Case report

A hispanic man at the age of 40 developed numbness and severe burning dysaesthesias in his legs associated with a 40 lb (18.1 kg) weight loss (figure) over two months. The diagnosis of diabetes mellitus was made and he was placed on chlorpropamide. Over the next five months, his sensory symptoms resolved and his weight gradually returned to baseline. The patient chose to discontinue his diabetic medication six years later and was lost to medical follow up. The next year, the patient developed numbness and burning dysaesthesias over his distal limbs and anterior trunk. Hyperaesthesia to touch was so pronounced that he was unable to wear a shirt. In addition, he experienced episodes of profuse sweating, impotence, and a 49 lb (22.2 kg) weight loss over three months. The patient’s fasting blood sugar was 242 mg/dl and he was started on glipizide. The patient’s painful dysaesthesias however, did not improve, despite trials with amitriptyline, fluoxetine, fluphenazine, carbamazepine, capsaicin, phenytoin, doxepin, TENS units, and epidural lidocaine injections.

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Patient’s weight over time and the onset of neuropathic pain and initiation of diabetic therapy. +=Initiation of oral hypoglycemic; *=initiation of insulin; ↓=onset of pain.  

Physical examination disclosed an emaciated and cachectic hispanic man. Mental status and cranial nerve function were normal. Motor strength was Medical Research Council2 grade 5 in all proximal and distal limb muscles tested, with normal tone throughout. Sensory examination disclosed very decreased vibratory sensation in the toes. Proprioception was intact. There was hyperaesthesia to light touch sensation over all limbs and the trunk. Pinprick sensation was diminished over the limbs, trunk, and face. Temperature sensation was greatly decreased to the level of the upper thighs and upper arms as well as across the chest and abdomen. Muscle stretch reflexes were grade 2 at the biceps, grade 2 at the triceps, grade 1 at the knees, and absent at the ankles with flexor plantar responses.

Laboratory evaluation including vitamin B12 concentration, venereal disease research laboratory, antinuclear antibody, RA, serum protein electrophoresis, thyroid function tests, creatine kinase, and heavy metal screen was normal. HGB A1c was 8.6% (normal 0–7%). Nerve conduction studies disclosed a sensorimotor neuropathy with a normal needle EMG (table). Sural nerve biopsy showed a severe loss of myelinated axons without ongoing axonal degeneration. Occasional clusters of thinly myelinated axons were seen surrounded by a Schwann cell indicating axonal regeneration. By contrast with the myelinated fibres, the small unmyelinated fibre population was not reduced.

The patient was placed on methadone for pain control and insulin therapy was initiated. He soon began to gain weight with gradual resolution of the truncal dysaesthesias over the next nine months. The patient continued to experience numbness in his distal limbs.

Discussion

The patient in this case developed clinical features that are typical of diabetic neuropathic cachexia on two separate occasions. Both episodes were associated with poor glucose control. Diabetes mellitus was first diagnosed when the patient presented with the initial episode of diabetic neuropathic cachexia, which resolved after treatment with oral hypoglycaemic agents. Our case is unique in that recurrent episodes of diabetic neuropathic cachexia have not been reported. The second episode of diabetic neuropathic cachexia occurred after one year without antihyperglycaemic therapy due to medical non-compliance and required the initiation of insulin therapy. Diabetic neuropathic cachexia is a syndrome initially described by Ellenberg1 in 1973 and is characterised by a symmetric peripheral neuropathy associated with profound weight loss and painful dysaesthesias. Most reported patients have been men, usually in the sixth or seventh decades of life1 3 4; there have been two cases described in women.5 6 All cases initially showed profound and precipitous weight loss up to 60% of total body weight, leading in many instances to an initially incorrect diagnosis of metastatic carcinoma or carcinomatous neuropathy. Weight gain typically occurs before resolution of the painful dysaesthesias, which are characteristically described as a constant, severe burning sensation. The dysaesthesias tend to be most severe in the distal lower limbs, but can occur in the proximal lower limbs, the hands, or the lower trunk.3

Patients with diabetic neuropathic cachexia may experience intense contact hypersensitivity which may be provoked by clothing or bedding, and may also describe intermittent stabbing or shooting pains in the legs. The pain tends to be worse at night or during periods of relaxation.1 3 The presence of proximal or truncal dysaesthesias associated with profound weight loss should be clinical clues that support the diagnosis of diabetic neuropathic cachexia, rather than the more common distal sensory neuropathy of diabetes mellitus. All of the patients reported also experienced associated symptoms of severe depression, anorexia, and impotence.

Sensory impairment associated with diabetic neuropathic cachexia is generally minimal, by contrast with the severity of the patient’s complaints of pain, and in some cases, may not be clinically detectable.3 Some reports have described associated muscle atrophy and weakness1 4 5 whereas others have reported normal strength.3

Archer et al 3 provide the only prior report in which nerve biopsies of patients with diabetic neuropathic cachexia are described in detail. In that series of three cases, sural nerve biopsies disclosed axonal degeneration of myelinated nerve fibres of all diameters as well as unmyelinated fibres. The density of unmyelinated fibres, however, was normal, presumably due to regenerating axons. In our case, there was a pronounced loss of myelinated fibres with evidence for axonal regeneration, but no active axonal degeneration. Similar to the findings of Archer et al, the unmyelinated fibres were relatively spared.

Diabetic neuropathic cachexia can occur in both insulin and non-insulin dependent diabetic patients. Interestingly, there is a lack of correlation with other complications of diabetes such as nephropathy or retinopathy,1 3 suggesting that diabetic neuropathic cachexia is not due to microvascular disease, but due to an underlying dysmetabolic state.

Treatment of diabetic neuropathic cachexia can be difficult and strict diabetic control with insulin is usually necessary.3Medications that can be given for symptomatic relief of the painful dysaesthesias include phenytoin, carbamazepine, clonazpem, and narcotic analgesics. A case report using combination therapy with amitriptyline and fluphenazine suggested excellent results,4 but this treatment was ineffective in our patient. The prognosis is usually good and patients typically recover their baseline weight with resolution of the painful sensory symptoms within one year. Our patient shows, however, that some symptoms may be prolonged for up to several years. A residual sensorimotor neuropathy is not uncommon. Our patient is the first case reported, however, who experienced a recurrent form of diabetic neuropathic cachexia, with an asymptomatic period of seven years between episodes. Both episodes occurred during periods of poor diabetic control, and it is interesting to speculate whether the patient would have experienced a relapse if he had been compliant with his diabetic medication after his initial episode of diabetic neuropathic cachexia.