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Having recently reviewed the chronology of diffuse toxic goitre (Parry-Graves-Basedow disease) we tackle the chronological descriptions behind Graves orbitopathy (GO).

Why? Well, I’m still working that out. But I think that in our KPI-driven quest for diagnostic certainty, we have forgotten the descriptive pioneers – the clinical diagnosticians.

Time to review the descriptions and eponymythology of the forgotten signs associated with Graves orbitopathy  – the signs of Dalrymple, Stellwag, von Graefe, Möbius and Joffroy…


It is no surprise that historically, semantic confusion reigns regarding Graves orbitopathy. ..

An interchangeable array of terms ranging from thyroid eye disease (TED) and thyroid-related ophthalmopathy (TRO) to dysthyroid/euthyroid/infiltrative/Graves ophthalmopathy; thyrotoxic/malignant/endocrine exophthalmos; exophthalmos of endocrine origin; and thyroid ophthalmopathy/orbitopathy have been used to describe ophthalmic signs that may accompany Graves disease, hypothyroidism, or Hashimoto thyroiditis.

Graves orbitopathy, thyroid dermopathy (pretibial myxedema) and acropachy are the extrathyroidal manifestations of Graves disease. They occur in 25%, 1.5% and 0.3% of patients with Graves disease respectively.

Graves orbitopathy is the commonest extrathyroidal manifestation of Graves disease and signs include proptosis or exophthalmos, eyelid retraction, eyelid lag, restrictive extraocular myopathy and optic neuropathy. GO is a noninfectious, inflammatory disorder of the orbit mostly associated with hyperthyroidism. However, this constellation of signs may also occur on patients without objective evidence of thyroid dysfunction (euthyroid Graves disease) and in patients who are hypothyroid secondary to chronic autoimmune (Hashimoto) thyroiditis.

Thyroid Eye Signs

Upwards of 40 eye signs have been described over the past two centuries. The most enduring of these are outlined.

John Dalrymple (1803–1852) [Dalrymple sign]

The most common clinical sign in Graves orbitopathy, is eyelid retraction. Dalrymple is associated with the description of ‘a widened lid opening in exophthalmus with sclera revealed above the upper margin of the cornea‘ better known as lid retraction.

1849 – The first published description was by Sir William White Cooper (1816-1886) in ‘On protrusion of the eyes in connexion with anemia, palpitation, and goitre‘. Cooper described Dalrymple’s extensive experience and pathophysiologic explanation for this ophthalmologic sign. Cooper provides Dalrymple’s explanation thus:

An absence of the proper tonicity of the muscles by which the eyes are retained in their natural positions in the orbit; and some amount of venous congestion of the tissues forming the cushion behind the globes. Dalrymple relates a case of a gentleman whose eyes were so protruded that they were nearly denuded of the protection of the upper lid by a constant and powerful spasm of the levator palpebrae *superioris, which drew the lids, so far upwards and backwards, that much of the sclera above the cornea was visible.’  WW Cooper 1849

1852 – The eponym ‘Dalrymple sign‘ may have originated after the publication of his book, ‘The Pathology of the Human Eye‘ in 1852. Cooper does not specifically use the eponym, suggesting it manifested later, probably posthumously. No separate accounts or case reports were published by Dalrymple on this topic.

Albrecht von Graefe (1828-1870) [Graefe sign]

1864 – Friedrich Wilhelm Ernst Albrecht von Graefe first described the finding now given his name at the Berlin Medical Society on March 9, 1864.

Von Graefe noted that in exophthalmos, the upper eyelid fails to follow the downward movement of the eye. He believed it was present even in very slight exophthalmos, was most likely due to involvement of Müller’s muscle, and was pathognomonic of Basedow disease.

When normal individuals elevate or lower their glance, the upper eyelid makes a corresponding movement. In patients suffering from Basedow disease, this is entirely abolished or reduced to the minimum. That is, as the cornea looks down, the upper eyelid does not follow.’ [1864;16:158-160]

1932 – Ruedemann applied the more commonly used term ‘lid lag‘ in his chapter on ‘Ocular changes associated with hyperthyroidism

Karl Stellwag von Carion (1823–1904) [Stellwag sign]

1869 – Stellwag von Carion reported his sign of ‘infrequent and incomplete blinking’ in patients with Basedow disease

The palpebral fissure was open very widely, so that thin slivers of sclera remained visible directly above and below the cornea, when the patient looked straight ahead, even under very bright conditions. Blinking became less frequent and incomplete. At various times over many days, I witnessed how both eyelids would not move for several minutes. At other times, only a marginal twitching of the eyelids was visible over several minutes. In no way was a full closure of the eyelids observed over this period of time. The immobility of the lids came to become ‘normal’ during quiet, undisturbed conditions or when the patient was staring / fixating on something.

