peripheral neuropathies: a practical approach for the hospitalist

REV I EW

Peripheral Neuropathies: A Practical Approach for the HospitalistRachel Thompson, MD, FHM1

Michael D. Weiss, MD2

1Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington.

2Department of Neurology, University of Washington Medical Center, Seattle, Washington.

Peripheral neuropathies are a common problem with a myriad of potential etiologies that may be encountered acutely. Early

diagnosis of certain neuropathies can lead to life-saving therapy. This article reviews the literature on diagnostic approaches

to peripheral neuropathies and suggests a structured framework of pattern recognition and systematic evaluation to aid the

hospitalist in efficient evaluation of urgent cases. Journal of Hospital Medicine 2009;4:371–374. VC 2009 Society of Hospital

Medicine.

Early diagnosis of peripheral neuropathies can lead to life-

saving or limb-saving intervention. While infrequently a

cause for concern in the hospital setting, peripheral neuro-

pathies are common—occurring in up to 10% of the general

population.1 The hospitalist needs to expeditiously identify

acute and life-threatening or limb-threatening causes

among an immense set of differentials. Fortunately, with an

informed and careful approach, most neuropathies in need

of urgent intervention can be readily identified. A thorough

history and examination, with the addition of electrodiag-

nostic testing, comprise the mainstays of this process. Inpa-

tient neurology consultation should be sought for any rap-

idly progressing or acute onset neuropathy. The aim of this

review is to equip the general hospitalist with a solid frame-

work for efficiently evaluating peripheral neuropathies in

urgent cases.

Literature ReviewSearch StrategyA PubMed search was conducted using the title word

‘‘peripheral,’’ the medical subject heading major topic ‘‘pe-

ripheral nervous system diseases/diagnosis,’’ and ‘‘algorithm

or diagnosis, differential or diagnostic techniques, neurolog-

ical or neurologic examination or evaluation or evaluating.’’

The search was limited to English language review articles

published between January 2002 and November 2007.

Articles were included in this review if they provided an

overview of an approach to the diagnosis of peripheral neu-

ropathies. References listed in these articles were cross-

checked and additional articles meeting these criteria were

included. Articles specific to subtypes of neuropathies or

diagnostic tools were excluded.

Search ResultsNo single guideline or algorithm has been widely endorsed

for the approach to diagnosing peripheral neuropathies.

Several are suggested in the literature, but none are directed

at the hospitalist. In general, acute and multifocal neuropa-

thies are characterized as neurologic emergencies requiring

immediate evaluation.2,3

Several articles underscore the importance of pattern rec-

ognition in diagnosing peripheral neuropathies.2,4,5 Many

articles present ‘‘essential questions’’ in evaluating periph-

eral neuropathy; some suggest an ordered approach.1–3,5–11

The nature of these questions and recommended order of

inquiry varies among authors (Table 1). Three essentials

common to all articles include: 1) noting the onset of symp-

toms; 2) determining the distribution of nerve involvement;

and 3) identifying the pathology as axonal, demyelinating,

or mixed. All articles underscore the importance of the

physical examination in determining and confirming distri-

bution and nerve type. A thorough examination evaluating

for systemic signs of etiologic possibilities is strongly recom-

mended. Electrodiagnostic testing provides confirmation of

the distribution of nerve involvement and further character-

izes a neuropathy as demyelinating, axonal, or mixed.

A General Approach for the HospitalistPattern recognition and employing the ‘‘essentials’’ outlined

above are key tools in the hospitalist’s evaluation of periph-

eral neuropathy. Pattern recognition relies on a familiarity

with the more common acute and severe neuropathies. For

circumstances in which the diagnosis is not immediately

recognizable, a systematic approach expedites evaluation.

Figure 1 presents an algorithm for evaluating peripheral

neuropathies in the acutely ill patient.

Pattern RecognitionIn general, most acute or subacute and rapidly progressive

neuropathies merit urgent neurology consultation. Patterns

to be aware of in the acutely ill patient include Guillan-

Barre syndrome, vasculitis, ischemia, toxins, medication

exposures, paraneoplastic syndromes, acute intermittent

porphyria, diphtheria, and critical illness neuropathy. Any

neuropathy presenting with associated respiratory symp-

toms or signs, such as shortness of breath, rapid shallow

breathing, or hypoxia or hypercarbia, should also trigger

urgent neurology consultation. As timely diagnosis of con-

cerning entities relies heavily on pattern recognition, the

typical presentation of more common etiologies and clues

to their diagnosis are reviewed in Table 2.

