Ross syndrome (RS) is a rare disorder of the peripheral autonomic nervous system. It is characterized by the triad of tonic pupil, diminished or absent deep tendon reflexes (hyporeflexia/areflexia), and anhidrosis or hypohidrosis.
The first case was reported by Dr. Alexander T. Ross in 1958. It is a rare disease with fewer than 100 cases reported in the literature to date. 1)
The average age at diagnosis is 36 years, with a slight female predominance. It can occur at any age, in any ethnicity, and in either sex. Nolano et al. reported 12 patients with RS, suggesting that many cases may go undiagnosed. Diagnosis is often made only after years of unexplained autonomic symptoms.
RS is considered a complication of Adie syndrome, which involves tonic pupil and abnormal tendon reflexes, with additional autonomic symptoms such as orthostatic hypotension and sweating abnormalities.
Holmes-Adie syndrome is characterized by tonic pupil and loss of deep tendon reflexes, but without sweating abnormalities. Ross syndrome includes additional sweating abnormalities such as anhidrosis or hypohidrosis, and is considered a complication of Adie syndrome.
Sweating abnormalities may follow a progressive course. Cases have been reported where hyperhidrosis on the left side precedes, then shifts to anhidrosis on the same side, followed by hyperhidrosis on the opposite side. 1) The simultaneous presence of hyperhidrosis and anhidrosis in the same patient is also characteristic.
The exact etiology is unknown. Nonspecific degeneration at multiple sites in the peripheral autonomic nervous system is thought to cause each symptom.
Clinical diagnosis is fundamental. Confirmation of the triad (tonic pupil, reduced or absent reflexes, and abnormal sweating) is the cornerstone of diagnosis, but the complete triad may not be present in the early stages.
The main differential diagnoses are listed below.
| Disease | Features | Difference from Ross Syndrome |
|---|---|---|
| Holmes-Adie syndrome | Tonic pupil + areflexia | No sweating abnormality |
| Harlequin syndrome | Segmental hypohidrosis | Pupils and reflexes normal |
| Horner syndrome | Miosis + ptosis + anhidrosis | Normal reflex, pupil is miotic (RS is mydriatic) |
In addition, differentiation from Argyll Robertson pupil (bilateral severe miosis), aberrant regeneration after oculomotor nerve palsy, tectal pupil (midbrain dorsal lesion), and Fisher syndrome (triad of ophthalmoplegia, cerebellar ataxia, and areflexia, positive anti-GQ1b antibody) is also important.
There is no curative treatment, and symptomatic therapy is the mainstay. If symptoms are mild, observation may be sufficient.
Treatment for Ocular Symptoms
Low-dose pilocarpine hydrochloride (0.125% or 0.25%): Symptomatic treatment for pupillary symptoms.
Reading glasses: For accommodative dysfunction.
Sunglasses or iris-colored contact lenses: For photophobia (light sensitivity).
Treatment for Sweating Abnormalities
Antiperspirants (10–25% aluminum chloride): First-line treatment for hyperhidrosis. Note potential worsening of body temperature elevation.
Anticholinergic drugs (oxybutynin, glycopyrrolate): Used for severe hyperhidrosis.
Botulinum toxin injection: Indicated for severe compensatory hyperhidrosis.
Iontophoresis: Physical therapy for severe hyperhidrosis.
Sympathectomy: Last resort for severe hyperhidrosis.
The prognosis is generally benign; pupillary symptoms tend to become miotic over time, and subjective symptoms often decrease. Prognosis is unfavorable when systemic diseases are present.
There is currently no curative treatment. However, pupillary symptoms usually follow a benign course, often spontaneously shifting toward miosis and reducing subjective symptoms. Sweating abnormalities may be progressive, so continuous follow-up is important.
Different denervation patterns occur in cholinergic and adrenergic fibers. Skin biopsy shows predominant selective loss of cholinergic fibers, while gastrointestinal and bladder biopsies show predominant loss of adrenergic fibers. 2)
The heart has dual innervation from cholinergic (vagus nerve) and adrenergic (stellate ganglion) systems, acting asymmetrically. The right autonomic nerves predominantly affect the sinoatrial node, while the left side predominantly affects the atrioventricular node. Excessive stimulation or damage to the left vagus nerve can cause decreased conduction and prolonged refractory period of the atrioventricular node, potentially leading to high-grade or complete atrioventricular block. 2)
Accumulation of α-synuclein has been detected in autonomic nerve endings of the lesser curvature of the stomach, and gastrointestinal and urinary symptoms may be explained by degeneration of adrenergic fibers due to α-synuclein accumulation. 1)
Reports in monozygotic twins suggest that multiple genes may be involved in the development and survival of selective sympathetic neuron populations. 1)
Fleischman et al. (2023) reported the first case of complete atrioventricular block associated with RS. 2) A 61-year-old woman (20 years after RS diagnosis) experienced four episodes of third-degree atrioventricular block lasting 7–13 seconds, accompanied by syncope. After emergency temporary transvenous pacing, a dual-chamber pacemaker was placed. Biopsy-proven ischemic colitis (without vascular occlusion) was also explained by chronic transient cardiac output reduction due to high-grade atrioventricular block. This report indicates that while RS has been considered benign, it may involve life-threatening cardiovascular complications.
Cardiac MIBG-SPECT showed reduced iodine-123 MIBG uptake in the posterolateral wall of the heart, but the clinical significance is currently unknown. 2)
Hamadeh et al. (2023) reported a 57-year-old man with concurrent right-sided hyperhidrosis and left-sided anhidrosis. 1) The left side was initially hyperhidrotic but later transitioned to anhidrosis, indicating the progressive nature of RS. ANA and various neural autoantibodies were negative, ruling out an autoimmune mechanism. The patient’s eldest son also had a tendency toward hyperhidrosis, suggesting a genetic involvement. The condition remained stable over three years of follow-up.
Ma M et al. (2020) reported that immunofluorescence analysis revealed α-synuclein accumulation in gastric autonomic nerve terminals, suggesting that RS may be classified as a novel α-synucleinopathy. 1)
IVIG therapy for ANA-positive cases (Vasudevan et al.) and mycophenolate mofetil use in patients with comorbid autoimmune diseases have been reported, but other reports indicate no clinical improvement with immunotherapy, so the efficacy remains unestablished. 1)
Rare cases of complete atrioventricular block have been reported, sometimes accompanied by syncope. 2) If syncope or presyncope episodes occur, evaluation by a cardiologist is important.
