Journal of the Neurological Sciences 288 (2010) 194–196

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Journal of the Neurological Sciences
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s

Short communication

Clinical manifestations, diagnostic criteria and therapy of Hashimoto's
encephalopathy: Report of two cases
Milija Mijajlovic a,⁎, Mihailo Mirkovic b, Jelena Dackovic a, Jasna Zidverc-Trajkovic a, Nadezda Sternic a
a
b

Institute of Neurology, Clinical Center of Serbia, Dr Subotica 6, 11000 Belgrade, Serbia
Department of Neurology, General hospital Valjevo Sindjeliceva 62, 14000 Valjevo, Serbia

a r t i c l e

i n f o

Article history:
Received 21 July 2009
Received in revised form 23 September 2009
Accepted 28 September 2009
Available online 28 October 2009
Keywords:
Hashimoto's encephalopathy
Clinical presentation
Diagnostic criteria
Therapy

a b s t r a c t
Hashimoto's encephalopathy (HE) is a rare, still not well understood, autoimmune disease with neurological
and psychiatric manifestations. and elevated titers of antithyroid antibodies in serum and cerebrospinal fluid
(CSF) as a hallmark of the disease. Patients are mostly women. Current diagnostic criteria include corticosteroide
responsiveness, but it is the case in only 50% of patients with HE. In steroid non-responders other immunomodulatory therapies or plasmapheresis could be applied. Disease course can be acute, subacute, chronic or
relapsing-remitting. Two distinct forms emerged from the reported cases: a vasculitic type characterized by
multiple relapsing-remitting stroke-like episodes and mild cognitive impairment and a diffuse progressive type
characterized by dementia and psychiatric symptoms. Both forms may be accompanied by depressed level of
consciousness (stupor or coma), tremor, seizures, or myoclonus. We present two patients with two distinct forms
of HE who had different clinical manifestations and response to therapy.
© 2009 Elsevier B.V. All rights reserved.

1. Introduction
Since the first description of this encephalopathy by Brain et al. [1]
40years ago, just about 100 cases have been reported [2]. HE is characterized by various neuropsychological symptoms, including cognition
and/or consciousness deterioration, personality changes, seizures and
myoclonus [3–7]. Recently, this entity has attracted growing attention
because it is included in the group of treatable dementias [5], and [8],
it has also been recognized as one of the most important items for
differential diagnosis of Creuzfeldt–Jakob disease [9–11]. Although autoimmune mechanisms are thought to play a pathogenetic role in
HE, the etiology of the disease is still incompletely understood. It is
closely associated with Hashimoto's thyroiditis (HT) and is thought to
be caused by disorders of immune mechanisms. Most recent reports
argue in favor of an inflammatory response to antineuronal antibodies
[12,13].
Generally accepted diagnostic criteria are based on the presence
of: cognitive impairment with or without neuropsychiatric symptoms;
seizures; stroke-like events; focal neurological deficit or movement
disorders; elevated antithyroid antibodies; and corticosteroid responsiveness [3]. Approximately 50% of HE cases have focal or diffuse nonenhancing brain magnetic resonance imaging (MRI) abnormalities and
50% respond to corticosteroid therapy.

⁎ Corresponding author. Tel.: +381 11 2887348; fax: +381 11 2684 577.
E-mail address: mmijajlovic@mail.neurologija.bg.ac.yu (M. Mijajlovic).
0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2009.09.030

On neurological examination, pyramidal tract signs without clear
focal deficit are frequently found. Investigation of these patients characteristically shows diffuse electroencephalogram (EEG) abnormalities
and high CSF protein levels without pleocytosis, although the most
relevant issue is the high titre of antithyroid antibodies found in most
cases [3]. Since there are no clinical, laboratory or neuroimaging findings
that are specific for this entity, the exhaustive exclusion of infectious,
metabolic, toxic, vascular, neoplastic and paraneoplastic causes of encephalopathy is mandatory.
We present two new cases with two distinct forms of HE: first with
vasculitic or stroke-like type and second with diffuse progressive type.

2. Case 1
A 56-year-old woman with a history of relapsing stroke-like
episodes of limbs weakness, especially legs, walking difficulties, tremor
of arms and legs, cognitive and psychiatric changes, had 3 similar
episodes during 2 years, and she was treated at the Institute of Neurology of the Clinical Center of Serbia in Belgrade. All episodes of limb
weakness were of sudden onset. In the physical examination, the patient
usually exhibited spontaneous and stimulus-induced myocloni in both
arms and legs, she had severe paraparesis, inability to seat, stand or
walk and she was extremely agitated, with visual hallucinations. Episodes of agitation lasted for several hours and were followed by somnolence lasting sometimes even up to 24 h. The patient showed marked
memory loss, and she reached 10 of 30 points in the Mini Mental State
examination. The cranial MRI was normal and the EEG showed diffuse
slowing without triphasic potentials. The CSF showed elevated total

