang JS, et al: A case of Hashimoto’s en-
Drs. Stich and Tebartz van Elst contributed equally to this study. cephalopathy presenting with seizures and psychosis. Korean J
Pediatr 2012; 55:111–113
Supported by the Department for Psychiatry and Psychotherapy of the
16. Lin YT, Liao SC: Hashimoto encephalopathy presenting as
University Medical Center Freiburg.
schizophrenia-like disorder. Cogn Behav Neurol 2009; 22:197–201
BF has received grant and research support from Bayer Vital GmbH. TH 17. Prat S, Jouan Y, Magnant J, et al: Hashimoto encephalopathy di-
has received travel grants from Bayer Vital GmbH and Novartis. BB has agnosis after 40 years of a schizophrenia-like disorder. Schizophr
received travel grants from Bayer Vital GmbH, Ipsen Pharma GmbH, and Res 2012; 139:269–270
Genzyme. AB has received consulting and lecture fees, as well as grant 18. Wilcox RA, To T, Koukourou A, et al: Hashimoto’s encephalopathy
and research support, from Bayer Vital GmbH, Biogen Idec, Merck masquerading as acute psychosis. J Clin Neurosci 2008; 15:
Serono, Novartis, Sanofi-Aventis, and Teva. NV has served on advisory 1301–1304
boards of, has participated in lectures for, and/or received research or 19. Arrojo M, Perez-Rodriguez MM, Mota M, et al: Psychiatric pre-
travel grants from AbbVie, GSK, Janssen-Cilag, Medac, Novartis, and sentation of Hashimoto’s encephalopathy. Psychosom Med 2007;
Roche. OS has received consulting and lecture fees and grant and re- 69:200–201
search support from Bayer Vital GmbH, Biogen Idec, Genzyme, Merck 20. Hollowell JG, Staehling NW, Flanders WD, et al: Serum TSH, T(4),
Serono, Novartis, Sanofi-Aventis, and Teva. LTvE has served on advisory and thyroid antibodies in the United States population (1988 to 1994):
boards of, has participated in lectures for, and/or received travel grants National Health and Nutrition Examination Survey (NHANES III). J
from Cyberonics, Eli Lilly, GlaxoSmithKline, Janssen, Janssen-Cilag, Clin Endocrinol Metab 2002; 87:489–499
Novartis, Servier, Shire, and UCB. All other authors report no financial 21. Endres D, Perlov E, Feige B, et al: Electroencephalographic find-
relationships with commercial interests. ings in schizophreniform and affective disorders. Int J Psychiatry
Received Nov. 3, 2016; revision received Dec. 17, 2016; accepted Jan. Clin Pract 2016; 20:157–164
11, 2017. 22. Reiber H, Peter JB: Cerebrospinal fluid analysis: disease-related
data patterns and evaluation programs. J Neurol Sci 2001; 184:
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