Continuing Education Activity

Diabetic amyotrophy, better known as diabetic lumbosacral radiculoplexus neuropathy (DLRPN), is a rare disorder englobed in the diabetic neuropathy spectrum. This disease consists of a monophasic, asymmetrical progression of pain, motor weakness, proximal muscle atrophy, weight loss, areflexia, progression to paraplegia, and recent diagnosis of diabetes. Diagnosis is mostly based on clinically suggestive findings in a recently diagnosed patient with diabetes. In cases were other likely etiologies need to be excluded, laboratory analysis (e.g., CBC, CMP, HbA1C, ESR, CRP, etc.) and other diagnostic studies may be warranted (CT, MRI, EMG, biopsy, etc.). Early use of immunomodulators (e.g., steroids, IVIG, etc.) has been proposed as a superior therapy, but symptomatic treatment to improve quality of life may suffice, as this disease is self-limited in most cases, with a variable degree of impairment. This activity describes the recognition, evaluation, and management of diabetic amyotrophy and highlights the role of the healthcare team in evaluating, identifying, and improving patient care for this condition.

Objectives:

• Describe the pathophysiology of diabetic amyotrophy.
• Outline the typical presentation of a patient with diabetic amyotrophy.
• Summarize the various management options available for diabetic amyotrophy.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with diabetic amyotrophy.

Introduction

Diabetic lumbosacral radiculoplexus neuropathy (DLRPN), also known as diabetic amyotrophy, Bruns-Garland syndrome, proximal diabetic neuropathy, diabetic polyradiculopathy, multifocal diabetic neuropathy, femoral-sciatic neuropathy of diabetes, diabetic myelopathy, diabetic motor neuropathy, diabetic mononeuritis multiplex, and paralytic neuropathy classifies as part of the diabetic neuropathy spectrum. The various terms that allude to this disorder constitute evidence of the contrasting viewpoints regarding the anatomical localization and underlying pathophysiology of this disorder.[1][2][3][4][5][6]

Initial recognition of this condition, dates back to the late 19th century, as Leyden first described it in 1877 and Auche in 1890, but the original description of DLRPN is attributed to Bruns in 1890 by most authors.[1] It was not until the 1950s when Hugh Garland brought into being the term “diabetic amyotrophy.” In his research, he described the clinical course of 12 patients with asymmetrical, progressing, diffuse lower extremity pain, motor-weakness, accompanied with muscle wasting, weight loss, and areflexia, with a clear relation to uncontrolled diabetes and close to complete recovery with appropriate glycemic management.[1][4][5]

The anatomical and pathophysiologic mechanism of diabetic amyotrophy is not completely understood, but there is evidence of injury to the peripheral nerves, nerve roots, lumbosacral plexus, with accompanying axonal degeneration, demyelination, inflammation, ischemia, and immune-mediated microvasculitis.[1][3][6][7][8][9][10]

Etiology

There is increasing evidence for an inflammatory-immune mediated microvasculitis, with clear association to diabetes, but an unclear link in its pathophysiology.[6][8][11]

Risk factors for DLRPN include [4][6][8][6]: 

• More commonly affecting patients with type 2 diabetes mellitus [6][8]:
• Rapid glycemic management 
• Tight glycemic management 

Other possible risk factors include [3]: 

• Starting hyperglycemic treatment
• Immunizations
• Trauma
• Infections 

As part of the lumbosacral plexopathies, there is a wide etiological array including [6]: 

• Diabetic lumbosacral radiculoplexus neuropathy (DLRNP - diabetic amyotrophy)
• Idiopathic lumbosacral radiculoplexus neuropathy (DLRNP)
• Inflammatory/microvasculitis
• Trauma
• Retroperitoneal hematoma
• Neoplasms/metastasis
• Dural arteriovenous fistulas 
• Infection
• Radiation
• Sarcoidosis

Epidemiology

DLRPN is a rare presentation of diabetic neuropathy, occurring in approximately 1% of all diabetic patients. This disorder is more frequently seen in males and type II diabetic patients, as compared to type I.[1][4][8][11][12] This syndrome affects an older diabetic group, usually over 50 years, but the median age of onset is over 65 years.[4][5][11]

The median period from the initial diagnosis of diabetes, to the onset of DLRPN, is estimated to be approximately 4.1 years.[11]

A population sample studied at Olmsted County, MN, estimated the incidence of LRPN at approximately 4.16 per 100,000 per year, while the estimated incidence of DLRPN was approximately 2.79 per 100,000 per year. This data may differ from the general US population, as a less ethnically diverse population was studied.[6]

Pathophysiology

Diabetic Amyotrophy or DLRPN is an episodic, monophasic, asymmetrical neuropathy, with acute to subacute onset. The belief is that it is due to an immune-mediated, inflammatory state, resulting in vasculitis with ischemic nerve injury. This disorder may last from a few months, and up to 2 years. Although comparable to other neuropathies seen with diabetes, this disease is associated with less prolonged exposure to hyperglycemia, better glycemic control, tight glucose management, less diabetic micro/macrovascular complication (i.e., retinopathy, cardiovascular disease, etc.) development and a lower body mass index (BMI) than the average diabetic population. This information suggests a less clear association between diabetes, DLRPN, and disease severity.

