BETPresentation DiabeticAmyotrophy (08!02!13)

8/10/2019 BETPresentation DiabeticAmyotrophy (08!02!13)

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Best Evidence Topic Presentation

Neurology Clerkship

NAMES

August 2, 2013

Title:Etiology, Manifestation and Management of Diabetic Amyotrophy in patients with NIDDM

Clinical Scenario:

Patient is a 51 year old African American male with Type II Diabetes who presented to the emergencydepartment with complaint of weakness and numbness in the lower extremities for over a month. Patient was

admitted to Neurology for further work up. Upon physical examination, weakness and numbness were exhibited

bilaterally (4/5) in the lower limbs. Decreased sensation and numbness were particularly localized to the lateral

portion of the patients left lower leg. Weakness and numbness were also elicited in the upper extremities, with

the right side exhibiting greater loss of sensation, and decreased strength (4/5) as compared to the left side.

Patient denies pain. Muscle wasting was evident in the right hand, and most pronounced in the thenar,

interossei, and abductor digiti minimi muscles. Patient has to concentrate on walking but physical exam

reveals no cerebellar defect. Bicep, tricep, brachioradialis, patellar, and achilles reflexes are intact and

responsive (5/5). Babinski sign is negative. MRI positive for central canal narrowing (T11-T12). MRI positive

for compression in the lumbosacral spine (L5-S1), with greater severity on the right side.

Search Strategy:

MEDLINE 1993-08/13 using the OVID interface, Google scholar, Pubmed. American Association of

Neuromuscular & Electrodiagnostic Medicine. UpToDate.com.

Author, date and

country

Kelkar, Praful MD; Masood, Moeen MD; Parry, Gareth J. MD. July 12, 2000.

USA

Patient group 15 patients with Proximal Diabetic Neuropathy (PDN) also known as diabetic

amyotrophy and two diabetic control groups

Study type (level of

evidence)

Case-control Study

Outcomes Support for humoral factors comes from findings of Ig and complement

deposition in peripheral nerves in diabetes. Noted small-vessel neutrophilic vasculitis with PMN infiltration in

postcapillary venules along with IgM deposition in endoneurium and in

affected vessel walls, and activated complement deposition in smallvessels.

Deposition of IgM in the endoneurium and in the walls of affected vessels.

We also found deposition of the activated complement along the

endothelium in small vessels with mAb directed against C5b-9 Humoral as well as T cell-mediated processes seem to be involved.

Diagnosis of PDN based on presence of subacute illness with progressive,asymmetric proximal lower extremity weakness and wasting, with orwithout pain, presenting in patients with a diagnosis ofdiabetes mellitus;


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reduced or absent lower extremity deep tendon reflexes; andelectrodiagnostic studies showing fibrillation potentials or positive sharpwaves in at least two proximal lower extremity muscles innervated by twodifferent nerves (may include paraspinal muscles), with or without

evidence ofperipheral neuropathy. Diagnosis of PDN requiredabsence of upper motor neuron signs

(spasticity, hyperreflexia, + Babinski), CNS disorder (excluding diabetic

neuropathy; presence of severe peripheral vascular disease as manifested

by femoral bruits or absent lower extremity pulses; and structural spinalcord or pelvic lesions such as lumbar canal stenosis, carcinomatousmeningitis,radiation to spinal cord or lumbosacral plexus, and malignantinfiltration of the lumbosacral plexus.

Key results Four patients showed the distinctive findings of polymorphonuclear small-

vessel vasculitis affecting epineurial vessels with transmural infiltration of

postcapillary venules with polymorphonuclear leukocytes.

Immunoglobulin M (IgM) deposits were found along the endothelium andintramurally in affected vessels. IgM staining was seen in the

subperineurial space and in the endoneurium.

