Eye‐of‐the‐Tiger Sign with an Unexpected Pathological Diagnosis

ABSTRACT

Background

Clinical diagnosis of atypical parkinsonisms may be challenging. The eye‐of‐the‐tiger sign on brain MRI, typical of neurodegeneration with brain iron accumulation, has been anecdotally observed in cases clinically diagnosed as atypical parkinsonisms.

Objectives

To show how clinical syndromes and even neuroimaging sometimes may lead the neurologist to a misunderstanding, just as to emphasize the important role of pathology to establish the final diagnosis in these cases.

Methods

Clinico‐pathological case.

Results

A 67‐year‐old‐woman presented with progressive painful stiffness and allodynia in her left arm. On examination, she presented parkinsonism without tremor with greater involvement of left limbs. She developed dystonia, with myoclonic tremor and hypoesthesia involving her left arm, as well as an impairment of balance with falls, a significant axial involvement with disabling rigidity, supranuclear gaze abnormalities, facial dystonia, dysphonia, severe dysphagia, and anarthria. There was no response to levodopa. Syndromic diagnosis and findings on neuroimaging are discussed. Afterwards, the underlying pathology is revealed.

Conclusions

We present the first case of neuropathologically confirmed multiple system atrophy with the eye‐of‐the‐tiger sign on brain MRI. The presence of supranuclear vertical gaze palsy further complicated a correct clinical diagnosis. A pathological postmortem study remains essential to establish a definite diagnosis in atypical parkinsonisms.

Case Report

A 67‐year‐old‐woman was referred to our clinic because of painful stiffness and allodynia in her left upper limb that had established progressively since their onset 6 months earlier. There was no relevant past medical history or toxic habits, neither a family history of neurological diseases. On initial examination, the patient presented hypomimia with normal pursuit and saccadic eye movements, and positive glabellar reflex. A moderate appendicular rigidity and bradykinesia were noted, with greater involvement of left limbs; tremor was absent. She also referred to spontaneous pain and allodynia in her left arm, with a distal mild paresis involving her left hand. Postural stability was intact.

Within the following 2 years she developed impairment of balance with recurrent falls, progressive dystonia with myoclonic postural tremor and hypoesthesia involving her left arm, without apraxia. Pyramidal or abnormal cerebellar signs were not elicited, and the orthostasis test was negative. In addition to the asymmetric parkinsonian syndrome, during the first years from the onset of the symptoms, she also referred to non‐motor symptoms such as constipation, urinary urgency without incontinence or incomplete bladder emptying, and restless legs syndrome. The mood was preserved and no anosmia, REM sleep disorder behavior, snoring, cognitive decline, or hallucinations were noted.

So far, the patient had received treatment with selegiline, dopamine agonists, levodopa, and amantadine without remarkable responsiveness. She never experienced dyskinesias under treatment with l‐dopa, although a dose up to 1500 mg was achieved. Botulinum toxin in the trapezius and levator scapulae muscles was helpful to alleviate the left upper limb dystonia. Although initially the diagnosis of Parkinson's disease was considered, given the evolution of symptoms, in the presence of upper limb dystonia, and myoclonus, in the absence of response to l‐dopa, the clinical diagnosis of atypical parkinsonism, was contemplated.

At age 70, the patient associated a significant axial involvement with disabling rigidity and stiffness of her neck. During the following year, the balance was fully affected to the point that she was confined to a wheelchair. Besides, she developed supranuclear vertical gaze abnormalities, facial dystonia with overactivity of frontal muscle, dysphonia, hypophonia with severe unintelligible dysarthria (Video 1), and aphagia that required to perform a gastrostomy. Frontal release reflexes were present in the absence of a positive “applause sign”. Cognitive functions were preserved. The subsequent appearance of prominent axial involvement with recurrent falls accompanied by supranuclear gaze abnormalities led us to reconsider the diagnosis since the patient presented clinical features more suggestive of the progressive supranuclear palsy spectrum within the atypicality of its clinical presentation. The patient died 5 years after symptoms onset, at the age of 72 years.

Video 1.

The video shows our patient presents supranuclear vertical gaze abnormalities, facial dystonia with overactivity of frontal muscle, dysphonia, dysphagia, hypophonia with severe unintelligible dysarthria as more prominent signs in neurological examination. A certain degree of antecollis can also be appreciated. Her balance was fully affected to the point that she was confined to a wheelchair.