Due to these findings and the negligible association between DLPRN and pre-diabetes, it may be theorized, that diabetes is a risk factor for this disease and not its primary cause. Abnormal sphingolipid metabolism has demonstrated a critical regulatory role in immunity and inflammation, which could also play a role in the pathogenic mechanism of injury.[13] Furthermore, there are striking pathophysiologic similarities between DLRPN and LRPN (idiopathic lumbosacral radiculoplexus neuropathy), suggesting they may be the same disease process. More studies are necessary to fully understand the mechanism of injury and the true role of diabetes in this disease.[4][8][9][10] 

Nerve biopsy evaluation has demonstrated degenerative changes secondary to microvasculitis with accompanying ischemia and inflammation, further ratified by CSF findings demonstrating elevated protein. These different degenerative changes due to inflammation and ischemia are presumed to be triggered by an immune response, possibly secondary to diabetes.[1][2][3][4][10]

Neurophysiology studies (i.e., nerve conduction studies, electromyographic examination) have demonstrated a multifocal process involving: the lumbosacral plexus, nerve roots, and the peripheral nerves (peripheral denervation changes).[10] Pathophysiologic similarities have been described between DLRPN, diabetic cervical radiculoplexus neuropathy (DCRPN), and diabetic thoracic radiculoplexus neuropathy (DTRPN). Similar pathophysiologic findings, as well as frequent comorbid occurrence, signal a common underlying mechanism and are the reason why these three entities may classify under the same spectrum of disease: diabetic radiculoplexus neuropathy.[1][3][4][6][7][3][9][10][12][14]

Histopathology

Nerve biopsy is not essential for the diagnosis of DLRPN, but cutaneous (sural and/or superficial peroneal) nerve biopsies have undergone analysis utilizing different histochemical stains, which have served for a better understanding of the disease process. As seen with ischemic injury, reports of asymmetrical, multifocal degeneration, loss of fibers within the nerve fascicles, perineurium fibrosis, neovascularization, and hemosiderin build-up have been recorded. Lastly, epineurial microvessel inflammatory infiltrates (mural and perivascular infiltration), vessel wall necrosis, separation of the smooth muscle layer of vessels, and bleeding (hemosiderin-laden macrophages) have also been evidenced.[1][2][3][4][5][6][7][8][10]

History and Physical

Typically presenting in the elderly (median age 65 years), DLRPN is an episodic, monophasic disease that is clinically active for a relatively short period (few months - 2 years). This neuropathy presents acutely/subacutely, with an asymmetrical, focalized, unilateral, and proximal lower extremity (thigh, buttocks, or hip) distribution early in the disease. Widespread, multifocal, bilateral progression becomes apparent as disease advances, with a wide range of symptomatic severity. 

Presentations include severe neuropathic pain (most aggravating initial symptom), with predominant motor-strength weakness, proximal muscle atrophy, and frequently associated weight loss (typically exceeding 10 lbs). Progressive worsening of the disease process is seen, until eventual stabilization, and gradual recovery, often with some degree of impairment. In comparison to other complications caused by diabetes, patients who present with diabetic amyotrophy, often have newly diagnosed diabetes, a short period of exposure to hyperglycemia, better glycemic control, less diabetic micro/macrovascular complications (i.e., retinopathy, CV disease, etc.), and a lower BMI than the average diabetic population.[3][1][4][5][6][7][8][12][14]

Other findings include[8]: 

• Numbness
• Tingling
• Areflexia 
• Para/quadriplegia
• Change in sweating 
• Foot drop (long-term complication)
• Orthostatic hypotension
• Diarrhea
• Constipation
• Change in sweating

Evaluation

Recognition of this syndrome may be challenging since its presentation may have similar findings as other more worrisome diagnoses. It is a clinical diagnosis, and no definitive test yet exists. Health professionals need to be aware and have a clinical suspicion based on characteristic features in a newly diagnosed diabetic patient to make an adequate diagnosis and avoiding unnecessary testing and procedures.[4] 

Laboratory/blood investigations may include blood chemistry (electrolytes, liver function tests), hemoglobin A1C level, inflammatory markers (erythrocyte sedimentation rate, C reactive protein), etc.[1][3][5][12]

CSF evaluation has demonstrated elevated protein levels and pleocytosis, suggesting inflammation.[1][3][12]