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195

protein content (90 mg/dl), no pleocytosis and negative oligoclonal
bands. There was no 14-3-3 protein in the CSF and we could not detect
any antithyroid antibodies in the CSF.
In spite of intensive serological screening for infectious, toxic,
paraneoplastic and metabolic etiologies, none could be determined.
Routine blood tests, the levels of antinuclear and anti-DNA antibodies,
angiotensin-converting enzyme, T3, T4, TSH and serum B12 and folic
acid were normal. The serologic tests for borreliosis, syphilis and HIV
were negative. The level of antithyroid peroxidase antibodies (TPOAb) in serum was raised (5250 IU/ml; normal < 50 IU/ml), while titer
of antithyreoglobulin antibodies (TG-Ab) in serum was normal. She
had HT which was histologically confirmed.
Following a high dose glucocorticoid therapy (methyl-prednisolone
1000 mg i.v.) over 5 days, the symptoms receded completely in all three
relapses, with normalisation of EEG and serum level of antithyroid
antibodies within 3–6 weeks. Subsequently, the methyl-prednisolone
was tapered off within 6 weeks. At the same time, after last relapse, an
immunsuppressive therapy with azathioprine was started, and she is
taking it continuously until now. One year has passed after last relapse
without new neuropsychiatric exacerbations and the patient returned
to work and everyday activities.

3. Case 2
A 75-year-old woman with slowly progressive memory loss during
last 3 years, disorientation in space and time, lack of concentration,
agitation and myocloni was admitted at the Neurology Department
of General Regional Hospital in Valjevo. Past medical history revealed
only a mild hyperthyroidism and HT which was proved by needle
biopsy. In the Mini Mental Test she reached 20 of 30 points and detailed
neuropsychological testing showed impairment of attention, declarative memory and executive functions. She was frequently confused with
several episodes of moderate agitation lasting for several days. She
had no focal motor, sensory, cranial nerve, or cerebellar abnormalities.
Routine blood test, imunoserology, VDRL, TPHA, HIV, antibodies against
Borelia burgdorferi, and serum vitamine B12 levels were normal.
Thyroid status showed euthyreosis with high titers of TG-Ab and TPOAb in serum (7884 IU/ml; normal <30 IU/ml and 8540 IU/ml, normal<50 IU/ml; respectively). In the CSF, by enzyme-immunoassay, we
detected an elevated level of TPO-Ab:1133 IU/ml; (normal level:0);
albumin CSF/serum quotient (Qalb) corrected by age was 7.7; (normal
range: <9). The calculated intrathecal TPO-Ab index was 12.4, thus was
suggestive of autochthone synthesis of thyroid autoantibodies in the CSF.
Angiotensin-converting enzyme in serum and CSF was in the normal range. Markers of autoimmune diseases were negative, including normal antinuclear antibody, rheumatoid factor level, anti-double
stranded DNA antibody, anti-SS-A antibody, anti-SS-B antibody, anticardiolipin antibody and myeloperoxidase anti-neutrophil cytoplasmic
antibody.
No clotting abnormalities were detected.
There was no CSF evidence of bacterial or viral infection, as determined
by culture or molecular analysis, but total protein content was elevated
(79 mg/dl) with parallel oligoclonal bands in CSF and serum. CSF showed
normal pressure.
The EEG showed diffuse slowing without triphasic potentials and
cranial MRI showed mild diffuse periventricular white matter hyperintensities on fluid-attenuated inversion recovery (FLAIR) and T2W
images (Fig. 1).
She was treated with high dose glucocorticoid therapy (methylprednisolone 1000 mg i.v.) over 5 days, with tapering during 4 weeks
but without clinical improvement.
Then an immunsuppressive therapy with azathioprine was introduced. Serum level of antithyroid antibodies was normalised, but in CSF it
remained high and it correlated with no significant clinical improvement
during 6 months of treatment and follow-up.

Fig. 1. Cranial MRI: FLAIR image and T2-weighted image reveals slight diffuse periventricular
hyperintensities of the deep white matter.

4. Discussion
The diagnosis of HE requires a relapsing-remitting or progressive
encephalopathy associated with the existence of antithyroid antibodies [14,15]. Both cases fulfilled these general diagnostic criteria. In
the first presented patient, symptoms and the clinical course belonged
to the vasculitic or stroke-like type and in the second to the diffuse
progressive type of HE.
The first set of criteria for the diagnosis of HE was published by
Peschen-Rosin et al. in 1999 [7]. These criteria encompassed unexplained occurrence of relapsing myoclonus, generalized seizures,
psychiatric disorders or focal neurological deficits and three conditions
among which are: abnormal EEG, elevated thyroid antibodies, elevated
CSF protein, excellent response to steroids and unrevealing cerebral
MRI. After this early proposal the clinical range of symptoms and signs
was much more widened and response to steroids has been shown to
vary substantially. Recent publications suggest also that beside high
serum titers, high cerebrospinal fluid titers of antithyroid antibodies
could be more patognomonic [16] then corticosteroid responsiveness
which occurs in only 50% of patients [7]. According to a recent analysis of
published cases and case series, 42 patients on a steroid therapy
recovered without relapses, 38 relapsed or had no effect, 11 patients

