15

cerebrospinal fluid (CSF), high antithyroid antibodies
titres in serum and/or in CSF, and a favourable response
to corticosteroid administration

1-7

.

Since the first description by Brain et al.

1

in 1966 of a case of

episodic HE, nearly 150 cases have been reported in adults
as well as in children

8-14

. Most of the patients with HE are

affected by chronic autoimmune thyroiditis, or Hashimoto’s
thyroiditis (HT), but a few cases have been reported in
patients with Graves’ disease (GD) or, less frequently, with
spontaneous autoimmune thyroid failure

3,7,15-17

. However,

clinical features and management of encephalopathy
associated with ATD (EAATD) do not differ between
patients with HT or GD. For this reason, and in view of the
fact that no direct association between thyroid disease and
the neurologic process has been proven yet, a denomination
such as EAATD would appear to be more appropriate than
the conventional term of HE

3

. Since the pathogenesis of

these coincident conditions remains largely undefined,
another more accurate denomination of the syndrome –
which includes its favourable response to therapy –, i.e.
corticosteroid-responsive encephalopathy associated with
autoimmune thyroiditis, has also been proposed, but it
appears to be excessively descriptive

18,19

.

Introduction

Both increased and lowered thyroid hormones may affect
brain function, as it is known to currently occur in
thyrotoxicosis and severe myxoedema. However, other
neurologic complications, largely independent of actual
thyroid hormone levels in blood and unrelated to other
known causes, may interfere with the clinical course of
patients with autoimmune thyroid disease (ATD). This is
the case of the so-called Hashimoto’s encephalopathy
(HE), a rare and possibly underestimated complication of
ATD characterised by a poorly codified clinical picture due
to protean neurologic and neuropsychiatric symptoms
associated with diffuse electroencephalographic (EEG)
abnormalities, increased protein concentration in the

Review article

Received 23 November 2005; revised 28 February 2006; accepted
13 March 2006.
Address for correspondence: Prof. Giovanni Murialdo, Clinica di
Medicina Interna 2, Dipartimento di Scienze Endocrinologiche e
Metaboliche, Università degli Studi, Viale Benedetto XV 6, 16132
Genova, Italy. E-mail: [e-mail]
© 2006 CEPI Srl

Encephalopathy associated with autoimmune thyroid disease,
currently known as Hashimoto’s encephalopathy, but also
defined as corticosteroid-responsive encephalopathy
associated with autoimmune thyroiditis, is a relatively rare
condition observed in a small percentage of patients presenting
with autoimmune thyroid disease. It consists of a subacute,
relapsing-remitting, steroid-responsive encephalopathy
characterised by protean neurologic and neuropsychiatric
symptoms, diffuse electroencephalographic abnormalities and
increased titres of antithyroid antibodies in serum and/or in
cerebrospinal fluid. Most of the cases presenting this
neurologic complication are affected by Hashimoto’s
thyroiditis or, less frequently, by other autoimmune thyroid
diseases, chiefly Graves’ disease.
The pathogenesis of this encephalopathy is still unknown and
largely debated, because of extremely varied clinical
presentation, possibly referable to different aetiologic and
pathophysiologic mechanisms, as confirmed by the two
clinical cases we report in this paper. Autoimmune aetiology
is, however, very likely in view of the well established

favourable response to corticosteroid administration. Both
vasculitis and autoimmunity directed against common brain-
thyroid antigens represent the most probable aetiologic
pathways.
Clinical manifestations include consciousness changes,
neurologic diffuse or focal signs, headache, and altered
cognitive function. Although unspecific, cerebral oedema has
also been described. Cerebrospinal fluid examination often
discloses an inflammatory process, with a mild increase in
protein content and occasionally in lymphocyte count. In this
review, clinical criteria for the diagnosis of defined, probable,
or possible encephalopathy associated with autoimmune
thyroid disease are suggested. Corticosteroid therapy
currently allows us to obtain rapid remission of disease
symptoms, but adverse outcomes as well as spontaneous
remissions have also been reported.

