50 Practical Neurology March 2005

europathy is one of the commonestreasons for patients to be referred to orto seek the care of a neurologist. Whilesymmetric and length-dependent neu-

ropathies are the most prevalent, their differentialdiagnosis is vast and they are often untreatable.

In contrast, asymmetric neuropathies have amore limited list of potential causes includ-

ing many that may be treatable.When confronted with a neuropathy

patient, the neurologist should be awareof historical and examination featuressuggestive of asymmetry. This is often

obvious in individuals suffering from oneor a few focal neuropathies. It is more difficult when multiplemononeuropathies become confluent and resemble polyneuropa-thy. This article will focus on some of the causes of asymmetricneuropathies. A subsequent article will discuss symmetric presen-tations.

DiabetesDiabetes mellitus is one of the most common causes of asymmetric neuropathic syndromes. The clinical forms includediabetic pelvifemoral neuropathies, one or more mononeu-ropathies and entrapment neuropathies.

Lumbosacral Plexopathy. This disorder presents with subacute weakness limited to both the proximal (iliopsoas,quadriceps, adductors and abductors) and distal (foot dorsi andplantar flexors) musculature of one leg. It is accompanied bynon-mechanical, aching pain that is often quite severe in theregion of the hip, buttocks and thigh. Sensory loss, if present, isdistal. Heralding symptoms include poor glucose control andweight loss.

EMG demonstrates acute denervative change in a non-length dependent pattern including lumbar paraspinal musclesas well as distal and proximal leg muscles. NCV demonstrates

low CMAP and SNAP amplitudes that may be asymmetric.

N

The suspected pathology is a vascular radiculoplexopathy.Treatment includes pain and glucose control. Some have advo-cated corticosteroids and/or IVIg. Slow recovery, which may bepartial, occurs over six to 24 months with or without treatment.

Diabetic Amyotrophy. This disorder shares many of thesame features as lumbosacral plexopathy. Weakness, however, isrestricted to proximal muscles and sensory loss is not a promi-nent component. Recovery occurs over six to 12 months. Somehave advocated treatment with corticosteroids and/or IVIg butanalgesia and glucose control are the usual treatments offered.

Mononeuropathies. Diabetes can produce lesions of singlenerves or single roots. Commonly involved cranial nervesinclude the third, fourth and fifth nerves. Onset is sudden andis accompanied by retro-orbital pain. The pupil is typicallyspared in diabetic third nerve lesions. The pathology is vascu-lar. Treatment consists of analgesia and diabetic control. Prog-nosis for recovery is good. Major limb nerves and the thoracicroots or intercostals nerves are similarly vulnerable to vascularocclusion. Onset is unilateral and abrupt with pain that issevere and non-mechanical. Weakness and sensory loss occurdistal to the site of the lesion. Weakened abdominal wall mus-culature that may accompany thoracic root or nerve injury canproduce asymmetric bulging of the abdomen. Treatment isagain directed at pain and glucose control.

Entrapments. Diabetes is commonly associated with medi-an neuropathy at the wrist and ulnar neuropathy at the elbowthat is often asymmetric. Treatment for median neuropathyconsists of splinting of the wrist, injection of the carpal tunnelor surgical decompression. Treatment for ulnar neuropathyconsists of padding of the elbow or ulnar nerve release.

Vasculitis andVascularInflammationConnective Tissue Dis-orders. Vasculitis associatedwith various inflammatory/immune disorders can resultin asymmetric neuropathy. Theseinclude Bechets, Scleroderma, Polyarteritis Nodosa,Wegeners Granulomatosis, Rheumatoid Arthritis,Lupus, Giant Cell Arteritis, and Churg Strauss. Onsetis usually abrupt and may be associated with systemicsymptoms such as weight loss, fever, rash and arthral-gias. Electrodiagnostic studies demonstrate asymmetricand multifocal axon loss. Pseudoconduction blockrelated to ischemia can be seen soon after lesiononset.

Biopsy is indicated for definitive diagnosis of aprogressing asymmetric neuropathy. The diagnos-tic yield is increased if both nerve and muscle arebiopsied. Pathological findings include perivas-cular epineurial inflammation, inflammation andnecrosis of vessels, patchy or fascicular axonal losswith Wallerian degeneration, and subperineurialedema. Treatment consists of high dose oral (e.g.,1mg/kg/day) or intravenous (e.g., 1g/day x 5 daysfollowed by 1g/day q week x 1 month followedby 1g/day qo week) corticosteroids. Patients withsystemic disease may require concomitantadministration of cyclophosphamide (e.g., IV

March 2005 Practical Neurology 51

There are hundreds of causes of nerve dysfunction, some of whichmay be difficult to diagnose. Part one of this two-part series considers some causes of asymmetric neuropathy, includingmononeuropathy and mononeuropathy multiplex.