For example, neuropathy from acute intermittent porphy-

ria classically presents with pain in the back and limbs and

progressive limb weakness (often more pronounced in the

upper extremities). Respiratory failure may follow. A key to

this history is that symptoms frequently follow within days

2009 Society of Hospital Medicine DOI 10.1002/jhm.404

Published online in wiley InterScience (www.interscience.wiley.com).

Journal of Hospital Medicine Vol 4 No 6 July/August 2009 371

of the colicky abdominal pain and encephalopathy of an

attack. Additionally, attacks typically follow a precipitating

event or drug exposure. These patients do not have the skin

changes seen in other forms of porphyria. Treatment of this

condition requires recognition and removal of any offending

drug, correction of associated metabolic abnormalities, and

the administration of hematin.12

Another, though rare, diagnosis that relies on pattern rec-

ognition is Bruns-Garland syndrome (also known as proxi-

mal diabetic neuropathy). This condition is usually self-lim-

ited, yet patients can be referred for unnecessary spinal

surgery due to the severity of its symptoms. The clinical

triad of severe thigh pain, absent knee jerk, and weakness in

the lumbar vertebrae L3-L4 distribution in a patient with di-

abetes should raise concern for this syndrome. The contra-

lateral lower extremity can become involved in the following

weeks. This syndrome is typified by a combination of inju-

ries to the nerve root, the lumbar plexus, and the peripheral

nerve. Electrodiagnostic testing confirms the syndrome,

thus avoiding an unwarranted surgery.13

A Systematic EvaluationWhen the etiology is not immediately evident, the ‘‘essential

questions’’ identified in the review above are useful, and

can be simplified for the hospitalist. First, understand the

onset and timing of symptoms. Second, localize the symp-

toms to and within the peripheral nervous system (includ-

ing classifying the distribution of nerve involvement). For

acute, rapidly progressing or multifocal neuropathies urgent

inpatient electrodiagnostic testing and neurology consulta-

tion should be obtained. Further testing, including labora-

tory testing, should be directed by these first steps.

Step 1Delineating onset, timing and progression is of tremendous

utility in establishing the diagnosis. Abrupt onset is typical of

trauma, compression, thermal injury, and ischemia (due to

vasculitis or other circulatory compromise). Guillan-Barre

syndrome, porphyria, critical illness neuropathy, and diph-

theria can also present acutely with profound weakness.

TABLE 1. Summary of Approaches to Diagnostic Evaluation

Article (Publication Year) Essentials of Recommended Approach

Lunn3 (2007) Details 6 essential questions in the history, highlighting: 1. Temporal evolution; 2. Autonomic involvement; 3. Nerve involvement (sensory/

motor); 4. Cranial nerve involvement; 5. Family history; and 6. Coexistent disease

Examination should confirm findings expected from history

Acute and multifocal neuropathies merit urgent evaluation

Electrodiagnostic testing and neurology consultation should ensue if no diagnosis identified from above

Burns et al.6 (2006) Focuses on evaluation of polyneuropathy

Poses 4 questions: 1. Nerve involvement (sensory/motor); 2. Distribution; 3. Onset; 4. Associated factors (family history, exposures,

associated systemic symptoms)

Recommends electrodiagnostic testing

Laboratory testing as indicated

Scott and Kothari5 (2005) Highlights importance of pattern recognition in the history and on examination

Ordered approach: 1. Localize site of neuropathic lesion, 2. Perform electrodiagnostic testing to determine pathology

Bromberg1 (2005) Proposes 7 ‘‘layers’’ to consider in investigation: 1. Localizing to peripheral nervous system; 2. Distribution; 3. Onset; 4. Nerve involvement

(sensory/motor); 5. Pathology (axonal/demyelinating); 6. Other associated features; and 7. Epidemiologic features

Kelly4 (2004) Highlights pattern recognition and features distribution, onset, and pathology in developing the differential diagnosis

Younger10 (2004) Several key elements, including: timing, nerve involvement (sensory/motor/autonomic), distribution, and pathology (axonal/demyelinating)

England and Asbury7 (2004) Details to determine: 1. Distribution; 2. Pathology (axonal/demyelinating); and 3. Timing

Smith and Bromberg9 (2003) Suggest an algorithm: 1. Confirm the localization (history, examination and electrodiagnostic testing); 2. Identify atypical patterns; and

3. Recognize prototypic neuropathy and perform focused laboratory testing

Bromberg and Smith11 (2002) 4 ‘‘basic steps:’’ 1. Nerve involvement (sensory/motor); 2. Distribution; 3. Timing; and 4. Pathology (axonal/demyelinating)

Hughes2 (2002) Pattern recognition

Suggests staged investigation: 1. Basic laboratory tests; 2. Electrodiagnostic testing and further laboratory tests; and 3. Additional laboratory

tests, imaging, and specialized testing

Pourmand8 (2002) Offers 7 key questions/steps highlighting: 1. Onset; 2. Course; 3. Distribution; 4. Nerve involvement (sensory/motor); 5. Nerve fiber type

(large/small); 6. Autonomic involvement; and 7. Pathology (axonal/demyelinating)

FIGURE 1. A practical approach to evaluating symptoms ofperipheral neuropathy for the hospitalist.