(Intern Emerg Med 2006; 1 (1): 15-23)

Key words: autoimmune thyroiditis, autoimmunity, corticosteroids,
Hashimoto’s thyroiditis

Clinical and diagnostic aspects of

encephalopathy associated with autoimmune

thyroid disease (or Hashimoto’s encephalopathy)

Gianluca Tamagno

1

, Giovanni Federspil

1

, Giovanni Murialdo

2

1

Medical Clinic 3, Department of Medical and Surgical Sciences, University of Padua, Padua,

2

Clinic of Internal Medicine 2, Department of Endocrine and Metabolic Sciences, University of Genoa, Genoa, Italy

IM

16

A wide variability in clinical presentation of EAATD and
the difficult diagnostic work-up, based on undefined
parameters and accounting for numerous possible
pitfalls, may affect the assessment of the prevalence of
encephalopathy in patients with ATD.
Several mechanisms, such as cerebral vasculitis, global
cerebral hypoperfusion, cerebral tissue-specific
autoimmunity, and thyrotropin-releasing hormone-
related neuronal deficit, have been proposed for
EAATD

7,20-26

, although an autoimmune process seems

the underlying cause

2,7

.

EAATD presents either as a medical emergency or with a
more progressive onset, whereas its course may be either
progressive or relapsing

6,26,27

. Exacerbations associated

with menstrual cycle have also been described

28,29

. The

symptoms usually respond promptly to corticosteroid
therapy, but occasional steroid resistance as well as
spontaneous remission may occur

30,31

.

EAATD appears to be largely independent of thyroid
function

2,4,7,25

. Nevertheless, some reports evidenced

thyroid hormone abnormalities at disease onset, or just
before, although these hormone changes do not account
for the neurologic signs and symptoms of EAATD
manifestations.
We herein report two cases of EAATD, which may be
considered as paradigmatic of the large variability of this
syndrome. After a review of the literature, the state of the
art of EAATD as for clinical presentation, diagnosis, and
management will be discussed along with some
considerations about its pathogenetic mechanisms.

Case reports

Case 1
A 29-year-old Caucasian woman affected by GD came to
our observation because of progressively worsening
headache localised in the frontal and occipitoparietal
regions, enhanced by orthostatic posture and head
flexion. Furthermore, nausea, some vomiting episodes
and slightly altered hearing were reported. About 1
month before, she had presented with autoimmune
thyrotoxicosis, treated with methimazole and after skin
adverse drug reaction with propylthiouracil.
On admission, physical evaluation disclosed an
enlarged homogeneous thyroid gland, bilateral
nystagmus, unclear right foot plantar reflex, vanishing
ocular papilla in the right eye. No signs of either
Graves’ ophthalmopathy or dermopathy were present.
Thyroid hormone, thyrotropin and antithyroid
antibodies laboratory findings are reported in Table 1.
In CSF, slightly increased glucose levels and leucocytes,
overall represented by lymphocytes, as well as raised
albumin concentration with higher CSF/serum IgG and
albumin link ratios were detected (Table 2). EEG records

showed diffuse mild electric alterations, mainly
localised in the temporal region and alternatively
prevailing on the two sides. In a following EEG study,
mild bilateral frontotemporal alterations, occasionally
spread to other areas, and diffuse slowed down activity
related to sleepiness were recorded. Brain computed
tomography scans disclosed a picture compatible with
cerebral oedema (Fig. 1), whereas nuclear magnetic
resonance imaging evidenced some bilateral areas of
sufferance in the subcortical white matter, within a
context of unspecific parenchymal alterations defined as
pachymeningeal thickness compatible with inflammation.
Other conditions causing encephalopathy were ruled out
by clinical examination and by blood and CSF laboratory
findings. Intravenous therapy with dexamethasone (4
mg/day) and a short course with mannitol rapidly
improved the clinical picture. Prednisone treatment (25
mg/day with progressive tapering of the dosage) was
continued for 6 months. One year after corticosteroid
withdrawal, the patient was still symptom-free and

Table 1. Serum levels of free thyroid hormones, thyrotropin, and
thyroid autoantibodies observed in the 2 patients with encephalopathy
associated with autoimmune thyroid disease described in the text.