Laboratory Investigations and Imaging Studies

Blood tests, including glucose, renal and liver function, electrolytes, lipids, coagulation, copper, ceruloplasmin, and ferric study, were normal. A nerve conduction study of the left arm revealed no abnormalities. The dopamine‐active transporter (DAT) scans and SPECT disclosed a reduced right striatal binding of ¹²³I‐FP‐CIT (N‐3–fluoropropyl‐2‐b‐carboxymethoxy‐3‐b‐(4‐iodophenyl) nortropane) with postsynaptic preservation determined by a ¹²³I‐iodobenzamide (IBZM), as well as bifrontal and bitemporal hypometabolism. A brain MRI showed mild atrophy in addition to bilateral hypointense globus pallidus on the iron sensitive T2‐weighted sequences, corresponding to iron accumulation, in the presence of a central hyperintensity, a characteristic pattern well‐known as the eye‐of‐the‐tiger sign (Fig. 1). A cervical MRI was normal. Cerebrospinal fluid analysis disclosed normal biochemical parameters, Tau 104 (reference value 160–425), with normal both beta‐A4 and alpha‐synuclein.

FIG 1.

T2‐weighted sequences MRI, axial (left) and coronal (right) views, show a radiological pattern well‐known as the “eye‐of‐the‐tiger”, characterized by a high signal intensity in anteromedial globus pallidus surrounded by a low signal ring, related to an excess of iron accumulation.

Pathological Findings

Macroscopically, both cerebral hemispheres showed an overall mild to moderate gyral atrophy, with frontoparietal predominance. On coronal sections, striking putaminal atrophy with a friable grayish appearance was noted in all its anteroposterior extension, while the subthalamic nucleus was preserved. Transverse midbrain sectioning featured an intense nigral pallor, in the absence of significant midbrain atrophy. Sagital serial sections of the cerebellum displayed no alterations, with the dentate nucleus and superior cerebellar peduncle preservation. The gross examination did not reveal additional pathological changes of significance.

For microscopical examination, left hemisphere histological sections were stained with hematoxylin and eosin (Fig. 2). An overall preserved cortical architecture was noted. The caudate nucleus, subthalamic nucleus, hypothalamus and thalamus were overall preserved. The red nucleus, pons and medulla oblongata were intact. Limbic structures showed no abnormalities. Mild to moderate microvascular pathology was evident in the basal ganglia and subcortical vessels. Cerebellar sections showed preserved cortical layers and no pathological changes in the dentate nucleus, while cerebellar white matter displayed mild to moderate diffuse gliosis and significant myelin degeneration.

FIG 2.

Hematoxylin and eosin stain. The main pathological feature was a putaminal a massive neuronal loss (left), accompanied by neuropil spongiosis and intense astrogliosis with a prominence of hypertrophic astrocytes, showing long and thick cytoplasmic processes. In the midbrain, the substantia nigra pars compacta (right) showed moderate neuronal loss and astrogliosis, with extracellular neuromelanin aggregates (blue arrows), and diffuse tegmental gliosis was observed. The globus pallidus (down) showed mild neuronal loss and astrogliosis, apart from vascular changes related to small vessel disease, with thickening of the microvascular walls and enlarged Virchow‐Robin spaces. Conspicuous mineralized vessels are found in the internal globus pallidus.

An immunohistochemical study of specific histological sections was conducted, using beta‐amyloid, tau, alpha‐synuclein and ubiquitin stains (Fig. 3). Beta‐amyloid stain revealed scant diffuse and focal neocortical plaques (Thal plaque phase 1), while tau stain demonstrated a low density of immunopositive neurons with neurofibrillary tangles, pretangles and neuropil threads confined to the transentorhinal cortex (Braak neurofibrillary stage I), in the absence of neuritic plaques (CERAD plaque score 0). Perls Prussian blue stain was performed on basal ganglia sections for histochemical iron detection (Fig. 4).

FIG 3.

Putaminal sections. Alpha‐synuclein positive oligodendroglial cytoplasmic inclusions (blue arrows), with rounded and angular contours, were widely detected spreading along with the internal and external capsule, putamen, midbrain tegmentum and cerebral peduncle, with a higher putaminal density; few oligodendroglial and astroglial inclusions were found in the neocortex and subjacent white matter. Alpha‐synuclein in the putamen highlighted sparse neuronal cytoplasmic inclusions showing characteristic thread‐like intranuclear expansions (red arrow), and occasional dystrophic neurites.