1g/m2 monthly x 4-6 months) or methotrexate (e.g., 15 to25mg po. weekly).

Drugs. Various drugs can produce a vasculitis that can affectperipheral nerves and frequently the skin as well. These includecocaine, amphetamine, heroin, phenylpropanolamine, pheny-toin, sulfonamides, and allopurinol. Treatment consists ofwithdrawal of the offending drug and use of corticosteroidsdepending upon severity

InfectionsHIV. HIV can result in acute inflammatory demyelinatingpolyradiculoneuropathy (AIDP or Guillain-Barre Syndrome)at the time of seroconversion or in symptomatic/asymptomaticseropositive individuals. A CSF pleocytosis is characteristic ofAIDP related to HIV. Treatment consists of plasma exchangeor IVIg. HIV can also produce chronic inflammatory demyeli-nating poly-radiculoneuropathy (CIDP) with a similar distinc-tive feature of a CSF pleocytosis. Treatment consists ofimmunomodulating therapy as with non-HIV related CIDP.This includes corticosteroids, cytotoxic medications,cyclosporine, mycofenelate-mofetil, IVIg and plasma exchange.

Multiple mononeuropathies (mononeuropathy multiplex),usually sensory greater than motor, caused by a necrotizing vas-culitis can occur in individuals with early symptomatic HIVinfection previously known as ARC (AIDS related complex).These individuals usually have a CD4 count greater than 200and so called “B symptoms” associated with early HIV infec-tion. The course is usually indolent.

Co-infection with CMV can produce two clinical syn-dromes. One is a rapidly developing mononeuropathy multi-plex of limb and or cranial nerves that occurs in individualswith CD4 counts <100. Nerve biopsy usually demonstratesinflammation with giant cells and CMV immunoreactivity.The other is an ascending polyradiculopathy that begins withback and leg pain and rapidly progresses to urinary inconti-nence and flaccid paraplegia in individuals with CD4 counts<50. At times it can progress to involve cervical level roots andcranial nerves. The latter syndrome is usually associated with aCSF pleocytosis, high protein and low glucose. The CSF PCRfor CMV is usually positive. In both of these syndromes theremay be evidence of systemic infection (e.g., retinal, blood,urine) with CMV. Treatment consists use of anti-retroviraltherapy along with gancyclovir or foscarnet for CMV.

Individuals with HIV may also develop one or more out-breaks of herpes zoster (VZV) that can produce sensory and attimes motor mononeuropathies affecting cranial nerves as wellas cervical, thoracic or lumbosacral roots. This should be treat-ed with acyclovir or famcyclovir.

Lyme (Borrelia burgdorferi). Lyme disease can produce anumber of asymmetric neuropathies. Cranial neuropathy most

c o m -monly affectsthe facial nerve(VII) but can affect theoculomotor nerves (III, IVand VI) and the trigeminal nerve(V). All may occur early in the diseasecourse even before serum antibody testingbecomes positive. CSF may demonstrate a pleocy-tosis but can be normal.

Asymmetric and multifocal radiculoneuropathy can pro-duce pain, often burning and radicular in quality, and sensorydisturbance that may be distally predominant in the legs butcan be dermatomal particularly in the thoracic and lum-bosacral regions. Lyme disease has also been associated with thesubacute development of brachial plexopathy, lumbosacralplexopathy, and multiple mononeuropathies. Electrodiagnosticstudies demonstrate evidence of asymmetric and non-lengthdependent axonal loss. CSF may demonstrate a pleocytosiswith evidence of a positive CSF Lyme titer, an elevated IgG,oligoclonal banding, positive CSF Lyme antibody synthesisindex and PCR for the Lyme agent. Nerve biopsy may demon-strate perivascular inflammatory infiltration.

Treatment of Lyme-related facial palsy or other cranial neu-ropathy is usually limited to 28 days of oral doxycycline,cefuroxime or amoxicillin. Radiculoneuropathy, brachial plex-opathy, lumbosacral plexopathy and mononeuropathies arealso usually treated with oral agents. If any of these asymmet-ric neuropathies are accompanied by evidence of meningitiswith positive Lyme serology in CSF the recommended treat-ment is IV ceftriaxone, cefotaxime or penicillin.