Patient 1

Patient 2

Reference interval

(IU)

Hormones

fT3 (pmol/l)

10.34

5.28

4.0-7.4

fT4 (pmol/l)

15.89

11.71

10.0-31.0

TSH (mU/l)

0.005

1.78

0.4-4.2

Autoantibodies

Anti-TPO (< 100 U/ml)

468

1542

< 100

Anti-Tg (< 100 U/ml)

93

4233

< 150

Anti TR (U/l)

418.5

Not assayed

0-14.0

anti-Tg, thyroglobulin antibodies; anti-TPO, thyroperoxidase antibodies; anti-TR,
thyrotropin receptor antibodies; fT3, free triiodothyronine; fT4, free thyroxine;
TSH, thyroid-stimulating hormone.

Table 2. Cerebrospinal fluid (CSF) data in a 29-year-old woman
affected by encephalopathy associated with autoimmune thyroid
disease in the course of Graves’ disease (case 1).

Parameter

Values

Reference values

Aspect

Clear, colourless

–

Glucose (mg/dl)

86.1

44.0-74.0

Proteins (g/l)

0.437

0.130-0.520

Albumin (mg/dl)

34.7

10.4-30.3

IgG (mg/dl)

2.7

0.71-4.19

CSF/serum IgG ratio x 10

3

4.060

0.82-3.26

CSF/serum albumin ratio x 10

3

10.877

1.92-7.30

Oligoclonal IgG bands (immunoblot)

Absent

Absent

Erythrocytes

0

Absent

Leucocytes (n/mm

3

)

12

< 4

Lymphocytes (n/%)

9/75

60-70

Stain for microorganisms, including
acid-fast bacteria, and antibodies

Negative

Negative

for infectious pathogens

Intern Emerg Med

2006, Vol 1 No 1

17

became pregnant. Pregnancy was uneventful and a
healthy child was delivered.

Case 2
A 65-year-old Caucasian woman known to be affected by
HT and type A autoimmune atrophic gastritis presented
recurrent episodes of transient mental confusion during
the previous 3 years and EAATD was diagnosed in
another hospital

25,26

. On first disease manifestation,

symptoms spontaneously recovered independently of
the prescribed treatment with corticosteroids. However,
mental confusion recurred after therapy withdrawal, so
that corticosteroids were restored with benefit. After
some symptom-free months, the patient presented
another similar episode and was admitted to our
hospital, where altered consciousness without other
neurologic or psychiatric alterations was confirmed.
Thyroid laboratory findings are shown in Table 1. High
levels of gastrin and chromogranin A, compatible with
the concomitant gastric autoimmune disease, were also
found. Both diabetes and adrenal insufficiency were
excluded. EEG examination showed hyperpnea-
enhanced abnormal slow activity in the left temporal
region. Brain

18

F-fluorodeoxyglucose positron emission

tomography evidenced mild bilateral lowered uptake in
the superior parietal cortex and left temporal lobe along
with reinforcement of the central low signal due to the
ventricles. Relapsed EAATD with autoimmune
polyendocrine syndrome type IIIB was diagnosed and
treatment with corticosteroids for 4 months was
instituted, starting with prednisone 50 mg/day and
progressively tapering daily doses. Symptoms

progressively disappeared and the patient did not show
any neuropsychiatric alterations during the following
period, even after corticosteroid discontinuation.

Pathogenesis

The pathogenesis of EAATD is largely debated and still
far from being understood, because it remains mainly
based on anecdotal observations and speculative deduc-
tions rather than on experimental and/or histological
evidence

2,7,18,21,22,32-42

. Current hypotheses encompass

autoimmune vasculitis, autoimmune reaction against
common brain-thyroid antigens (with or without the
involvement of intrathecal immune complex), demyelin-
izing processes with disseminated encephalomyelitis,
global cerebral hypoperfusion (by itself or as an epiphe-
nomenon of vasculitis), neuronal dysfunction due to
brain oedema, direct toxic effect by excessive thyrotropin-
releasing hormone output

1,2,7,18,20,21,23-26,33,34,38-40,42

. Some

antigens, such as alpha-enolase and a 36-kDa protein
recently detected in a soluble fraction from the cerebral
cortex, have been thought to play a role in EAATD

38,39

. A

further study has recently suggested that autoantibodies
in EAATD are directed against the amino-terminal por-
tion of alpha-enolase

40

.