Within a short period of time of becoming agitated or excited, the patient’s blinking would increase in frequency, yet the closure remained incomplete. Voluntary blinking however remained unaffected. Upon asking the patient to blink, they would do so lightly and with normal power. However, I discovered that the voluntary movement was followed by several involuntary complete blinks in rapid succession. Gradually, the blinking became less frequent and incomplete as to stop altogether.Stellwag 1869;25:40.

Paul Julius Möbius (1853-1907) [Möbius sign]

1883 – Paul Julius Möbius first drew attention to finding of ‘incomplete convergence’ in cases of Basedow disease [1883;CC:100]

1886 – Möbius went on to discuss “…the sign in more detail on the basis of the examination of 10 patients, 8 of whom demonstrated a varying severity of the finding“. [1886;CCXII:136-138]

1891 – Möbius reviewed the clinical signs, symptoms and related pathology since the original description of diffuse toxic goitre and added further to his original description of the insufficiency of convergence [1891;1 (5-6):400-444]

All other movements of the eyeballs are normal, but if the patient is to look at a nearby object (such as the tip of his nose or a finger held in front of his face), the eyes look to the right or to the left, and only one eye sees the object. This is seen most prominently when the patient is asked to first look at the ceiling and then at his own nose.

On looking at a finger moved toward the patients nose, the eyes converge to a point that varies between patients and at different times for the same patient. After this point, only one of the eyes fixates onto the object, whilst the other abducts to align in parallel with the adducted eye’s axis.

Whilst the eyes converge, the patient complains of eye strain. They are not however aware of the abnormal movements, nor do they suffer with double vision. The inability to converge is not directly related to the degree of exophthalmos. It also occurs without Basedow disease.

Charcot et al, corroborate my findings but have described them as ‘rare’ occurrences. In my experience over the past years, its incidence is less frequent than I had originally thought, however it does occur in most cases of Basedow’s disease, if only to a mild degree.

The insufficiency is not a real paralysis, neither is it caused by the exophthalmos. Exophthalmos does limit eye movements. Eye movements are also weakened at the onset of Basedow disease. The weakness is seen at the earliest during convergence, the most strenuous of the eye movements.Möbius 1891;1(5-6):402 Translation: Ercleve T. 2018

Alix Joffroy (1844-1908) – [Joffroy sign]

1893 –  Alix Joffroy presented a lecture at the Hospice de la. Salpêtrière on the ‘epidemiology and treatment of exophthalmic goitre’ by request of Jean-Martin Charcot.

Along with general observations of clinical signs in Graves Ophthalmopathy, Joffroy made particular mention of a new sign ‘Paralasie des muscles de la partie supérieure de la face‘. He described ‘absence of of wrinkling of the forehead‘ when a patient with Graves Ophthalmopathy looks upwards with the head bent forwards.

In our patient, these muscles are affected in a rather unique way that I have already encountered in three other cases, without this particularity having been so far reported. When the eyes are rotated upwards, normally there occurs a synergistic contraction of the elevator of the lids, and a contraction of the frontalis with concomitant wrinkling of the skin of the forehead. However in these cases, the synergistic action is disturbed, the frontalis does not contract and there is an absence of wrinkling of the skin of the forehead. The frontalis that is paralyzed, as the patient can perform voluntary eyebrow movements.’ [Joffroy 1893:479]

In modern summary…

  • Graves orbitopathy (ophthalmopathy) is considered to be present if eyelid retraction occurs in association with objective evidence of thyroid dysfunction or abnormal regulation; exophthalmos; optic nerve dysfunction or extraocular muscle involvement.
  • The ophthalmic signs may be unilateral or bilateral, and confounding causes must be excluded.
  • If eyelid retraction is absent, then Graves orbitopathy may be diagnosed only if exophthalmos; optic nerve involvement; or restrictive extraocular myopathy is associated with thyroid dysfunction or abnormal regulation and if no other cause for the ophthalmic feature is apparent.


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Last update: Feb 12, 2018 @ 10:24 pm

Eponymythology: Graves orbitopathy
Mike Cadogan

Article source here:Life in the Fast Lane