Colchicine myopathy typically presents acutely to subacutely with progressive limb weakness. The patients may not be on high doses of colchicine but almost always have acute kidney injury. Dehydration from colchicine-induced diarrhoea is often a precipitating factor. The concomitant neurotoxicity may produce mild sensory complaints. This combination of acute neurological symptoms preceded by diarrhoea prompts the diagnosis of Guillain-Barre syndrome (GBS). The absence of cranial nerve deficits, raised creatine kinase and myotonic discharges on electromyogram may help in differentiating this condition from GBS. We describe a clinical sign, myoedema — a mounding phenomenon of muscle that is elicited by percussion and resolves when the patient recovers. It aids in the bedside diagnosis of acute colchicine myopathy as well as distinguish it from other more common causes of acute flaccid paralysis. We also discuss the possible mechanism of colchicine toxicity and the mounding phenomenon.
- Neurology (drugs and medicines)
- Neuromuscular disease
- Drugs: musculoskeletal and joint diseases
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Colchicine is commonly used to treat acute gouty arthritis. It is known to induce acute myopathy.1–4 Severe cases with rhabdomyolysis have been reported. It is often associated with diarrhoea, indicating some level of systemic toxicity. The acute kidney injury from the consequent dehydration in turn raises the blood colchicine levels further, setting up a vicious cycle of toxicity5 6 Treatment necessitates early recognition, immediate discontinuation of the offending drug and aggressive correction of kidney impairment. The combination of acute, progressive and flaccid weakness, with variable sensory loss and preceding diarrhoea, almost always prompts the misdiagnosis of Guillain-Barre syndrome (GBS). Elevated creatine kinase (CK) and classic myotonic discharges on needle electromyogram help confirm the diagnosis. We describe a bedside neurological sign, myoedema, a mounding phenomenon of the muscle elicited by percussion, that can be helpful in diagnosing acute colchicine myopathy and distinguishing it from GBS and other causes of acute flaccid paralysis.7 This sign is particularly useful in under-resourced regions where blood tests and electrodiagnosis may not be readily accessible.
A patient in her late 70s, with hypertension, diabetes mellitus and stage 3 chronic kidney disease, presented with abdominal pain, diarrhoea, weakness and paresthesia; that gradually increased over 1 week. She was transferred from a primary care facility with a diagnosis of GBS and impaired kidney function. On clinical examination, the patient was alert and oriented. No abnormality of the cranial nerves was noted. Muscle weakness was, 3/5 proximally and 4/5 distally, in all four limbs. Superficial sensation was decreased on her fingers and toes. Deep tendon reflexes were absent. However, percussion of the anterior tibialis muscle revealed a remarkable mounding phenomenon, also known as myoedema (video 1). There was no percussion or grip myotonia. Blood tests revealed a very high CK level (table 1). Patient reported recent use of colchicine (1 mg/day for 7 days) for gouty arthritis. Nerve conduction study showed only incidental carpal tunnel syndrome. Needle electromyogram revealed myotonic discharges in all observed muscles of both upper and lower limbs. Motor units were myopathic with early recruitment. MRI of the lower limb (figure 1) showed mild oedema of the left adductor, biceps, semitendinosus, semimembranosus, vastus lateralis and adductor magnus muscles. Biopsy of left bicep brachii muscle showed no feature of primary inflammation, but necrosis and vacuoles (figure 2). The diagnosis of acute colchicine-induced myopathy was made.
Colchicine was stopped. The patient experienced gradual recovery of muscle strength, kidney function (serum creatinine 0.89 mg/dL, eGFR 62 mL/min/1.73 m2 after 7 days) and liver function. Thyroid function tests (thyroid stimulating hormone and FT4) were normal. The patient was independent in activities of daily living at the time of discharge 9 days after hospitalisation. At the 2-week follow-up visit, the myoedema resolved completely.
A patient in their late 50s with diabetes mellitus and stage 2 chronic kidney disease presented with proximal muscle weakness that progressively worsened over 1 week. The symptoms appeared after the patient had self-medicated with febuxostat 40 mg for 3 weeks, followed by 2 weeks of both colchicine 1 mg daily and febuxostat 40 mg for a gout flare. Clinical examination revealed 4/5 proximal weakness. Sensory examination demonstrated mild decrease in superficial sensation (pain, touch, temperature) on the palms and feet. Deep tendon reflexes were absent. Like in the first case, we noticed myoedema or a mounding phenomenon when percussing on both anterior tibialis muscles (video 2). There was no clinical myotonia. Blood investigations showed an acute-on-chronic kidney failure which improved after 3 days (table 2). Serum CK was slightly raised. Thyroid function tests were normal. Nerve conduction study was within normal limits. Needle electromyogram showed myotonic discharges as well as volitional myopathic motor unit potentials (figure 3).