Pathogenesis based on the presence of cerebral vasculitis
is supported by converging evidence. Infiltration of the
cerebral small vessel wall has been described in 2
patients

22,34

. Single-photon emission computed tomogra-

phy disclosed cerebral hypoperfusion in some cases,
compatible with that observed in diffuse brain vasculi-
tis

21,24

.

Probably, both focal and diffuse patterns of cerebral
vasculitis may be present in EAATD, thus differently
influencing the clinical presentation

43-45

. Focal involvement

of the brain could determine stroke-like clinical
manifestations, but cerebellar subacute syndrome

19

,

sensory ganglionopathy

46

or a selective involvement of the

nucleus accumbens

13

have recently been described in

patients with EAATD. On the other hand, diffuse cerebral
hypoperfusion could lead to progressive worsening
conditions, often characterised by subacute onset and
psychiatric symptoms. However, the inclusion of EAATD
within non-vasculitic autoimmune inflammatory
meningoencephalitis cannot be definitively ruled out

47

.

One of the most interesting recent observations giving
further insights into EAATD pathogenesis concerns the
disclosure of undetectable hypocretin-1 levels in the CSF
of patients presenting with relevant consciousness
changes and coma, suggesting that an antineuron
autoimmune reaction might be directed against
hypocretin-1-secreting hypothalamic neurons, which
modulate consciousness

48

. However, lowered hypocretin-

1 levels in symptomatic EAATD patients as well as in

Figure 1. Brain computed tomography scan in a female patient
affected by encephalopathy associated with autoimmune thyroid
disease, showing aspecific findings such as ventricular reduction
and virtual disappearance of the subarachnoidal space, compatible
with cerebral oedema; neither shift of the median axis structures nor
abnormal focal areas were detected.

Gianluca Tamagno et al.

18

subjects with sleep disorders might be secondary to
changes in arousal and vigilance activity rather than
being the cause of consciousness impairment

49

.

Within the spectrum of largely overlapping ATD, HT and
GD are characterised by some differences in the
autoantibody pattern, antithyroid-stimulating hormone
receptor antibodies being more frequently observed in
the latter. Although with different prevalence, both HT
and GD may be complicated by EAATD, but no specific
aetiologic mechanism accounting for the neurologic
involvement occurring in these thyroid diseases has been
disclosed yet.

Clinical features

A variety of unspecific neurologic and/or psychiatric
symptoms unrelated to thyroid hormone levels have
been described in EAATD patients affected by either HT
or GD. The clinical presentation of EAATD can be
characterised by focal signs secondary to stroke-like
events as well as by generalised symptoms, including
consciousness and cognitive alterations, seizures,
psychiatric and bipolar affective disorders, gait
impairment, headache, and inflammatory signs of
encephalitis or meningitis

1,10,12,42,45-47,50-74

.

Recently, recurrent status epilepticus has been viewed as
the main feature of EAATD

75

. For instance, an

electrophysiological study on the hearing organ of a
paediatric population with HT showed involvement of
the central part of the auditory organ

76

.

By analysing 85 patients with EAATD in the literature,
Chong et al.

45

listed the most frequent symptoms along

with the proper percentage of presentation. Galluzzi et
al.

77

reviewed all published cases of EAATD in the elderly

population presenting with cognitive impairment.
Neurologic, psychiatric and systemic symptoms derived
from the analysis of 145 cases with EAATD in the
literature, and including the two above-mentioned
reviews, are listed in Table 3.
In summary, altered consciousness and stroke-like
episodes mostly affect EAATD patients

45,54

. Among

neurologic changes, focal signs, progressive cognitive
impairment, seizures and status epilepticus, myoclonus,
involuntary movements, and tremors have often been
described. Hallucinations and psychosis seem to be the
most frequent psychiatric symptoms in EAATD, but also
affective disorders may be represented.
A further clinical aspect is the possible coexistence of
EAATD with autoimmune disease other than ATD as
observed in the above described case 2. Thus, the occurrence
of arthritis, dermatitis, atrophic gastritis and autoimmune
diabetes mellitus may deserve consideration

6,7,45,61

. A case of

overlapping EAATD and autoimmune scleromyxoedema
has also been published

78

. Thus, brain involvement could

be enlisted in the group of possible manifestations of
polyendocrine autoimmune syndromes, although it is not
currently considered as such

79

.

