A 34-year-old man, recently diagnosed as diabetic, presented an acute painful neuropathy. He reported a profound weight loss during the months preceding onset. There were no motor symptoms, and only mild neurological signs were observed on examination. Improvement was related to a good glycemic control and weight gain. Acute painful diabetic neuropathy is a rare condition that may affect diabetic patients shortly after development of the disease. The pathogenetic roles played by different factors are reviewed. 0 1996 John Wiley & Sons, Inc. Key words: diabetes neuropathy pain weight loss

MUSCLE & NERVE 19:463-467 1996

ACUTE PAINFUL DIABETIC NEUROPATHY FOLLOWING SEVERE WEIGHT LOSS

FERNANDO CASTELLANOS, MD, JAVIER MASCiAS, MD, JUAN ANTONIO ZABALA, MD, CINTA RICART, MD, ANA CABELLO, MD, and ANTONIO GARC/A-MERINO, MD

Neuropathy is an important source of morbidity in diabetic patients. Its prevalence rises as the diabetes evolves; thus, 25 years after the onset of the disease, 50% of patients have a clinical neuropathy,16 and an altered nerve conduction can be found in 100% of this population.22 Different clinical subtypes of diabetic neuropathy (DN) have been described; most develop years after the onset of diabetes, and then usuallyprog- ress with few, if any, possibilities of recovery.

In 1974, Ellenberg reported 6 patients with DN beginning shortly after, or even before, the diagnosis of diabetes. These patients had had a profound weight loss before the onset of neuropathy and the term diabetic neuropathic cachexia (DNC) was pro- posed." Nine years later, Archer et al. described 9 similar cases as acute painful diabetic neuropathy (AF'DN) .z Interestingly, all patients reported had a good recovery.

We report here a new case of this rare condition and review its most relevant aspects. We also discuss

From the Department of Neurology, Clinica Puerta de Hierro, Universidad Autonoma (Drs. Castellanos, Mascias, Zabala, Ricart, and Garcia-Merino), and the Department of Neuropathology, Hospital Doce de Octubre, Uni- versidad Complutense (Dr. Cabello), Madrid, Spain

Acknowledgments: We wish to thank Dr Gabriela Goizueta for performing the electrophysiological studies and Martha Messrnan for her editorial ex- pertise.

Address reprint requests to Dr. Fernando Castellanos, Department of Neurology, Clinica Puerta de Hierro. C/ San Martin de Porres 4, 28035 Madrid, Spain.

Accepted for publication October 1, 1995.

0 1996 John Wiley & Sons, Inc. CCC 01 48-639X/96/040463-05

the similarity between this syndrome and other acute diabetic neuropathies, as well as the role that weight loss seems to play as a precipitating factor.

CASE REPORT

A 34year-old man was diagnosed as diabetic in No- vember 1992. One year earlier, he had developed polyuria and polydipsia and he had experienced a progressive weight loss during the preceding 3-4 months, amounting to 15 kg (nearly 20% of his previ- ous weight) at the time of diagnosis. He had also noticed paresthesia in the soles of both feet for some weeks. Treatment with subcutaneous insulin was initi- ated, with an adequate glycemic control. Two weeks later, he began to develop paroxysmal attacks of shooting pain spreading from his feet toward his legs, thighs, and the lower part of the abdomen. This symptom worsened at night. There was also a more persistent dull pain in feet, with contact discomfort. The patient became depressed. Motor and auto- nomic symptoms were absent except for impotence.

On examination, he appeared cachectic, his height was 190 cm and his weight 70 kg. There was no postural hypotension and retinopathy was not ob- served on funduscopy. Neurologic examination re- vealed mild distal loss of pain and vibratory senses in lower limbs; ankle and knee reflexes were absent and biceps and triceps reflexes were diminished. Muscle strength was normal.

A battery of analyses and radiological examina- tions was performed to rule out neoplastic, infectious, metabolic, and autoimmune disorders. The results of those tests were all negative.

APDN following Severe Weight Loss MUSCLE & NERVE April 1996 463

Analysis of the cerebrospinal fluid was normal. Electromyographic studies showed signs of denerva- tion in distal muscles of the lower limbs. Nerve con- duction studies revealed a 30% reduction in motor nerve conduction velocity (NCV) , prolonged distal motor latencies, and decreased compound muscle action potentials (CMAPs) in peroneal and median nerves. Sensory NCV was also slow and sensory nerve action potentials (SNAPS) had a low amplitude in sural, right ulnar, and right median nerves (Table 1). Sural nerve biopsy disclosed a moderate loss of myelinated fibers. Teased fiber preparations demon- strated acute axonal degeneration of some fibers and isolated segmental demyelination (Fig. 1).