Activated complement deposition was seen along endothelium of small

vessels. Six patients showed "perivasculitis" with mononuclear cell infiltrates

around small epineurial vessels without vasculitis (fibrinoid necrosis or

transmural inflammation). One patient showed recanalized vessels with transmural lymphocytes

without fibrinoid necrosis, possibly suggesting healed vasculitis

Study Weaknesses Patient population (cases) was not completely uniform, and thus they may

introduce unseen biases to the study

Because of the progressive nature of (diabetic) neuropathyfunctional impairment varied from mild difficulty in ambulation to

being wheelchair bound (3 wheelchair-bound, 4 walker forambulation, and 8 required minimum support with a cane)

Results may be affected by Lead-time Bias

Thirteen patients experienced significant weight loss, which ranged from

10 to 43 pounds; muscle weakness can be associated with malnutrition orsudden weight loss. Therefore this finding may introduce a Confounding

bias into the study

Study was not blinded

Pygmalion effect- occurs when a researcher's belief in the efficacyof a treatment changes the outcome of that treatment

Author, date and country Howard W. Sander, M.D., and Sudhansu Chokroverty, M.D.

Patient group Journal article on the current conceptual understanding of diabeticamyotrophy distinguishing it from other forms of neuropathies.

Study type (level of evidence) Meta-analysis

Electrodiagnostic studies:


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Nerve conduction and needle electromyography examinations assist in

distinguishing diabetic amyotrophy from other possible disorders.

Femoral motor nerve conduction studies usually reveal prolonged femoral

nerve latency and reduced amplitude of the femoral nerve compound

muscle action potential (CMAP). Conduction velocity and distal latencies

in the peroneal and tibial nerves are normal or mildly decreased and the

CMAP amplitude may be reduced. These studies indicate a

predominantly proximal axonopathy in the lower limbs, with or without a

superimposed mild distal sensorimotor polyneuropathy.

Outcomes Diabetic amyotrophy is a distinct clinical entity that can be

differentiated from other diabetic neuropathies. Electrodiagnosticand pathologic studies reveal evidence of a neurogenic lesion

affecting predominantly proximal musculature. A concomitant distal

sensorimotor polyneuropathy may be present, in which case there isoften a slower progression and more symmetrical involvement

While recovering from diabetic amyotrophy strength may improves

but the muscle wasting may persist. Muscle stretch reflexes often do

not recover. Sanders cites a study by Coppack and Watkins of 26

patients with diabetic amyotrophy, no additional recovery occurredfollowing 18 months. Mild residual functional weakness (difficulty

ambulating and climbing stairs) was present in seven patients, anddecreased thigh circumference with depressed knee reflexes

persisted in 13 of the patient. He also cites a prior study by Casey

and Harrison of 12 patients only 3 recovered full function and 5 hadsignificant residual disability. Improvement has been correlated with

better glycemic control, although Improvement also occurs in some

patients without concomitant control of hyperglycemia."

The severe pain associated with diabetic amyotrophy begins to abate

several months after onset, but residual pain may continue for

several years. Analgesics are helpful for pain control in most of the

cases. Amitriptyline and desipramine have been shown to beefficacious for treatment of pain in the more common distal

sensorimotor neuropathy of diabetes, and phenytoin and

carbamazepine have been used as well. Transcutaneous nervestimulation has been beneficial in an occasional patient.

Key results Study of 13 patients with either diabetic amyotrophy or mononeuritis

multiplex (Krendel et al)

10 patients (biopsy of leg muscle or nerve performed)

reported small vessel disease 7 of these 10 had perivascular chronic inflammatory cells and

3 had arterial occlusion with inflammation.

Sural nerve biopsy study in 12 patients with proximal diabeticneuropathy (among 20 patients with diabetic neuropathy) (Younger

et al)

6 had a T-cell microvasculitis 6 had perivascular lymphocytic infiltration

4 had mononuclear cell infiltration of nerve


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2 had focal changes suggestive of ischemia

All patients showed a predominantly CD8+ T-cell infiltration

of nerve Neurogenic changes were seen in four of five proximal

diabetic neuropathy patients who underwent muscle biopsy

Myopathic changes were present in one patient.

All (21) patients (including the 13 patients with either diabetic

amyotrophy or mononeuritis multiplex) who were treated with a

variety of immunomodulating agents stopped worsening and began

to improve. All (8) patients (including 5 with proximal diabetic neuropathy)

whose treatment with intravenous immunoglobulin (IVIG) was

based on vasculitic sural nerve biopsy findings had decreased painand significant improvement in strength.

