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A bad dose of 'flu

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Q1: What is the most likely diagnosis and how would you confirm it?

The most likely diagnosis is one of acute rhabdomyolysis together with myoglobinuria, as demonstrated by the generalised oedema, muscle tenderness and weakness, and the brown discoloration of the urine. To confirm the diagnosis, the urine should be tested for myoglobin (radioimmunoassay is the best technique) and muscle enzymes should be measured.

In this patient, the urine was positive for myoglobin and had an acidic pH of 6.0. Muscle enzymes were grossly raised, with creatine kinase 30 000 U/l, lactate dehydrogenase 2900 U/l, and aspartate aminotransferase 710 U/l.

The differential diagnosis of a patient becoming weak on a background of such a prodromal illness as that described here would normally include an acute inflammatory demyelinating polyneuropathy (or Guillain-Barré syndrome), but the presence of such oedema and muscle tenderness makes this an unlikely diagnosis even prior to the biochemical results.

A patient presenting in such a manner in the postoperative period would lead to suspicion of a diagnosis of malignant hyperthermia. This is a rare autosomal dominant condition, linked to a mutation in the ryanodine receptor gene on chromosome 19,1 in which susceptible individuals are endangered by exposure to certain anaesthetic triggering agents (see box 1).

Box 1: Aetiology of rhabdomyolysis

  • Trauma.

  • Seizures.

  • Ischaemia.

  • Metabolic defects: glycogenoses, carnitine palmitoyltransferase deficiency.

  • Drugs: clofibrate, gemfibrozil, epsilon-aminocaproic acid, statins, etretinate, high dose steroids.

  • Alcohol.

  • Infectious diseases.

  • Malignant hyperpyrexia: halothane, enflurane, isoflurane, succinylcholine, calcium channel blockers.

  • Malignant neuroleptic syndrome.

  • Electrolyte imbalance: hypokalaemia, hypomagnesaemia, hypophosphataemia.

Q2: What is the possible aetiology of this condition?

The potential aetiology of rhabdomyolysis is wide (see box 1). In this particular patient there would appear to be three main possibilities. Firstly given the nature of the prodromal symptoms, any one of a range of infectious agents could be implicated (see box 2). Secondly, rhabdomyolysis is well recognised as a complication of certain types of drug therapy and this patient had been exposed to several agents over the 48 hours immediately before admission, although not before the time that he first became unwell. Thirdly, the possibility of a primary muscle disease should always be considered (many would not necessarily be relevant in this particular age group), although such an acute, de novo presentation would be unusual.

Box 2: Infectious agents implicated in rhabdomyolysis

  • Influenza A and B.

  • Coxsackie virus.

  • Epstein-Barr virus.

  • Cytomegalovirus.

  • Echovirus.

  • Adenovirus.

  • Legionella pneumophila.

  • Streptococcus pneumoniae.

  • HIV.

In this particular patient, the aetiological agent was a virus, influenza type B, serological testing indicating a rising antibody titre to 1 in 320.

Q3: What potential complications may occur?

There are several potential complications. Massive rhabdomyolysis may result in electrolyte imbalance, particularly hyperkalaemia, hyperphosphataemia, and hypercalcaemia. Disseminated intravascular coagulation and venous thromboses may also occur. Most seriously, severe myoglobinuria may cause renal damage and anuria. The exact mechanism by which this occurs is uncertain but hypotheses include renal tubular obstruction by precipitated myoglobin, reduction in renal blood flow, and direct toxic injury to the tubular epithelium.

Q4: How would you manage this patient?

In general, good nursing and medical care with close monitoring of electrolyte balance, renal function, and urinary output are essential. More specifically, a high fluid intake and alkalinisation of the urine by infusion or ingestion of sodium bicarbonate helps to protect the kidney by preventing the formation of myoglobin casts. This patient received 3 g of sodium bicarbonate, every two hours, by intravenous infusion, until the urine pH was >7.0. He was also treated with 2 mg/kg of dantrolene by intravenous infusion, daily for five days.