372 Journal of Hospital Medicine Vol 4 No 6 July/August 2009

Neuropathies developing suddenly or over days to weeks

merit urgent inpatient evaluation. Metabolic, paraneoplastic,

and toxic causes tend to present with progressive symptoms

over weeks to months. Chronic, insidious onset is most char-

acteristic of hereditary neuropathies and some metabolic dis-

eases such as diabetes mellitus. Evaluation of chronic neuro-

pathies can be deferred to the outpatient setting.

Nonneuropathy causes of acute generalized weakness to

consider in the differential diagnosis include: 1) muscle dis-

orders such as periodic paralyses, metabolic defects, and

myopathies (including acute viral and Lyme disease); 2) dis-

orders of the neuromuscular junction such as myasthenia

gravis, Eaton-Lambert syndrome, organophosphate poison-

ing, and botulism; 3) central nervous system disorders such

as brainstem ischemia, global ischemia, or multiple sclero-

sis; and 4) electrolyte disturbances such as hyperkalemia or

hypercalcemia.14

Step 2It is important to localize symptoms to the peripheral nervous

system. Cortical lesions are unlikely to cause focal or positive

sensory symptoms (ie, pain), and more frequently involve the

face or upper and lower unilateral limb (ie, in the case of a

stroke). Hyperreflexia can accompany cortical lesions. Con-

versely, peripheral nerve lesions often localize to a discrete

region of a single limb or involve the contralateral limb in a

symmetric fashion (ie, a stocking-glove distribution or the

ascending symmetric pattern seen in Guillan-Barre syndrome).

With a thorough history and neurological examination

the clinician can localize and classify the neuropathic

lesion. Noting a motor or sensory predominance can narrow

the diagnosis; for example, motor predominance is seen in

Guillan-Barre syndrome, critical illness neuropathy, and

acute intermittent porphyria. Associated symptoms and

signs discovered in a thorough review and physical exami-

nation of all systems can indicate the specific diagnosis. For

example, a careful skin examination may find signs of vas-

culitis or Mees’ lines (transverse white lines across the nails

that can indicate heavy metal poisoning).12 Helpful tips for

this evaluation are included in Table 3.

The hospitalist should be able to classify the distribution

as a mononeuropathy (involving a single nerve), a

TABLE 2. Typical Presentations of Acute and Concerning Peripheral Neuropathies

Etiology Typical Presentation Onset Distribution Electrodiagnostic Findings

Traumatic neuropathy Weakness and numbness in a limb

following injury

Sudden Asymmetric Axonal

Guillan-Barre syndrome Acute inflammatory demyelinating

polyneuropathy is most common

but several variants exist; often

follows URI or GI illness by 1-3

weeks

Days to weeks Ascending, symmetric Usually demyelinating, largely

motor

Diphtheria Tonsillopharyngeal pseudomembrane Days to weeks Bulbar, descending, symmetric Mostly demyelinating

Vasculitis Waxing and waning, painful Days to weeks Asymmetric Axonal

Acute intermittent porphyria Can be associated with seizures/

encephalopathy, abdominal pain

Days to weeks Ascending, symmetric Axonal, largely motor

Ischemic neuropathy May follow vascular procedure by days

to months; can be associated with

poor peripheral pulses

Days to weeks Asymmetric Axonal

Toxins/drugs Temporal association with offending

agent: heavy metals: arsenic, lead,

thallium; biologic toxins: ciguatera

and shellfish poisoning.

Medications: chemotherapies (ie,

vincristine), colchicine, statins,

nitrofurantoin, chloroquine

Days to months Symmetric Axonal

Critical illness neuropathy Quadriparesis in the setting of sepsis/

corticosteroids/neuromuscular

blockade

Weeks Symmetric Axonal, largely motor

Paraneoplastic Sensory ataxia most common;

symptoms may precede cancer

diagnosis; frequently associated

tumors: small cell carcinoma of the

lung; breast, ovarian, stomach

cancers

Weeks Symmetric Axonal, largely sensory

Proximal diabetic neuropathy Also known as diabetic lumbosacral

plexopathy or Bruns-Garland; leg

pain followed by weakness/wasting

Weeks to months Asymmetric Axonal, largely motor

Abbreviations: AIDP, acute inflammatory demyelinating polyneuropathy; GBS, Guillan-Barre syndrome; GI, gastrointestinal; URI, upper respiratory infection.



