Rachel Thompson, MD, FHM

Search Strategy

A PubMed search was conducted using the title word peripheral, the medical subject heading major topic peripheral nervous system diseases/diagnosis, and algorithm or diagnosis, differential or diagnostic techniques, neurological 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 neuropathies. 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 Results

No 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 neuropathies are characterized as neurologic emergencies requiring immediate evaluation.2, 3

Several articles underscore the importance of pattern recognition in diagnosing peripheral neuropathies.2, 4, 5 Many articles present essential questions in evaluating peripheral neuropathy; some suggest an ordered approach.13, 511 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 symptoms; 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 distribution and nerve type. A thorough examination evaluating for systemic signs of etiologic possibilities is strongly recommended. Electrodiagnostic testing provides confirmation of the distribution of nerve involvement and further characterizes a neuropathy as demyelinating, axonal, or mixed.

Pattern Recognition

In 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‐Barr syndrome, vasculitis, ischemia, toxins, medication exposures, paraneoplastic syndromes, acute intermittent porphyria, diphtheria, and critical illness neuropathy. Any neuropathy presenting with associated respiratory symptoms or signs, such as shortness of breath, rapid shallow breathing, or hypoxia or hypercarbia, should also trigger urgent neurology consultation. As timely diagnosis of concerning 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 porphyria 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 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 recognition is Bruns‐Garland syndrome (also known as proximal diabetic neuropathy). This condition is usually self‐limited, 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 diabetes should raise concern for this syndrome. The contralateral lower extremity can become involved in the following weeks. This syndrome is typified by a combination of injuries to the nerve root, the lumbar plexus, and the peripheral nerve. Electrodiagnostic testing confirms the syndrome, thus avoiding an unwarranted surgery.13

Step 1

Delineating 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‐Barr syndrome, porphyria, critical illness neuropathy, and diphtheria can also present acutely with profound weakness. 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 characteristic of hereditary neuropathies and some metabolic diseases such as diabetes mellitus. Evaluation of chronic neuropathies can be deferred to the outpatient setting.

Nonneuropathy causes of acute generalized weakness to consider in the differential diagnosis include: 1) muscle disorders such as periodic paralyses, metabolic defects, and myopathies (including acute viral and Lyme disease); 2) disorders of the neuromuscular junction such as myasthenia gravis, Eaton‐Lambert syndrome, organophosphate poisoning, and botulism; 3) central nervous system disorders such as brainstem ischemia, global ischemia, or multiple sclerosis; and 4) electrolyte disturbances such as hyperkalemia or hypercalcemia.14

Step 2

It 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. Conversely, 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‐Barr 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‐Barr syndrome, critical illness neuropathy, and acute intermittent porphyria. Associated symptoms and signs discovered in a thorough review and physical examination of all systems can indicate the specific diagnosis. For example, a careful skin examination may find signs of vasculitis 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 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‐Barr syndrome, which can be fatal but is often reversible with early plasmapheresis. Vasculitis is another potentially treatable 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 3

Inpatient electrodiagnostic testing and neurology consultation should be ordered for any neuropathy with rapid onset, progression or severe symptoms or any neuropathy following 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 4

Focused, 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 tomographypositron emission tomography (CT‐PET), and nerve biopsy are diagnostic modalities available to the clinician. In general, nerve biopsy should be reserved for suspected vasculitis, sarcoidosis, lymphoma, leprosy, or amyloidosis.

In summary, symptoms and signs of multifocal or proximal 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) delineating 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‐saving therapy.

Search Strategy

A PubMed search was conducted using the title word peripheral, the medical subject heading major topic peripheral nervous system diseases/diagnosis, and algorithm or diagnosis, differential or diagnostic techniques, neurological 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 neuropathies. 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 Results

No 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 neuropathies are characterized as neurologic emergencies requiring immediate evaluation.2, 3

Several articles underscore the importance of pattern recognition in diagnosing peripheral neuropathies.2, 4, 5 Many articles present essential questions in evaluating peripheral neuropathy; some suggest an ordered approach.13, 511 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 symptoms; 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 distribution and nerve type. A thorough examination evaluating for systemic signs of etiologic possibilities is strongly recommended. Electrodiagnostic testing provides confirmation of the distribution of nerve involvement and further characterizes a neuropathy as demyelinating, axonal, or mixed.

Pattern Recognition

In 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‐Barr syndrome, vasculitis, ischemia, toxins, medication exposures, paraneoplastic syndromes, acute intermittent porphyria, diphtheria, and critical illness neuropathy. Any neuropathy presenting with associated respiratory symptoms or signs, such as shortness of breath, rapid shallow breathing, or hypoxia or hypercarbia, should also trigger urgent neurology consultation. As timely diagnosis of concerning 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 porphyria 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 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 recognition is Bruns‐Garland syndrome (also known as proximal diabetic neuropathy). This condition is usually self‐limited, 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 diabetes should raise concern for this syndrome. The contralateral lower extremity can become involved in the following weeks. This syndrome is typified by a combination of injuries to the nerve root, the lumbar plexus, and the peripheral nerve. Electrodiagnostic testing confirms the syndrome, thus avoiding an unwarranted surgery.13

Step 1

Delineating 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‐Barr syndrome, porphyria, critical illness neuropathy, and diphtheria can also present acutely with profound weakness. 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 characteristic of hereditary neuropathies and some metabolic diseases such as diabetes mellitus. Evaluation of chronic neuropathies can be deferred to the outpatient setting.