Dose of IVIG was 2g/kg total body weight over 5 days, monthly for 3

months

Study Weaknesses No additional primary evidence

Author, date and country Bruce Taylor, and John Dunne. May 7, 2004. USA

Patient group Two patients with definite diabetic amyotrophy progressing subacutely tosevere quadriparesis are discuss extensively within the article.

Study type (level of

evidence)

Case Report

Case 1.A 76-year-old woman presented with a 6-week historyof

bilateral but asymmetric (right left) knee pain followed by

progressive difficulty with walking, because of the knees givingway.

Case 2.A 56-year-old woman presented with 2 weeks of increasing

asymmetric medial thigh pain and paresthesias (right > left), andproximal leg weakness.

Outcomes Both cases presented with asymmetric proximal lower-limb pain

followed by weakness, as has been previously described as typical

for diabetic amyotrophy.

Case 1then had a stepwise progression of asymmetric lower-

then upper-limb weakness that occurred over 3 months

resulting in quadriparesis, with severe residual disabilities.

Case 2 had a gradual progression to generalized weaknessover 6 weeks that resulted in severe quadriparesis, but

ultimately had an excellent although incomplete recovery.

Presence of distal sensory peripheral neuropathy in both cases

supports the view that the various forms of diabetic peripheralnervous system disease are not necessarily mutually exclusive

conditions.

An argument can be made for distinct diabetic neuropathies However, the clinical descriptions of diabetic amyotrophy


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and subacute diabetic proximal neuropathy make the

distinction far from clear.

Most authors would now favor a distinction betweenprincipally metabolic/microangiopathic neuropathy as in

diabetic length-dependent peripheral neuropathy and immune

vasculopathy as seen in diabetic amyotrophy.

Key results Case 1

Findings were consistent with an evolving and severepolyradiculoneuropathy

Stepwise progression of patchy and asymmetric lower- and then

upper-limb weakness and sensory losscontinued over a total of 20weeks from onset, leading to severe quadriparesis (mostly grades 0

3),

Respiratory function tests indicative of respiratory muscle weakness.

Patient became totally bedbound Slow recovery then commenced, however after 42 months she had at

least moderate weakness (grades 34) of all limbs, and remained

chairbound and dependent

Sural nerve biopsy on light microscopy showed prominent axonalloss mainly involving large myelinated (1012 m) fibers, patchy

perivascular mononuclearcell infiltrates without involvement of the

vessel wall, and no demyelination, consistent with diabeticneuropathy

Electron microscopy showed loss of myelinated fibers

Case 2 Initial examination showed grade 3 hip-flexor weaknessonly and

absent knee jerks, with minor and patchy impairment of pinprick

sensation distal to the mid-calves.

Gradual progression over 4 weeks led to asymmetric and severe

quadriparesis (mostly grades 12), the weakest muscles beingproximal and in the lower limbs. All deep tendon reflexes were lost.

Patchy sensory impairment to all modalities was present in thefingers and toes. Patient was bed-bound and totally dependent

Sural nerve biopsy showed prominent axon loss mainly affecting

large-diameter (1216 m) myelinated fibers, with increased

endoneurial collagen, some areas of segmental myelin breakdownand remyelination, and thickening of the media and intima of

epineural blood vessels.

Slow recovery commenced 8 weeks after onset

After an additional 3 months patient was able to walk with a stick

and was independent Moderate diffuse weakness and stocking sensory impairment

persisted to the mid-calf. After 12 months, only residual signs were mild truncal and proximal

lower-limb weakness affecting particularly the iliopsoas, hip

adductors, and abdominal muscles, and diffuse hyporeflexia.

Overview

The two cases we present indicate the potential for patients

presenting with diabetic amyotrophy to progress to severe


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quadriparesis

Clinical spectrum of diabetic neuropathy, particularly diabetic

amyotrophy, includes progression to severe quadriparesis,and major residual disabilities

In both patients, neurophysiological findings were consistent with a

severe and diffuse polyradiculoneuropathy, predominantly axonal intype.

Sural nerve biopsies showed primary changes of axon loss

with predominant loss of large myelinated fibers

Perivascular inflammatory changes were prominent in onecase but absent in the other.