Diagnosis

In absence of other possible causes that may justify the
symptoms, the concomitant presence of encephalopathy
and ATD often leads to suspect EAATD. This hypothesis
is often strengthened by the finding of increased serum
titres of antithyroid antibodies and unspecific EEG
abnormalities

2-4,25,39,43,45,52,80-82

.

An additional clue may be provided by the detection of
antithyroid antibodies in the CSF

2,21,22,83

. The detection of

anti-alpha-enolase antibodies could be a possible additional
tool for the diagnosis

40

. Increased protein concentrations are

often detected in the CSF of these patients, although this
finding cannot be considered as a specific one. Thus, the real
specificity of both laboratory and EEG parameters remains
largely undefined

42,45,54,75,81,82,84

. Computed tomography

scans and magnetic resonance imaging are currently
adopted for studying EAATD

17,43,85,86

, but a recent

review revealed that brain imaging was either normal in
about 50% of 82 patients or presented non-specific
alterations in the other half

45

. Some other brain imaging

procedures, namely single-photon emission computed
tomography and

18

F-fluorodeoxyglucose positron

Table 3. Neurologic, psychiatric and systemic symptoms described
in 145 patients affected by encephalopathy associated with
autoimmune thyroid disease.

Most frequent symptoms

Seizures and lost consciousness (51%)

Cognitive deterioration and loss memory (48%)

Myoclonus (32%)

Hallucinations and psychosis (26%)

Stroke-like episodes (21%)

Tremors and involuntary movements (12%)

Language and fluency impairment (8%)

Ataxia and gait impairment (6%)

Behavioural changes (6%)

Sensory deficits (6%)

Other symptoms

Anxiousness

Apraxia

Depression and bipolar affective disorder

Dizziness

Headache

Insomnia

Muscle hypertonus

Mydriasis

Nystagmus

See references 5,13-18,26,28,31,37,39,44,45 for review of 85 patients,

references 46-48,50-74,76,78,81 for review of 17 patients, and references

83,94,96,100,103,104.

Intern Emerg Med

2006, Vol 1 No 1

19

emission tomography, have been applied for EAATD
diagnosis, but their effective utility remains uncertain
because of their low specificity

16,20,43,87,88

.

If no specific evidence for other diseases is obtained, the
concomitant report of neurologic and/or psychiatric
symptoms with acute or subacute onset, euthyroidism or
thyroid hormone changes unable to justify the
symptoms, and a prompt remission achieved by
corticosteroid administration may direct the diagnosis
towards EAATD. However, no definitive criteria for
EAATD diagnosis are available so far

7,89

.

The uncertain diagnostic EAATD work-up may
contribute to underestimate its epidemiological
prevalence

26

. On the other hand, in the absence of well

defined criteria, EAATD could also be inappropriately
diagnosed. In Table 4, we propose some criteria for the
diagnosis of defined, probable, or possible EAATD.
Differential diagnosis versus neurologic illness
characterised by unspecific clinical presentation and
inflammatory signs of the central nervous system, such
as Creutzfeldt-Jacob disease, systemic vasculitis and
infiltrative diseases, could raise some difficulties even for
expert clinicians

36,42,47,90,91

.

Canton et al.

3

described the onset of encephalopathy 1

month after radioiodine treatment for GD. Although this
association of events has not been further reported, it
could be related to an increase in circulating antithyroid
antibodies due to

131

I-induced follicular cell destruction

92

.

Both in patients with GD

3,15-17

and in those with

hyperthyroidism at the onset or during the course of
HT

3,93,94

, mildly increased or very high thyroid hormone

levels have been detected in the early stage of EAATD, or

a few weeks before it. However, some counteracting
descriptions of patients with clinical or subclinical
hypothyroidism have also been reported independently
of their antithyroid treatment

23,45,54,56,58,95,96

. In our case 1,

EAATD arose when thyroid hormones were decreased or
normalised by antithyroid therapy, whereas they were
normal in the second patient. Thus, the role of thyroid
hormones in the development of EAATD remains unclear
and in most EAATD cases hormonal alterations do not
seem so relevant as to justify neurologic symptoms.
High CSF antithyroglobulin and antithyroid peroxidase
antibody titres have been detected in several patients with
HT and encephalopathy

25,39

. No data concerning CSF

antithyroid-stimulating hormone receptor antibodies in
EAATD patients with GD have been published.