Electrophysiologic testing: 

• Nerve conduction study: Asymmetrically reduced sensory and motor action potential amplitude in affected muscle sites.[4][12][14]
• Electromyography (EMG) has shown wide-spread (sensory, motor, autonomic nerves) patchy involvement, fibrillation potentials, prolonged-duration, and high-amplitude motor unit potentials.[1][3][4][12][14] 

MRI most commonly is seen with a T2 signal increase, with varying severity.[1][3][12][14]

Sural nerve biopsy has been described extensively, to aid for the diagnosis of DLSRP but is not integral in the diagnosis of this syndrome.[1][3][12][14]

Laboratory studies, electrophysiologic studies, biopsies, and imaging (X-ray, CT, MRI suspecting compression) may be useful for exclusion of other etiological causes of neurologic symptoms, but emphasis must focus on DLRPN being primarily a clinically based diagnosis.[4][14]

Treatment / Management

Diabetic lumbosacral radiculoplexus neuropathy follows a limited disease course. Multiple small studies have correlated improvement of patient outcomes regarding symptomatic improvement with the use of immunosuppressant agents: steroids, immunoglobulin, and plasma exchange, but clear evidence is still necessary due to conflicting outcomes.[4]

In a double blinded-study, including 75 patients, comparing high-dose steroid (weekly dose of 1g methylprednisolone, for 12 weeks) vs. placebo, there was a statistically significant improvement in the patient’s secondary end-point (symptomatic improvement of pain and weakness). The primary outcome, which measured time to improvement, was not met, as it demonstrated both patient samples had improvement in subsequent evaluations. The hypothesis is that earlier intervention in patients using steroids would result in a more favorable outcome than patients not using steroids. Ultimately, no conclusive evidence has shown support for the use of immunomodulators.[4][7][8][9][11][12][15][16]

The treatment itself is centered mainly on symptomatic management of pain, management of hyperglycemia, and improvement in mobility. Pain management with paracetamol and NSAIDS is an option. Amitriptyline at night (particularly in accompanying insomnia), selective serotonin receptor inhibitors (SSRIs) for depression/anxiety and anticonvulsant agents are also possibilities. Opiates (tramadol, oxycodone) or steroids may merit consideration in severe disease, and hospitalization or pain management consultation may also be contemplated in cases with unremitting pain.[9][12] 

In some cases, when total pain relief is not possible, the goal becomes to make the pain more tolerable for the patient. Appropriate counseling should be given regarding the prolonged course of the disease, providing encouragement due to potential disability and reassurance on some degree of improvement. Disability and home safety, among other problems, should also receive attention. Management of diabetes may be recommended.[1]

Differential Diagnosis

• Diabetic neuropathy
• Nerve root compression 
• Diabetic muscle infarction 
• Infiltrative pelvic malignancy
• Chronic inflammatory demyelinating polyradiculoneuropathy
• Vasculitides
• Sarcoidosis
• Infections (HIV, Epstein-Barr virus, Cytomegalovirus, varicella-zoster virus, syphilis)
• Post-radiotherapy, postoperative and obstetric instrumentation.[4][6][12]

Prognosis

Overall, a good prognosis is expected for diabetic amyotrophy, as this is a self-limited process. The course of the disease tends to worsen progressively, followed by stabilization and ultimately complete recovery, with some cases presenting with some degree of residual motor deficit. The disease course happens in a period of months and lasts up to 2 years after onset.[1][3][17] In some cases, although rarely described, progression to quadriparesis has been reported, with an unknown degree of recovery.[18]

Complications

• Paraplegia 
• Quadriplegia
• Depression
• Anxiety
• Unnecessary spinal surgery[4][17][18]

Deterrence and Patient Education

Education is important in patients presenting with this disease, regarding awareness of the possibility of progression to significant motor weakness (i.e., paraplegia/quadriplegia) and accompanied by unremitting pain in atypical cases from the most severe side of the spectrum. Patients should be encouraged, and reassurance provided, as this is a limited disease process, with an expectation of complete or partial self-resolution.[1][4][1] 

Enhancing Healthcare Team Outcomes

In severe cases, where patients have an atypical or severe presentation of the disease, they may benefit from a neurologist evaluation. Radiologists and pathologists may assist in diagnosing, as imaging and ultimately nerve biopsies may help clarify ambiguous presentations or rule-out other potential etiologies. In conjunction with these specialists, primary care physicians, endocrinologists, psychologists, psychiatrists, social workers, neuromuscular/physiatry specialists may aid in recognition, recovery, physical therapy/rehabilitation, tight glycemic management, orthotic device procurement, and patient education, to ultimately provide an interprofessional approach to improve patient outcomes.[1][3][4][3][6] [Level 3]