Approach to Peripheral Neuropathies Thompson and Weiss 373

polyneuropathy (symmetric involvement of multiple

nerves), or a mononeuropathy multiplex (asymmetric

involvement of multiple nerves). Multifocal and proximal

symmetric neuropathies commonly merit urgent evaluation.

The most devastating polyneuropathy is Guillan-Barre

syndrome, which can be fatal but is often reversible with

early plasmapheresis. Vasculitis is another potentially treat-

able diagnosis that is critical to establish early; it most often

presents as a mononeuropathy multiplex. Ischemic and

traumatic mononeuropathies may be overshadowed by

other illnesses and injuries, but finding these early can

result in dramatically improved patient outcomes.

Step 3Inpatient electrodiagnostic testing and neurology consulta-

tion should be ordered for any neuropathy with rapid onset,

progression or severe symptoms or any neuropathy follow-

ing one of the patterns described above. Electrodiagnostic

testing characterizes the pathologic cause of the neuropathy

as axonal, demyelinating, or mixed. It also assesses severity,

chronicity, location, and symmetry of the neuropathy.15 It is

imperative to have localized the neuropathy by history and

examination prior to electrodiagnostic evaluation to ensure

that the involved nerves are tested.

Step 4Focused, further testing may be ordered more efficiently

subsequent to the above data collection. Directed laboratory

examination should be performed when indicated rather

than cast as an initial broad diagnostic net. Ultrasound,

magnetic resonance imaging (MRI), computed tomography–

positron emission tomography (CT-PET), and nerve biopsy

are diagnostic modalities available to the clinician. In gen-

eral, nerve biopsy should be reserved for suspected vasculi-

tis, sarcoidosis, lymphoma, leprosy, or amyloidosis.

In summary, symptoms and signs of multifocal or proxi-

mal nerve involvement, acute onset, or rapid progression

demand immediate diagnostic attention. Pattern recognition

and a systematic approach expedite the diagnostic process,

focusing necessary testing and decreasing overall cost.

Focused steps in a systematic approach include: (1) delin-

eating timing and onset of symptoms; (2) localizing and

classifying the neuropathy; (3) obtaining electrodiagnostic

testing and neurology consultation; and (4) further testing

as directed by the preceding steps. Early diagnosis of acute

peripheral neuropathies can lead to life-saving or limb-sav-

ing therapy.

Address for correspondence and reprint requests:Rachel Thompson, MD, Assistant Professor, General InternalMedicine, Harborview Medical Center, University of WashingtonBox 359780, 325 9th Ave, Seattle, WA 98104; Telephone: 206 7442854; Fax: 206 744 6303; E-mail: [email protected] 20 June 2007; revision received 18 April 2008; accepted 26May 2008.

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67–68, 71–74, 6–7 passim.

4. Kelly JJ. The evaluation of peripheral neuropathy. Part I: Clinical and

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system complaints. J Am Osteopath Assoc. 2005;105:71–83.

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TABLE 3. Keys and Clues to Localizing AcuteNeuropathic Lesions

History Examination

Ask the patient to outline the region involved General findings

Dermatome ! radiculopathy Screening for malignancy

Stocking-glove ! polyneuropathy Evaluate for vascular sufficiency

Single peripheral nerve ! mononeuropathy Pes cavus suggests inherited

disease

Asymmetry ! vasculitic neuropathy

or other mononeuropathy multiplex

Skin exam for signs of vasculitis,

Mees’ lines

Associated symptoms Neurologic findings: For each of

the following, noting the

distribution of abnormality will

help classify the neuropathic

lesion

Constitutional ! neoplasm Decreased sensation (often the

earliest sign)

Recent respiratory or GI illness ! GBS Weakness without atrophy

indicates recent axonal

neuropathy or isolated

demyelinating disease

Respiratory difficulties ! GBS Marked atrophy indicates severe

axonal damage

Autonomic symptoms ! GBS, porphyria Decreased reflexes often present

(except when only small

sensory fibers are involved)

Colicky abdominal pain, encephalopathy

! Porphyria

Abbreviations: GBS, Guillian-Barre syndrome; GI, gastrointestinal.



374 Journal of Hospital Medicine Vol 4 No 6 July/August 2009

peripheral neuropathies: a practical approach for the hospitalist

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