Treatment with different drugs, including antide- pressants and anticonvulsants, was ineffective. The patient began to recover some months later, when his glycemic situation was under control, and he gained weight. One year later, he was pain free; slight pares- thesia in both feet remained as the only symptom. He had returned to his daily routine.

DISCUSSION

In 1983, Archer et al.' described an acute syndrome of painful sensory neuropathy in 9 diabetic patients; the authors remarked that these patients resembled those described by Ellenberg" as having DNC 9 years earlier. These are the only two series of such patients in the medical literature. Features that are common to all of them, as well as to the patient reported here, may be summarized as follows: all patients were male and adults, aged 30-60 years at the time of diagnosis, except for a 13-year-old boy.' Weight loss was always severe and closely related to the neurological disease in such a way that the intensity of the symptoms peaked at the time of maximal weight loss and recov- ery was coincident with weight gain. Intermittent shooting or burning pain is described in every case, affecting mainly legs but spreading upward to include the trunk or the upper limbs. Sensitivity to touch and

worsening of pain at night are also often reported. Other additional features are: depression, impo- tence, and absence of other diabetic complications such as nephropathy or advanced retinopathy. The prognosis is extremely good, with marked improve- ment or disappearance of symptoms and restoration of the previous weight. Recurrences have not been observed.

The most remarkable difference between patients with DNC and patients with APDN is that 4 of Ellen- berg's patients had motor involvement and severe neurological signs on examination," while patients of Archer et al. had only mild neurological signs without weakness2 In this respect, our patient repre- sents an intermediate degree, as subclinical motor fiber involvement was evident in neurophysiological testing. In our view, all these patients have the same condition with different degrees of severity, the selec- tive sensory disturbances being the mildest symp toms. Moreover, in Ellenberg's report," the clinical picture of 2 patients who lacked motor abnormalities is indistinguishable from the described by Archer et a1.*

Another aspect worthy of note is the interval be- tween diagnosis of diabetes and onset of neuropathy. Ellenberg reported neuropathic symptoms before the diagnosis of diabetes in 3 of his patients."' In 9 more patients (3 from Ellenberg's series, 5 from that of Archer et al. and our patient), both findings were nearly simultaneous. Four patients of Archer et al. had been diabetic for a longer period, ranging from 6 to 15 years.' Our patient presented symptoms con- sistent with glycosuria for 1 year before diagnosis; thus, weight loss may have been due to prolonged hypoinsulinemia. The same explanation could be valid for at least 2 patients in Ellenberg's series"' and 1 reported by Archer et a1.2

An additional interesting fact was the dramatic exacerbation of symptoms seen in our patient 2 weeks after starting insulin therapy. Ellenberg noticed the

Table 1. Nerve conduction results.

Sensory NCV Distal motor CAMP (mV) SNAP (pV) Motor NCV (rn/s) (rnls) latency (rns)

Nerve Right Left Right Left Right Left Right Left Right Left

Median 1.6 ND 15.2 ND 31.7' ND 42.8* ND 7.05 ND Ulnar ND ND 6.3 ND ND ND 45.4-f ND ND ND Peroneal 1.4 2.3 - 30.3t 29.4t - 5.85 6.15 Sural - 2.6 5.3 - 30.5 29.7 -

CAMP = compound muscle action potential; SNAP = sensory nerve action potential; NCV = nerve conduction velocity; ND = not done. * €/bow-wrist. tBe/ow knee-ankle.

464 APDN following Severe Weight Loss MUSCLE & NERVE April 1996

FIGURE 1. Transverse section from sural nerve showing moderate loss of myelinated fibers. Some fibers undergo axonal degeneration (arrows). [Toluidine blue stain. (A) x500; (B) x1600.]

same phenomenon in the 3 patients in whom insulin was administered." It also occurred in 1 of the 3 patients described in detail by Archer et a1.* Develop- ment of a painful neuropathy following initiation of treatment with insulin, or an adjustment of the insu- lin dose, has been described elsewhere, with a clinical picture similar to that reported

With regard to electrophysiological studies, El- lenberg only mentioned that the results were abnor- mal in 3 patients and that NCV was low in 1 more case."Archer et al. summarized all patients' data and emphasized the reduced amplitude of SNAPs. All parameters were normal in 1 patient.2 On the other hand, the outcome of neurophysiological testing of our patient was remarkably pathological, with find- ings of muscle denervation on electromyography, re- duction of SNAPs and CMAF's, and slowing of NCV. Thus, reduction of SNAPs seems to be the most persis- tent finding, although there is a wide spectrum of possibilities ranging from normal results2 to motor fiber involvement and marked slowing of NCV (El- lenberg" and the present case), which is rarely seen in DN.