FIG 4.

Perls Prussian blue stain. Moderate and disperse ferric deposits, both intracellular and extracellular, are enhanced with Perls Prussian blue stain in this putaminal section (left). In the globus pallidus, there is no significant iron accumulation, with only minimal ferric presence inside the scant iron‐laden macrophages and erythrocyte extravasation around the dystrophic calcified vessels (right).

In summary, the histopathologic workup disclosed neurodegenerative changes with a striatonigral system predominance, in the presence of widespread alpha‐synuclein positive glial inclusions and sparse neuronal inclusions in the affected systems, fulfilling neuropathological criteria for a definite diagnosis of multiple system atrophy. No histopathological evidence of excessive iron accumulation in the globus pallidus was obtained with special stains.

Discussion

The “eye‐of‐the‐tiger” sign is a well‐known radiological pattern on T2‐weighted sequences MR images. It is characterized by a high signal intensity in anteromedial globus pallidus, related to gliosis and neuropil destruction, surrounded by a low signal ring, appearing due to an excess of iron accumulation. ¹ For a long time, this radiological finding has been considered as a pathognomonic sign of pantothenate kinase‐associated neurodegeneration (PKAN), due to PKAN2 gene mutations, the core syndrome among the neurodegeneration with brain iron accumulation (NBIA) disorders. ² Nevertheless, this one‐to‐one association seems far from being established. ³ There are several case reports of this image in basal ganglia on iron sensitive T2*‐weighted MRI with a clinical diagnosis of atypical parkinsonism, such as Steele‐Richardson‐Olszewski syndrome, ⁴ cortico‐basal syndrome, ⁵ pure akinesia and freezing of gait ⁶ or multiple system atrophy (MSA). ⁷ , ⁸ Nevertheless, only one of these patients had a confirmed pathological diagnosis suggestive of Steele‐Richardson‐Olszewski syndrome. ⁴ Our patient presented pathological findings consistent with MSA and, to our knowledge, none of the previous cases reported of MSA with the “eye‐of‐the‐tiger” sign on brain MRI was pathologically confirmed postmortem. ⁷ , ⁸ Some cases of atypical parkinsonism have been reported with an image similar to the eye‐of‐the tiger in the brain MRI, but in which T2*‐weighted brain MRI sequences showed no abnormalities, so it was considered a “pseudo eye‐of‐the‐tiger” sign since these radiological abnormalities are not considered to correspond to iron deposition. ⁹ In our case, we do not discard the presence of dystrophic calcified vessels related to small vessel disease could be contributing to the MRI findings, although moderate and disperse ferric deposits, both intracellular and extracellular were found in the putamen and globus pallidus.

Intracellular deposition of amyloidogenic proteins is the main pathology feature of atypical parkinsonisms. However, clinical features cannot be unequivocally associated with a specific entity and different molecular pathologies can underlie overlapping syndromes. ¹⁰ Our patient presented symptoms and signs highly suggestive of atypical parkinsonism, more probably in the spectrum of tauopathies. Nevertheless, in our case, pathology excluded this possibility, based on the absence of astrocytic plaques or tuft‐shaped astrocytes. The presence of alpha‐synuclein positive oligodendroglial cytoplasmic inclusions supported the definite pathological diagnosis of multiple system atrophy, in the synucleinopathies spectrum. ¹¹ Different tauopathies and synucleopathies are known to clinically overlap among themselves, but a tauopathy mimicking a synucleinopathy or the other way round, as in our case, is extremely rare. ¹⁰

