WHO IS AT RISK?
An ongoing epidemiological study at the Mayo Clinic shows that diabetic proximal neuropathy is relatively rare, affecting fewer than 1 in 100 diabetic patients, according to Dr. Windebank. In contrast, distal symmetric neuropathy is thought to affect 20 to 50 percent of diabetic patients, he said.
Studies also show that the disorder most commonly strikes in middle age, Dr. Barrett said, although it can be seen in patients as young as 20 years old.
Neither ethnicity nor gender places one at increased risk, he added, and there does not appear to be any genetic predisposition.
Most patients with diabetic proximal neuropathy suffer from type 2 diabetes, Dr. Windebank said, where the incidence is 1.1 percent, compared with 0.3 percent for those with type 1 diabetes.
Of interest, he said, is that unlike most other diabetic complications, diabetic proximal neuropathy is not associated with poor control of blood sugar. In fact, non-diabetic patients, too, can develop lumbosacral radiculoplexus neuropathy, Dr. Dyck said.
To better understand the pathophysiology of the disease, the Mayo researchers performed ipsilateral nerve biopsies on the 33 patients in their prospective study. They then retrospectively identified 57 non-diabetic patients with the condition who had also had nerve biopsies performed and compared the clinical and pathological features of the two conditions.
The clinical features of the conditions were virtually indistinguishable in the two groups of patients, the study showed. “Like diabetic lumbosacral radiculoplexus neuropathy, nondiabetic lumbosacral radiculoplexus neuropathy begins with a subacute, painful neuropathy with focal involvement of the leg or thigh. It usually becomes more generalized and bilateral within several months. Early in the course, pain is the predominant symptom, whereas later weakness predominates,” Dr. Dyck said.
As for the nerve biopsies, Dr. Windebank said that there was “fairly strong evidence that there is an immune mechanism at play in this disease. In nerve biopsies from diabetic patients with the disorder, it looks like inflammation in the lining of the blood vessel – almost like a form of vasculitis.”
Added Dr. Dyck, “The nerve biopsies on our group of patients showed the condition was due to an immune attack on the nerves, specifically the microvessels – that is, microvasculitis. So we now believe that the disease is caused not by diabetes, but by an ischemic disorder caused by an autoimmune attack on the nerves.”
Bolstering that explanation, he said, was the finding that the group who did not have diabetes suffered from the same pathology. “Again, altered immunity was at play. Since diabetics and non-diabetics share the same pathology, it's difficult to blame diabetes for the condition.”
Hypergyclemia, may, however, be a risk factor, playing a role in the disease process, Dr. Dyck said.
The study also showed that, as expected, fasting blood glucose levels and glycated hemoglobin levels were higher in diabetic patients with the condition, compared with non-diabetics. But even in the diabetic patients, serum glucose levels were usually only mildly elevated.
And when the diabetic patients with the condition were compared with a group of community diabetics who did not suffer from lumbosacral radiculoplexus neuropathy, “we found our group had better blood sugar control, less stroke, and less atherosclerotic complications in general than the average diabetic,” Dr. Dyck said.
OPTIMAL TREATMENT UNKNOWN
The optimal course of therapy for patients with diabetic proximal neuropathy is still an open question, researchers say. Dr. Subramony said that in most patients, the condition spontaneously improves after a period of months to years.
“If you leave patients alone, prognosis is generally pretty good,” he said. “Even though they do badly at first, pain starts subsiding after three to six months, then muscle function comes back. Most get better and can eventually walk again.”
The problem, however, is that not everyone gets better and that when patients are ill, they are very ill, Dr. Windebank said. “In one of our studies, about half were confined to a wheelchair at the height of their illness and almost all required canes or other aids to get around,” Dr. Windebank said.
“By two years later, only 5 percent were in a wheelchair but most had residual weakness,” he said, “So even though patients improve, they don't improve completely.”
Treatment, therefore, centers on shortening the period of disability and improving outcome, Dr. Windebank said. During the acute illness, topical anesthetics, capsaicin cream, mexiletine, opioids, and anticonvulsants and tricyclic antidepressants for chronic neuropathic pain may be prescribed, according to Douglas W. Zochodne, MD, of the Department of Clinical Neurosciences at the University of Calgary in Alberta.
Also, amitriptyline may offer relief from nocturnal pain, he said (Cur Treat Opt Neurol 2000;2:23–30). Low evening doses of 10 mg to 25 mg, slowly titrated upward, are recommended to avoid excessive sedation, postural hypotension, constipation, and urinary retention, he said.
Noting that the protracted pain and weakness almost inevitably lead to depression, Dr. Dyck said that antidepressant medication should also be considered. Also, patients should be encouraged to stay busy with hobbies and other interests, he said.
Bracing such as ankle-foot orthoses may also help, he said.
According to Dr. Barrett, some patients may respond to plasmapheresis. Most important, he said, are proper nutrition, reassurance, and physical therapy. If a patients doesn't respond to these treatments in three months, Dr. Barrett suggests looking for other causes of the problem.
IMMUNOTHERAPY REMAINS CONTROVERSIAL
While most experts agree on the best supportive care, the use of immunotherapy is controversial. Since vasculitis was implicated in the pathology and vasculitis in the peripheral nerves responds to steroid treatment, many researchers are now trying different immunotherapies, Dr. Windebank explained.