Leprosy (Mycobacterium leprae). Tuberculoid leprosy pro-duces focal granulomatous enlargement within one or morenerves. The nerves most commonly affected are cutaneous sen-sory nerves including finger and toe digital nerves, the suralnerve and the posterior auricular nerve and the median, ulnarand peroneal mixed nerves. Nerves are often enlarged. Distal tothe enlarged nerves there may be a few skin lesions that arehypopigmented, hairless and anesthetic. Electrodiagnosticstudies may demonstrate asymmetric prolongation of distalmotor and sensory latencies as well as focal conduction slowing(e.g., ulnar nerve at the elbow). Evidence of axon loss may also

Causes of Neuropathy

52 Practical Neurology March 2005

occur partic-ularly when chronic. Nerve biopsy of enlarged nerves

demonstrates marked inflammation with granulomas and giantcells. There may be differential involvement of some fascicles.Few organisms are seen.

Lepromatous leprosy produces skin and nerve lesions par-ticularly in the cooler regions of the body. The result is anapparent length-dependent and symmetric neuropathy withthe additional sensory involvement of the ears, cheeks andnose. There is often an associated bilateral ulnar neuropathyabove the elbow. Small-fiber sensory loss (pin and temperature)is usually greater than large-fiber loss (proprioception and dis-criminative touch) and tendon reflexes can be preserved.Involved nerves are diffusely enlarged. Nerve biopsy demon-strates little inflammation with many organisms often con-tained within Schwann cells.

Borderline leprosy has features of both the tuberculoid andlepromatous forms. There are often many skin lesions andmany nerves may be involved. It often progresses more rapidlythan the other forms. Leprosy is also capable of producing neu-ropathy, often in a mononeuropathy multiplex pattern, with-out associated skin lesions.

Treatment of tuberculoid leprosy usually consists of dap-sone 100mg/day and Rifampin 600mg/day for one year.Treatment of lepromatous leprosy also includes clofazimine50mg/day. Treatment of leprosy, particularly the borderlineand lepromatous forms, with antibiotics may produce an acuteneuritis as a result of a vasculitis associated with the immuneresponse to degenerating organisms. This may producemononeuropathy multiplex in association with painful, red,subcutaneous nodules referred to as erythema nodosum lepro-sum. This complication of the treatment of leprosy is treatedwith corticosteroids.

Hepatitis C. Infection with hepatitis C can result in a

nerve-specific small-vessel vasculitis that produces a subacuteto chronic asymmetric sensory or mixed sensory and motorneuropathy. Less commonly, hepatitis C can result in a sys-temic medium-sized vessel vasculitis producing polyarteritisnodosa. Mononeuropathy multiplex is associated with featuresof a systemic vasculitis such as stroke, renal insufficiency andmesenteric occlusion. The treatment is high-dose steroids,cytotoxic medications and/or plasma exchange. When hepati-tis C is associated with mixed essential cryoglobulinemia, it canproduce a cutaneous sensory neuropathy often with cutaneousvasculitis manifested as palpable purpura.

Immune-Mediated Chronic, Asymmetric NeuropathiesChronic Inflammatory Demyelinating Polyradiculoneuro-pathy. CIDP can take the form of a multifocal and non-lengthdependent sensory and motor disorder with hand > leg/footweakness. Multifocal motor neuropathy (MMN) is a motor-specific disorder that is asymmetric and non-length dependent.Arm weakness is usually greater than leg weakness. Nerve con-duction study may demonstrate focal motor without sensoryconduction block. Fifty to 80 percent of these individualsdemonstrate an antibody to GM1 while less than one quartermay have a paraprotein spike. Patients with antibodies direct-ed at GM2 and/or GalNAc-GD1A may present with an asym-

March 2005 Practical Neurology 53

Episodes of HNPP may

be precipitated by trauma,

repetitive activities or

stretching but can occur

after sleeping or seemingly

without any obvious

precipitant.

54 Practical Neurology March 2005

metric sensory > motor demyelinating neuropathy. Many ofthese patients may also have a paraprotein spike.

Treatment for all of these immune-mediated neuropathiesinvolves immunosuppressive therapy that may include corti-costeroids, IVIg, plasma exchange and cytotoxic medications.Cyclosporine and rituxan have also been advocated for CIDPand MMN respectively.

Sarcoidosis. Sarcoidosis can cause acute to subacutemononeuropathy or multiple asymmetric neuropathies. It caninvolve cranial nerves (most commonly VII, II, VIII, IX, X) aswell as limb and truncal nerves (median, ulnar, radial, peroneal,intercostals, phrenic). Sarcoid may also produce lumbosacralplexopathy and polyradiculopathy. Diagnosis requires biopsydemonstration of non-caseating granulomas most commonlyfound in lymph nodes or in muscle. Treatment consists of cor-ticosteroids and possibly other immunosuppression.