These findings are consistent with those that have been previously

reported in diabetes mellitusassociated neuropathies

Study Weaknesses Power of the study is weak (only two patients)

Author, date and country D. Kilfoyle, P. Kelkar, and G. J. Parry. 2003. NZ

Patient group 9 patients (5 men and 4 women; mean age 65 years (range, 4388 y)) with

diabetic amiotrophy occurring between 2000 and 2002

Study type (level of evidence) Outcomes Research/ Retrospective Cohort Study

Retrospectively reviewed the case records of 10 episodes ofdiabetic amyotrophy in 9 patients treated with pulsed oral or

intravenous methylprednisolone.

Outcomes Pulsed methylprednisolone (MP) appears to be a safe and effective

treatment for diabetic amyotrophy Patients were considered to have benefited from the treatment if pain

had improved by 3 months after symptom onset and strength or functionhad improved by 6 months.

MP at a dosage of 500 mg was administered either

intravenously or orally on 2 consecutive days every 2 weeks

for up to 3 months, depending on response.

Key results 6 episodes there was marked improvement in pain within days ofstarting treatment. Strength improved more slowly but faster than

the natural history of the disease.

Treatment started within 2 months of symptom onset was

associated with rapid improvement in pain Very early treatment, started within 4 weeks of symptom onset,

resulted in rapid improvement of both strength and pain. Blood glucose increased on treatment days but no patient required

lasting changes in diabetic treatment as the result of this therapy

and no other serious adverse effects were seen.

Each MP pulse was associated with transient asymptomatichyperglycemia.

In one patient, temporary insulin treatment was instituted

but in no other patient was the diabetes treatment altered.

One 84-year-old patient had a mild transient elevation of


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blood pressure during some treatments and experienced

visual hallucinations with her final treatment.

Insomnia and irritability on the treatment days were theonly other adverse effects.

Study Weaknesses Patients were considered to have benefited from the treatment if

pain had improved by 3 months after symptom onset and strength

or function had improved by 6 months.

Pain and Strength are often relative markers; lack ofempiricism may affect interpretation of results

Recurrence of severe pain and weakness in the opposite leg thatoccurred 2 months after completion of a 3-month course of

treatment of initial symptoms in one patient was treated within 2

weeks of onset, and was regarded by the authors as a second

episode This relapse may actually point to failure of the treatment,

which did not seem to be accounted for in the authors

assessment.

Patients level of weakness, strength, and immobility varied

significantly This may introduce lead-time bias into interpretation of the

success of the treatment plan and outcome Although there was a clear trend toward a more rapid improvement

(in patients with a shorter pretreatment duration of symptoms), the

numbers are too small for statistical analysis; Power of the study is

weak

Author, date and country Pascoe MK, Low PA, Windebank AJ, Litchy WJ. 1997. USA

Patient group 44 patients with subacute diabetic proximal neuropathy

Study type (level of evidence) A retrospective review of medical records of Mayo Clinic patients with

diabetes who had subacute onset and progression of proximal weakness.The responses of treated versus untreated patients were compared

statistically.

Outcomes During the designated study period, 44 patients with subacute

diabetic proximal neuropathy were encountered. Most patients


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were middle-aged or elderly, and no sex preponderance was noted.

The proximal muscle weakness often was associated with reduced

or absent lower extremity reflexes. Associated weight loss was acommon finding. Frequently, patients had some evidence of

demyelination on nerve conduction studies, but it invariably was

accompanied by concomitant axonal degeneration. Thecerebrospinal fluid protein concentration was usually increased.

Diffuse and substantial autonomic failure was generally present.

In most cases, a sural nerve biopsy specimen suggested

demyelination, although evidence of an inflammatory infiltrate wasless common. Of 12 patients who received treatment (with

prednisone, intravenous immunoglobulin, or plasma exchange), 9

had improvement of their conditions, but 17 of 29 untreatedpatients (59%) with follow-up also eventually had improvement,

albeit at a much slower rate.

Key results the entity of subacute diabetic proximal neuropathy is an extensive

and severe variant of bilateral lumbosacral radiculoplexopathy,

with some features suggestive of an immune-mediated cause.