The diagnosis of colchicine-induced myopathy was made. Colchicine and febuxostat were stopped. The kidney function improved with rehydration. The patient’s muscle strength gradually recovered. At 2-week follow-up visit, the mounding phenomenon at the anterior tibialis muscle disappeared.
This mounding phenomenon was first described in a series of 12 patients with colchine myopathy and kidney impairment.1 At the molecular level, colchicine binds to the intracellular protein tubulin, preventing the polymerising process and the formation of microtubules. This disruption of the microtubule network leads to impaired protein polymerization in the Golgi apparatus, decreased intracellular and extracellular matrix, altered cell shape, impaired cell motility and mitotic arrest.2 At toxic doses, colchicine suppresses mitosis because chromosomal segregation is dependent on microtubule function, thereby inhibiting cell division.2 These effects occur in all cells in the body, which explains both the therapeutic and the multiorgan effects of colchicine toxicity. The most vulnerable are the metabolic active cells, such as those in the bone marrow, gastrointestinal tract, hair follicles, muscle and, to much lesser extent nerve.3 Although the pathogenesis of colchicine induced myopathy has not been fully understood, colchicine’s disruption of microtubules is believed to cause muscle fibre injury and lead to the appearance of vacuoles on muscle biopsies. The first case had a highly elevated serum CK, myoglobinuria and vacuolar myopathic histological changes, consistent with the typical manifestations of colchicine toxicity. However, in the second patient, despite acute and severe muscle weakness, serum CK was not elevated. Both cases showed abnormal muscle membrane electrical discharges or myotonia. Myotonic discharge, similar to fibrillation potentials and positive sharp waves, is spontaneous activity originating from muscle fibre membrane. It waxes and wanes in frequency and amplitude . The most common causes of this phenomenon include myotonic dystrophy, myotonia congenita and paramyotonia congenita, all of which are associated with clinical myotonia. Other myopathic conditions such as acid maltase deficiency, polymyositis, myotubular myopathy, hyperkalaemic periodic paralysis and colchicine myopathy show electrical myotonia without clinical myotonia (table 3).8 9 Colchicine likely induces muscle weakness by both causing severe muscle necrosis, as evidenced by the raised CK and the biopsy changes in case 1, as well as by affecting the muscle cell membrane potential that induces electrical myotonia, as evidenced in case 2 where the weakness was not associated with raised CK.2
Myoedema is localised contraction of striated muscle produced by direct percussion; and it does not induce electrical activity on electromyogram.7 This phenomena has been reported extensively in cases of hypothyroidism and severe malnutrition.10 Our patients had no signs of hypothyroidism nor nutritional deficiencies. The pathophysiological basis of myoedema is uncertain. An in-vitro study showed that myoedema persists after chemicals in transverse ducts and the transverse duct–organ mesh junction are removed but terminates after the network is destroyed.11 These findings suggest that the percussion-induced local muscle mounding in myoedema is probably triggered by calcium ion release from the sarcoplasmic reticulum and subsequent delay in its uptake. Another hypothesis is that mounding may be caused by colchicine-related muscle membrane damage that also causes spontaneous myotonic discharge. However, if this was the case one would not expect electrical silence during the mounding phenomenon. Percussion myoedema was found in five out of eight patients with colchicine myopathy in a case series.1 Although we did not systematically test its presence in a cohort of patients with GBS, we do not expect a mounding phenomenon to occur in neurogenic paralysis of muscles, and therefore this sign could be useful in its clinical distinction. Another possible differential diagnosis of acute flaccid quadriparesis, especially in patients of East Asian origin, is hyperthyroidism-related hypokalaemic acute periodic paralysis. In this condition, the muscle membrane is electrically inexcitable, and the muscles do not contract to percussion, distinguishing it from the mounding of acute colchicine myopathy-induced weakness.
In summary, we present a new application of an old clinical sign, myoedema, that helps make a bedside clinical diagnosis of colchicine-induced myopathy in a patient with acute flaccid paralysis. In a region where needle electromyogram or CK assay are not easily available, the presence of myoedema could rapidly and readily identify this treatable drug-induced toxicity.
Statement of ethics approval
We obtained approval from the two patients to publish this case report.
Myoedema could be useful in distinguishing colchicine myopathy from other causes of acute weakness such as Guillain-Barre syndrome and periodic paralysis.
The appearance and disappearance of myoedema correlate with the clinical weakness.
Electrical myotonia without clinical myotonia when associated with myoedema and in an appropriate setting can suggest colchicine myopathy.
Patient consent for publication
Contributors STL is the chief investigator, who examined the patient and made the diagnosis and treatment. He also wrote and edited the manuscript. KVN, TQD and UT made substantial contributions to drafting and revising the manuscript. All authors read and approved the final manuscript. The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: all authors. The following authors gave final approval of the manuscript: all authors.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.