But to date, there have been no double-blind controlled clinical trials, and case reports show conflicting results.
David Krendel, MD, and colleagues reported that 15 patients with progressive peripheral neuropathy improved after treatment with immunotherapy (Arch Neurol 1995;52:1053–1061). The researchers studied 15 patients with type 2 diabetes and evidence of axonal neuropathy on electrophysiologic studies. Ten patients had suffered significant weight loss, and 13 patients had prominent involvement of thighs and/or thoracic bands consistent with diabetic amyotrophy or mononeuropathy multiplex. Small vessel disease was seen in all 10 patients who underwent biopsy, with perivascular or vascular inflammation in seven patients.
Seven patients were given intravenous immunoglobulin (IVIG) and prednisone, five were given IVIG alone, two were given IVIG with prednisone and cyclophosphamide, and one was treated with prednisone alone.
“All the patients improved, and five were reported to be markedly better,” Dr. Dyck said.
Gerard Said, MD, of the Hopital de Bicetre in France, has had mixed results. In 1994, he reported that three patients with severe and prolonged painful disability and inflammatory nerve lesions responded dramatically to corticosteroids (Ann Neurol 1994;35:559–569). But several years later, his team found that four patients with different types of inflammatory nerve lesions improved spontaneously after performance of a nerve biopsy (Ann Neurol 1997;41:762–770).
“The presence of inflammatory nerve lesions does not preclude a spontaneously favorable outcome nor invariably requires treatment,” the researchers wrote. “The spontaneously favorable outcome of proximal diabetic neuropathy in most patients, the cost of treatment with intravenous immunoglobulins, and the disequilibrium in diabetic control induced by corticosteroids must be taken into account before starting such treatments.”
At Mayo, Dr. Dyck and colleagues performed an open-label trial of weekly infusions of intravenous methylprednisolone in 11 non-diabetics with lumbosacral radiculoplexus neuropathy. Over an average of 3 months of treatment, all 11 patients had improvements in their neuropathy and skeletal scores, with marked improvement in pain and some improvement in weakness (Can J Neurol Sci 2001;28:224–227).
“The results were very impressive,” Dr. Dyck said. “But it was an open-label study so the data must be considered preliminary. Dr. Windebank, too, has had success in treating patients with steroids and IVIG, but again there was no control group,” he said.
In the Acta Neurologica Scandinavica (2003;107:299), Dr. Zochodne described three patients whose diabetic lumbosacral plexopathy progressed despite active immunosuppressive therapy.
Noting that spontaneous recovery is a well-recognized feature of diabetic lumbosacral plexopathy, he wrote, “The cases raise questions about current unsupported practices of treatment for this condition. Robust clinical trial evidence is required before immunosuppression can be recommended.”
Dr. Subramony agreed, “There have been no blinded or controlled trials. Most of us are still not sure of the treatment's value. There are some serious side effects associated with IVIG and particularly in diabetics, who tend to be elderly patients with vascular disease, I tend to be cautious.”
While Dr. Dyck agreed that controlled trials need to be performed before immunotherapy can be incorporated into clinical practice, he said he believes some physicians may overstate its risks. “These are type 2 diabetics and so far we've had no problems with side effects. But blood sugar does need to be monitored.”
The Mayo researchers hope that a multicenter study that has just completed enrollment will provide more definitive results. In that trial, two-thirds of patients will receive intravenous methylprednisolone and one-third, placebo. But until the results are in, “I wouldn't recommend its use – or that of IVIG – outside of the clinical trials,” Dr. Windebank said,
For now, he said, the gold standard remains painkillers, modulation of diabetes, and physical therapy. Regardless of the pharmacological intervention, “physical therapy to improve mobility and strength is of paramount importance,” he said. “The patients are profoundly weak and physical therapy can help them recover faster.”
DIAGNOSTIC CLUES: DIABETIC PROXIMAL NEUROPATHY
Among symptoms neurologists can look for are:
- relatively rapid onset of pain and weakness, typically in one leg and involving the proximal muscles around the hip and knee, that spreads rapidly over a period of weeks to months;
- pain that is exacerbated at night;
- progression from pain to weakness involving muscles in the proximal portion of the legs such as the vastus lateralis, the adductor, and buttock muscles; and
- autonomic symptoms, including changes in sexual, bowel, and bladder function and unexplained weight loss.
FOR FURTHER INFORMATION
©2004 American Academy of Neurology
- Podwall D, Gooch C. Diabetic neuropathy: clinical features, etiology, and therapy. Curr Neurol Neurosci Rep 2004;4(1):55–61.
- Dyck PJB, Windebank AJ. Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment. Muscle Nerve 2003;25:477–491.
- Zochodne DW, Isaac D, Jones C. Case report: failure of immunotherapy to prevent, arrest or reverse diabetic lumbosacral plexopathy. Acta Neurological Scandinavia 2003;107(4):299.
- Pascoe MK, Low PA, Windebank AJ, Litchy WJ. Subacute diabetic proximal neuropathy. Mayo Clin Proc 1997;72:1123–1132.
- Said G, Elbrably F, Lacroix C, et.al. Painful proximal diabetic neuropathy: inflammatory nerve lesions and spontaneous favorable outcomes. Ann Neurol 1997;41:762–770.
- Krendel DA, Costigan DA, Hopkins LC. Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 1995;52:1053–1061.
Neurology Today Quick Links