Vascular Occlusion. Thrombotic or embolic occlusion oflarge lower-extremity arteries produces an ascending sensoryand motor neuropathy up to the site of the occlusion. Withouttimely re-vascularization, infarction of nerve will ensue with adistal-to-proximal progression. The end result can be an asym-metric sock or boot type sensory and motor neuropathy.

Aortic cholesterol emboli produce occlusion of smallerarteries in the feet and legs. This can be precipitated by instru-mentation of the aorta during arterial imaging procedures andby the institution of anticoagulation. This can result in a sym-metric or asymmetric (mononeuropathy multiplex) neuropa-thy associated with livedo reticularis, blue toes, and myalgia.Biopsy of muscle and/or nerve can demonstrate cholesterolcrystals within small arteries.

Sickle cell crisis can produce nerve infarction(s) that canresult in painful sensory or sensory and motor mononeuropa-thy multiplex.

Lymphoma. Angiocentric lymphoma can produce amononeuropathy or multiple mononeuropathies that involvecranial as well as limb sensory and motor nerves. The clinicalcourse is subacute and progressive but at times can be relapsingand remitting. Nerve and/or muscle biopsy may demonstratelymphoma within small arteries. Treatment, which oftenincludes steroids, is directed at the lymphoma.

Hereditary Neuropathy with Predisposition to PressurePalsies. HNPP is an autosomal dominant disorder with vari-able penetrance caused in most cases by a deletion of the PMP-22 gene on chromosome 17. This is the same gene that isduplicated in CMT 1A. Less commonly, HNPP is caused bypoint mutations in the same region. Patients often developacute, transient, usually painless episodes of focal sensory,motor or sensory and motor neuropathy that usually resolveover weeks to months.

Episodes may be precipitated by trauma, repetitive activities

or stretching but it can occur after sleeping or seemingly with-out any obvious precipitant. Nerves are affected at expectedsites of compression (e.g., median at wrist, ulnar at elbow, per-oneal at knee). HNPP can also produce painless brachial plex-opathy. Over time patients may develop permanent deficitsthat are rarely severely disabling.

Wartenberg’s Migratory Sensory Neuritis. This cutaneous,sensory mononeuropathy multiplex occurs as a subacute epi-sodes but it can be recurrent. Any cutaneous sensory nerve canbe involved. At times, the focal nerve lesions can be painful.Most symptoms resolve but permanent sensory loss can persist.Electrodiagnostic studies demonstrate axon loss in the distribu-tion of the involved cutaneous nerves.

Evaluation of Asymmetric NeuropathiesFollowing a comprehensive history and physical examination,the clinical evaluation of mononeuropathy and mononeuropa-thy multiplex begins with the electrodiagnostic evaluation. Athorough nerve conduction study is essential to assess theanatomic site(s) of involvement and the underlying pathophys-iologic mechanism (axonal loss vs. segmental demyelination).Nerve conduction is also useful to choose the appropriate nerve(sural, superficial radial) for biopsy when appropriate.

Laboratory studies should be chosen based upon the resultsof the electrodiagnostic evaluation as well as the features of thehistory and physical examination. Laboratory studies for non-entrapment site mononeuropathy or mononeuropathy multi-plex that demonstrates axonal physiology on nerve conductionstudy include FBS, two-hour postprandial glucose, ESR, ANA,anti-double stranded DNA, p/c ANCA, SSA, SSB, RF, ACElevel, LFTs, HIV serology, hepatitis serology and Lyme serolo-gy. CSF analysis, CXR, chest CT, PFTs with diffusion, musclebiopsy and nerve biopsy should be considered in the appropri-ate clinical situations.

Laboratory studies for non-entrapment site mononeuropa-thy or mononeuropathy multiplex that demonstrates demyeli-nating physiology (conduction block, segmental slowing ofconduction, temporal dispersion) should also include CSFevaluation, immunofixation SPEP and UPEP, anti-GM2 andanti-GalNAc-GD1A.

Evaluation for multifocal motor neuropathy with demyeli-nating physiology should also include anti-GM1 antibodies.AIDP and CIDP with CSF pleocytosis should prompt HIVserology. HNPP gene testing should be performed in patientswith a demyelinating neuropathy with evidence of slowing lim-ited to or predominantly involving anatomic entrapment sites.

Nerve and muscle biopsy should be considered in any pro-gressing asymmetric neuropathy or mononeuropathy multiplexparticularly when the electrodiagnostic study demonstratesaxonal physiology. PN

Causes of Neuropathy