Peripheral nerve and muscle biopsy was per- formed in 2 patients in Ellenberg's series. He found axonal loss and neurogenic atrophy of muscle fi- bers." The findings of Archer et al. on sural nerve biopsies performed in 3 of their patients are similar to ours: acute axonal degeneration, myelinated fiber loss, and sporadic segmental remyelination. More- over, morphometric studies in 2 samples showed a reduction in myelinated fiber density.*

The correlation between nerve pathology and pain is still a subject of discussion. The most striking biopsy finding in our patient, and also in those of Archer et a1.,2 was acute axonal degeneration. This finding was associated with neuropathic pain in a series of 72 patients with polyneuropathies of diverse origin reported by Dyck et al. in 1976.' Asbury and Fields suggested that sprouts from regenerating un- myelinated axons, previously damaged, might be the cause of pain in peripheral ne~ropathy.~ Although some authors have supported this theory,'~'' three main clinicopathological studies have demonstrated that axonal degeneration and regeneration occur both in painful and painless sensory DN and that

APDN following Severe Weight Loss MUSCLE & NERVE April 1996 465

findings in nerve biopsies are not significantly differ- ent in the t w ~ . ' , ~ , ' ~ Nevertheless, in one of these stud- ies, Britland et al. found that later phases of regenera- tion were more successful in painful than in painless DN, suggesting that some influence could inhibit the maturation of axon sprouts in the latter.fi

The pathogenesis of this kind of neuropathy is unknown. Different factors are probably involved, but diabetes and weight loss seem to be the most important ones. Other nondiabetic neuropathies have been described in association with weight

a fact which raises the question of a nutri- tional origin, such as vitamin deficiency. However, we found no trace of nutritional deficiency in our patient. Interestingly, an acute painful neuropathy has been reported in 4 diabetic women with anorexia nervosa who had had profound weight IOSS, '~ and other diabetic neuropathies have been associated with weight loss in some patients: namely, poximal diabetic neuropathy (PDN) 4,821 and diabetic thoracoab dominal neuropathy." Remarkably, these syndromes are also painful neuropathies that have an acute or subacute onset. Moreover, there seems to be a time- dependent relationship between maximal weight loss and onset of neuropathy in DNC, APDN, and PDN, a fact that would support an active pathogenetic role being played by weight loss through unknown mecha- nisms. Alternatively, the possibility exists that weight loss might be just a consequence of uncontrolled diabetes, the latter being responsible for the neu- ropathy .

At least, three different hypotheses have been pro- posed to explain the appearance of pain following insulin therapy: (a) regeneration of previously dam- aged axons; (b) development of an acute neuropathy; and (c) acute exacerbation of a previous neuropa- thy.'? The fact that some of these patients, like ours, presented neuropathic symptoms some weeks, or even months, before developing the acute illness may support the last possibility. Recently, Kihara et al. have shown that intravenous insulin impairs tissue oxygenation in nerves of diabetic rats when hypergly- cemia is controlled.'' One could, therefore, hypothe- size that uncontrolled diabetes along with weight loss would damage peripheral nerves, resulting in mild symptoms until insulin therapy is inititated; then, a hypoxic effect is possibly added and acute degenera- tion of some fibers occurs, leading to more severe dis- turbances.

In conclusion, weight loss is a frequent finding in acute painful neuropathies of diabetic patients, and is related timewise to the come of the neuro- pathic disorder, suggesting that it can be a precipitat- ing factor. However, its exact role in the pathogenesis

of the neuropathy, if any, is unknown. In some pa- tients, weight loss can be explained as a consequence of uncontrolled diabetes. Detailed clinical descrip- tions of more patients with similar neuropathies would be helpful to understand their mechanism of production. Moreover, it is important to recognize the clinical syndrome of APDN, as it represents a distinct group of patients with DN, severe intractable pain, and good recovery.

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