It differs from chronic inflammatory demyelinatingpolyradiculoneuropathy in that most cases have a more restricted

distribution and seem to be monophasic and self-limiting.

The efficacy of immunotherapy is unproved, but such interventionmay be considered in the severe and progressive cases or ones

associated with severe neuropathic pain.

Study Weaknesses Power of the study is weak (sample size 44)

Author, date and country Barohn RJ, Sahenk Z, Warmolts JR, Mendell JR. 1991. USA

Patient group Clinical, laboratory, and biopsy results were reviewed from 17 consecutive

patients (14 women and three men) who were examined between January

1984 and July 1988 at the Neuromuscular Service at Ohio State University,Columbus. The diagnosis of proximal diabetic neuropathy, also referred to

as diabetic lumbosacral radiculoplexopathy, was made on the basis of the

following criteria: (1) onset of diabetes mellitus 2 either before or at the

onset of neurologic symptoms; (2) abrupt onset of hip, back, or leg pain,either unilateral or bilateral; (3) weakness of the lower extremities

involving proximal muscles or proximal and distal muscles, unilaterally or

bilaterally (patients with weakness confined to a peripheral-nervedistribution were excluded); (4) results of electrophysiologic studiesexcluding myopathy; and (5) lumbosacral magnetic resonance images,

computed tomograms, or myelograms excluding neoplastic disease,

multiple compressive radiculopathy, and spinal stenosis.

Study type (level of evidence) Retrospective Study

Outcomes Fourteen patients had unilateral onset that later involved the other

extremity in 3 days to 8 months.


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All patients reported stepwise or steady progression during 2 to 18

months that was documented during serial examinations. In 16

patients, both proximal and distal muscles were involved. Sural nerve biopsy specimens demonstrated multifocal variability

in nerve fiber density manifesting as nonrandom fiber loss between

and within fascicles compared with age-matched controls. Thesefindings demonstrate that patients may have a rapidly evolving

course of proximal diabetic neuropathy followed by continued

progression for many months and emphasize the overlap between

proximal diabetic neuropathies of presumed different types.

Key results Dr. Barohn states that their cases, as well as others, cast doubt on notionssupporting two distinct types of proximal diabetic neuropathies represented

by the rapid evolution of asymmetric weakness on an ischemic basis, in

contrast to a more slowly progressive condition of metabolic pathogenesis.

Study Weaknesses Power of the study is weak (sample size 17)

Conclusion:

The etiology of Diabetic Amyotrophy (DA) is not very well understood. There is a strong argument for immune

involvement, and increasing evidence points to a cause by microvasculitis of the vasa nervorum. There may be

nerve ischemia secondary to immune-mediated vasculopathy rather than diabetic microangiopathy. It is further

argued that neuropathy seen in DA has an immune-mediated inflammatory basis and suggest that

polymorphonuclear (PMN) vasculitis with immune complex and complement deposition may be the primary

impetus.

Diabetic amyotrophy often occurs in patients with a concomitant, preexisting distal sensorimotor

polyneuropathy. Incidence in diabetics, and concomitance with other neuropathies cause DA to be difficult toidentify. However the localization of muscle weakness and loss of sensation may assist in recognizing this

condition. Presentation of DA is often subacute and progressive with involvement often clinically first noted in

the proximal lower limbs particularly quadriceps femoris. However simultaneous involvement of the gluteal,

hamstring, adductor, and iliopsoas muscles often occurs. The predominantly proximal motor involvement is in

clear contrast to the distal, predominantly sensory "stocking"distribution typical of the common diabetic

polyneuropathy. In addition to proximal muscle weakness, wasting in muscles of the proximal lower extremity

favors a diagnosis of DA.

The Clinical Bottom Line:

Diabetic Amyotrophy is difficult to identify and treat. It can be recognized by proximal muscle weakness andloss of sensation in the lower limbs, particularly in the pelvifemoral muscles. There may be associated pain and

loss of sensation in the affected muscles and limbs. Upper limb involvement is rare. Etiology of the condition

may have an autoimmune component, and thus further research needs to be conducted into management with

IVIG and steroids.

Reference Images


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