Box 3: Learning points

  • Acute rhabdomyolysis represents a medical and neurological emergency.

  • Rhabdomyolysis may complicate even usually innocent infections.

  • Maintenance of high fluid intake and alkalinisation of urine are fundamental to preserving renal function.

  • Intravenous dantrolene is a useful therapeutic option.

  • Patients should be monitored for the possible development of a compartment syndrome and these should be managed appropriately.

Discussion

In the period immediately after admission, the patient continued to deteriorate. There was progression in muscle weakness with lower limb muscle strength ranging between 0/5 at knee flexion and 3/5 at knee extension. In the upper limb, weakness was less marked, muscle strength generally 3–4/5. He also developed decreased sensation on the dorsum of the right foot and increased tension in the anterior tibial compartments of both legs. Consideration at this stage was given to surgical release.

The creatine kinase level continued to rise, peaking at 140 000 U/l 48 hours after admission, before declining rapidly thereafter. Electromyography and nerve conduction studies showed clear myopathic changes in all sampled muscles with evidence of moderate bilateral carpal tunnel compression and moderate-severe right peroneal and tibial nerve lesions. The neuropathy was attributed to oedema and compression.

In the days after the decline in creatine kinase, the patient's condition stabilised and then gradually improved. Four weeks after the onset of illness he was discharged home, mobilising with the aid of a Zimmer frame. At the most recent follow up several months later, he was mobilising independently, had full return of upper limb strength, and had full power in the lower limb, apart from the right ankle where dorsiflexion and plantar flexion were 4/5.

Infectious agents are believed to be implicated in only 5% of cases of rhabdomyolysis.2 The association with influenza infection, although uncommon, is well described in the literature. A recent review listed 22 cases of rhabdomyolysis associated with generalised, non-pneumonic influenza A infection.3 Of these, 12 developed acute renal failure (55%) and four of these died. Influenza type B is much less commonly implicated in rhabdomyolysis. There has been a report of two cases of influenza B in elderly men being associated with rhabdomyolysis, but each of these occurred in the context of hyperpyrexia and the clinical course was much milder with smaller enzyme rises than that documented in our patient.4

The mechanism by which viruses can cause rhabdomyolysis is unclear, although at least two theories have been advanced.5 One theory is that there is direct viral invasion into muscle fibres causing myonecrosis. This is supported by muscle biopsy findings of lymphocytic infiltrates, viral inclusions, and viral DNA identified by polymerase chain reaction. Conversely, where muscle biopsy is either normal or shows hyaline degeneration and myonecrosis but no viral particles, it is postulated that the virus releases a circulating toxin or stimulates cytokine release. To date however, no putative toxins have been identified.

Dantrolene has been used to beneficial effect in rhabdomyolysis arising from malignant hyperpyrexia, malignant neuroleptic syndrome, exertion, acute alcoholic intoxication, and both cocaine and ecstasy overdose. It is known to decrease the release of calcium from the sarcoplasmic reticulum.6 Calcium may play a part in muscle pain as has been suggested in McArdle's disease and in the development of malignant hyperthermia. Muscle cell necrosis is also explained by an increased calcium influx into the cell, triggering a vicious cycle of mitochondrial overloading and energy depletion, which leads to hypercontraction and finally, to cell death.

Experiments with dantrolene in cases of exertional rhabdomyolysis have shown an 83% reduction in intracellular calcium levels, which has been associated with marked improvements in both clinical symptoms (muscle stiffness, rigidity and pain) and laboratory values (83% reduction in creatine kinase by day 4).7

This case demonstrates the potentially acute course of rhabdomyolysis in even healthy individuals, highlights the potential complications arising from this condition and emphasises the routine but effective methods of avoiding these.

Final Diagnosis

Acute rhabdomyolysis with myoglobinuria.

References

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