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improved with residual deficits and 19 had spontaneous improvement
of which 14 relapsed and 5 remained stable. Course after treatment
differs from improvement (normal or with residual impairments) to
chronic disease with fluctuations [17]. Our cases support this analysis of
corticosteroid responsiveness in HE. Namely, the first patient with
vasculitic type of HE had good response to corticosteroid therapy and
remained stabile for 1 year, while the second, with diffuse progressive
form of HE did not improve and the course of the disease after treatment
was chronic with fluctuations.
Diagnostic criteria proposed by Peschen-Rosin et al. also underestimate the significance of raised antithyroid antibodies. Ferracci and
Carnevale in 2006 [17] summarized the diagnostic principle followed
by the majority of authors: after ruling out of other diagnoses, the
elevated serum antithyroid antibodies support the diagnosis of HE
but is not confirmatory. The presence of HT is not necessary for the
diagnosis of HE as some patients have elevated autoantibodies and
brain disease without autoimmune thyroiditis. The usual cluster of
findings associated with HE is recurrent neurological illness mostly
presented as generalized seizures, myoclonus, ataxia, cognitive defects, focal neurological deficits and other signs, high antithyroid
antibodies in serum and CSF, non-specific EEG changes, non-specific
MRI white matter changes, elevated CSF proteins and possibly abnormal thyroid functional tests [18].
Elevated titers of antithyroid antibodies (especially TPO-Ab) are
the most relevant paraclinical finding, which could be considered to
be a hallmark of HE. We found elevated serum levels of TPO-Ab in the
patient with vasculitic type HE and TPO-Ab and TG-Ab in the second
patient with diffuse progressive type of HE. Both types of antibodies
were predominantly detected in HE [19]. In the CSF, cell count is found
to be normal in most cases [6,7], like it was in our patients.
Analysis of neurochemical CSF parameters reveals usually pathological results like oligoclonal bands [14] or an increased total protein
concentration [17,20]. Both findings were shown in our patients. In
our patient with diffuse progressive type of HE, there was evidence for
an intrathecal synthesis of antithyroid antibodies. In the study of
Ferracci and Carnevale, 16 HE patients were tested and all of them had
elevated titers of TG-Ab and TPO-Ab in CSF. Serum and CSF specimens
were evaluated also for albumin CSF/serum quotient (Qalb), specific
TG-Ab and TPO-Ab index according to the formula AbCSF/AbSerum:
IgGCSF/IgGSerum [17,21].
In 70 control patients there were neither elevated TG-Ab nor TPO-Ab
CSF titers [17]. Antithyroid antibodies in CSF are undetectable even in
patients with autoimmune thyroiditis or other neurological disorders [22].
The normal autoantibody concentration was zero or had an absorbance
value that could not be reliably distinguished from zero (range 0–8UI/ml),
even in the presence of blood–brain barrier dysfunction [16,17,21]. However, in our patient, the raised TPO-Ab-specific indexes and the normal
Qalb are consistent with the integrity of the blood–brain barrier and the
intrathecal synthesis of autoantibodies.
The second case we presented, points out the need for reevaluation of current diagnostic criteria for HE. Namely, this patient had
not responded to glucocorticoid therapy, but had high CSF titers of
antithyroid antibodies which remained elevated after high dose glucocorticoid therapy.
Further measurements of the antithyroid antibodies in CSF and serum
in a larger number of subjects are needed to clarify the significance of
the elevated CSF titer of antithyroid antibodies in the etiology and prognosis of HE.
The EEG is a good apparative marker for the effect of pharmacological treatment and correlates well with the clinical course of HE [7,10], as
shown in our first case in which clinical improvement correlated with
EEG normalisation.
The most common MRI findings are small bilateral subcortical highsignal lesions [6] like it was shown in our second case with diffuse
progressive type of HE.

Presented cases show, that all patients with recurrent stroke-like
episodes, progressive cognitive impairment or with a dementia of
unclear origin should be tested for an HE.
The diagnosis of HE should be considered even if Hashimoto's
thyroiditis is not known in patients with even normal thyroid function
but with high serum and/or CSF titers of antithyroid antibodies. It is
important for the clinicians to be aware that only about 50% of cases
respond completely to corticosteroid therapy, thus non-responsiveness should not be exclusion criteria for HE. In patients with steroid
resistance, other therapeutical strategies should be tried: immunosuppresive therapy (azathioprine or cyclophosphamide) and recently
proposed in some cases plasmapheresis or intravenous immunoglobulins [23] [24].
Acknowledgments
This work was funded by the Ministry of Science, Republic of Serbia
(Project No. 145025D).
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