Nonneuropathy causes of acute generalized weakness to consider in the differential diagnosis include: 1) muscle disorders such as periodic paralyses, metabolic defects, and myopathies (including acute viral and Lyme disease); 2) disorders of the neuromuscular junction such as myasthenia gravis, Eaton‐Lambert syndrome, organophosphate poisoning, and botulism; 3) central nervous system disorders such as brainstem ischemia, global ischemia, or multiple sclerosis; and 4) electrolyte disturbances such as hyperkalemia or hypercalcemia.14

Step 2

It 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. Conversely, 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‐Barr 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‐Barr syndrome, critical illness neuropathy, and acute intermittent porphyria. Associated symptoms and signs discovered in a thorough review and physical examination of all systems can indicate the specific diagnosis. For example, a careful skin examination may find signs of vasculitis 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 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‐Barr syndrome, which can be fatal but is often reversible with early plasmapheresis. Vasculitis is another potentially treatable 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 3

Inpatient electrodiagnostic testing and neurology consultation should be ordered for any neuropathy with rapid onset, progression or severe symptoms or any neuropathy following 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 4

Focused, 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 tomographypositron emission tomography (CT‐PET), and nerve biopsy are diagnostic modalities available to the clinician. In general, nerve biopsy should be reserved for suspected vasculitis, sarcoidosis, lymphoma, leprosy, or amyloidosis.

In summary, symptoms and signs of multifocal or proximal 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) delineating 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‐saving therapy.

Search Strategy

A PubMed search was conducted using the title word peripheral, the medical subject heading major topic peripheral nervous system diseases/diagnosis, and algorithm or diagnosis, differential or diagnostic techniques, neurological 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 neuropathies. 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 Results

No 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 neuropathies are characterized as neurologic emergencies requiring immediate evaluation.2, 3

Several articles underscore the importance of pattern recognition in diagnosing peripheral neuropathies.2, 4, 5 Many articles present essential questions in evaluating peripheral neuropathy; some suggest an ordered approach.13, 511 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 symptoms; 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 distribution and nerve type. A thorough examination evaluating for systemic signs of etiologic possibilities is strongly recommended. Electrodiagnostic testing provides confirmation of the distribution of nerve involvement and further characterizes a neuropathy as demyelinating, axonal, or mixed.

Pattern Recognition

In 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‐Barr syndrome, vasculitis, ischemia, toxins, medication exposures, paraneoplastic syndromes, acute intermittent porphyria, diphtheria, and critical illness neuropathy. Any neuropathy presenting with associated respiratory symptoms or signs, such as shortness of breath, rapid shallow breathing, or hypoxia or hypercarbia, should also trigger urgent neurology consultation. As timely diagnosis of concerning 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 porphyria 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 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 recognition is Bruns‐Garland syndrome (also known as proximal diabetic neuropathy). This condition is usually self‐limited, 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 diabetes should raise concern for this syndrome. The contralateral lower extremity can become involved in the following weeks. This syndrome is typified by a combination of injuries to the nerve root, the lumbar plexus, and the peripheral nerve. Electrodiagnostic testing confirms the syndrome, thus avoiding an unwarranted surgery.13

Step 1

Delineating 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‐Barr syndrome, porphyria, critical illness neuropathy, and diphtheria can also present acutely with profound weakness. 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 characteristic of hereditary neuropathies and some metabolic diseases such as diabetes mellitus. Evaluation of chronic neuropathies can be deferred to the outpatient setting.

Nonneuropathy causes of acute generalized weakness to consider in the differential diagnosis include: 1) muscle disorders such as periodic paralyses, metabolic defects, and myopathies (including acute viral and Lyme disease); 2) disorders of the neuromuscular junction such as myasthenia gravis, Eaton‐Lambert syndrome, organophosphate poisoning, and botulism; 3) central nervous system disorders such as brainstem ischemia, global ischemia, or multiple sclerosis; and 4) electrolyte disturbances such as hyperkalemia or hypercalcemia.14

Step 2

It 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. Conversely, 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‐Barr 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‐Barr syndrome, critical illness neuropathy, and acute intermittent porphyria. Associated symptoms and signs discovered in a thorough review and physical examination of all systems can indicate the specific diagnosis. For example, a careful skin examination may find signs of vasculitis 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 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‐Barr syndrome, which can be fatal but is often reversible with early plasmapheresis. Vasculitis is another potentially treatable 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 3

Inpatient electrodiagnostic testing and neurology consultation should be ordered for any neuropathy with rapid onset, progression or severe symptoms or any neuropathy following 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 4

Focused, 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 tomographypositron emission tomography (CT‐PET), and nerve biopsy are diagnostic modalities available to the clinician. In general, nerve biopsy should be reserved for suspected vasculitis, sarcoidosis, lymphoma, leprosy, or amyloidosis.

In summary, symptoms and signs of multifocal or proximal 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) delineating 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‐saving therapy.