Our patient presented l‐dopa‐unresponsive parkinsonism in the absence of dopa‐related dyskinesias, resting tremor or anosmia. In addition, prominent bulbar symptoms (dysphonia, severe dysphagia and anarthria), and rapidly progressive balance impairment appeared shortly, all red flags arguing against Parkinson's disease diagnosis. ¹² Despite the myoclonic postural tremor, different from the typical pattern of PD, may be seen in MSA patients, our patient also presented a prominent axial involvement with a disabling balance impairment and frequent falls, severe bulbar symptoms, and especially vertical gaze palsy and overactivity of frontal muscle, more suggestive of progressive supranuclear palsy. ¹³ Supranuclear gaze abnormalities, which are not a characteristic feature of MSA, further complicating the clinical diagnosis and, although oculomotor movements mimicking PSP have been described in patients with clinically suspected MSA, they are exceptional in pathologically confirmed MSA. ¹⁴ The main criteria for the diagnosis of probable MSA highlight autonomic dysfunction and/or cerebellar syndrome. ¹⁵ Abnormal cerebellar signs were not elicited, neither orthostatic hypotension; only symptoms suggestive of urinary urgency were reported by the patient, but these may also be common in elderly people, and they were not accompanied by the sudden and unexplained onset of incontinence or incomplete bladder emptying, which would more strongly support the presence of autonomic failure. Our patient also did have constipation, which is seen as a symptom that could accompany other symptoms of autonomic dysfunction in patients diagnosed with MSA. However, it is seen more like a collateral accompanying symptom and may be very prominent in other types of parkinsonisms, such as Parkinson's disease.

MSA is a well‐known chameleon and misdiagnosis with Parkinson's disease or other atypical parkinsonisms is not infrequent. ¹⁴ Koga et al demonstrated in a retrospective autopsy study of 134 patients with an antemortem clinical diagnosis of MSA: only 62% were correctly diagnosed, being dementia with Lewy bodies the most common misdiagnosis, ahead of progressive supranuclear palsy and Parkinson's disease. ¹⁶ Misdiagnosis of MSA with corticobasal degeneration appears to be much less frequent, although it has been anecdotally reported. ¹⁷

In our case, also ancillary tests were misleading. In nuclear neuroimaging tests, MSA patients usually present symmetric striatal dopaminergic denervation as well as symmetric postsynaptic and striatal degeneration, with hypometabolism in the putamen, brainstem, or cerebellum. ¹⁰ Our patient scan showed an asymmetric reduced right striatal binding of ¹²³I‐FP‐CIT in the right striatum with postsynaptic preservation according to 123I‐IBZM SPECT findings, as well as bifrontal and bitemporal hypometabolism. However, the normality of the D2‐SPECT seems not to be pathognomonic of PD, and there are some cases of clinically suspected multiple system atrophy with normal D2 SPECT reported. ¹⁸ Nevertheless, reviewing in the light of the pathology, some aspects might have made us suspect the diagnosis of MSA, such as non‐responsive to l‐dopa parkinsonism accompanied by postural instability within the first 3 years and, especially, the contractured limb with jerky tremor, the early severe dysphagia and dysarthria. ¹⁴ , ¹⁵ In addition, in terms of radiological findings, the presence of the striking “eye‐of‐the‐tiger” sign in the brain MRI further complicated a correct clinical diagnosis in this challenging and unique case and probably led us to overlook other radiological signs, such as putaminal atrophy or the excessive low putaminal signal as a sign suggestive of iron deposition, both of them considered radiological features highlighted for MSA.

In conclusion, we present the first case of pathologically confirmed multiple system atrophy with an eye‐of‐the‐tiger sign on brain MRI. The clinical syndrome and imaging tests may be helpful, but also misleading in the clinical and neuropathological diagnosis. This case underscores how pathological postmortem study remains essential to establish a definite diagnosis in atypical parkinsonisms.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution. (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique. (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

E.N.V.: 1A, 1B, 1C, 3A, 3B

J.M.C.: 1A, 1B, 3B

J.L.L.S.M.: 1A, 1B, 3B

A.G.L.: 1A, 3B

A.S.S.: 1A, 3B

M.J.L.M.: 1C, 3A, 3B

A.R.: 1C, 3A, 3B

A.A.C.: 1A, 1B, 1C, 3B

Disclosures

Ethical Compliance Statement

The authors confirm that the approval of an institutional review board was not required for this work. Written informed consent was obtained and documented. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest

No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months

ENV has received research funding from Zambon. JMC has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambon; research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. JLLSM has received advisory honoraria from Roche La Hoffman & Novartis. AGL has received research funding from Zambon and expenses to attend scientific meetings from Roche. ASS has received expenses to attend scientific meetings and research funding from Daiichi Sankyo. MJLM has no conflicts of interest. AR has no conflicts of interest. AAC has received lecture honoraria from AbbVie, Zambon, Alter, Krka, Lundbeck, research funding from Italfarmaco, advisory boards for AbbVie, Zambon, Bial, travel grants from AbbVie and Zambon.