Prognosis and treatment

EAATD symptoms are rapidly responsive to medical
treatment and prognosis is usually good. Nevertheless,
the persistence of neurologic alterations and death
cannot be excluded

37,97

.

Neurologic and/or psychiatric impairment associated
with ATD is responsive to corticosteroids in a rapid and
complete manner, including resolution of neuroimaging
and EEG changes that may be observed during the
critical phase of EAATD

3,4,54,70,81,83,85,98-100

. It has been

hypothesized that this outcome might be associated with
corticosteroid treatment, but not necessarily as a
consequence of corticosteroid administration

45

. However,

responsiveness to corticosteroids should be considered as
a primary diagnostic criterion

45,72,89,101

.

In a large number of patients, relapses and recurrence of
symptoms seem to be quite common, without the
effectiveness of steroid treatment being lost

64

.

When EAATD is suspected, corticosteroid administration
is always advisable as the first-line therapeutic approach.
Various regimens of corticosteroid treatment have been
proposed, diverging in both doses and timings. An
advisable approach may be represented by acute high-dose
corticosteroid administration, followed by the progressive
tapering until withdrawal of the drug after 6-12 months,
according to clinical evolution and responsiveness. The
administration of immunosuppressive drugs, although
potentially suitable, has not yet been defined

2

.

In patients with steroid resistance, intravenous
administration of high doses of immunoglobulins has
also been successfully tried

31

, whereas plasmapheresis

has been positively practised in a few patients

100,102-104

.

Infusion of mannitol might also be adopted, when signs
of cerebral oedema are predominating. Nevertheless,
spontaneous remission of the syndrome may also occur
and sometimes psychiatric symptoms improve along
with normalisation of thyroid function

30,56,105,106

.

Table 4. Clinical criteria proposed for the diagnosis of defined*,
probable**, or possible*** encephalopathy associated with
autoimmune thyroid disease.

Necessary criteria

- Acute or subacute onset of neurologic/psychiatric symptoms in

absence of other possible causes

- Exclusion of other known causes of encephalopathy (i.e., bacterial,

viral or fungal infections, metabolic encephalopathy, Creutzfeldt-Jacob

disease, etc.)

- Association with clinical or subclinical autoimmune thyroid disease

- Serum thyroid hormone levels unable to justify the symptoms and

persistence (or presentation) of symptoms or concomitant normal

thyroid hormones

- Clinical response to corticosteroids

Other criteria

-

Elevated antithyroid autoantibodies levels in serum and/or

cerebrospinal fluid

- Increased protein concentration in cerebrospinal fluid without

pleocytosis

- Unspecific electroencephalographic abnormalities

* necessary criteria plus all the above listed criteria; ** necessary criteria plus
one of the above listed criteria; *** necessary criteria but none of the above
listed criteria.

Gianluca Tamagno et al.

20

Conclusions

Several data confirm the existence of a peculiar kind of
encephalopathy associated with ATD, commonly called
HE but better defined as EAATD. The increasing number
of cases described suggests a growing interest in this
disease among clinicians. However, this infrequent but
often severe complication of ATD encompasses a great
variability of clinical signs and symptoms possibly
underlying differentiated aetiologic and pathogenic
mechanisms. Thus, it remains uncertain whether this
clinical condition should be considered as a well defined
syndrome rather than a variety of neurologic distresses
complicating the clinical course of patients with
autoimmune thyroid dysfunction.
It seems highly probable that EAATD may be due to
cerebral vasculitis and that both HT and GD represent
the possible background for the immunological
involvement of the nervous system. EAATD should be
considered in all cases of encephalopathy of unknown
origin occurring in patients with ATD, which should be
carefully evaluated and managed in order to rule out any
other possible illness affecting brain function and to
achieve remission by prompt corticosteroid treatment.

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