10.1. Introduction
The differential diagnosis of peripheral neuropathy is based on six major constructs:
- The size of the fiber that is involved in the peripheral nerve that is affected
- The pattern of motor or sensory loss
- The time course
- Genetics
- Associated medical conditions
- Exposure to toxins and medicines
Seventy-five percent of peripheral neuropathies can be diagnosed. This percentage will increase as new epitopes on dorsal root ganglion cells, Schwamm cells, and peripheral myelin are identified and their corresponding genes cloned.
The patient's predominant symptoms suggest the fiber size that is involved which focuses the examination on the physical findings subserved by that fiber size. The smallest unmyelinated fibers are C-fibers and autonomic fibers that are 1u in size. The predominant symptom expressed by these patients is burning pain or autonomic dysregulation. These fibers are primarily involved in neuropathic pain in which the nerve fibers themselves are injured. A-delta (1–4u) fibers or thinly myelinated fibers are also considered small fibers and cause sharp lancinating pain, cold sensation and deep ache (muscle pain afferents). Allodynia, hyperalgesia and hyperpathia characterize neuropathic pain. These sensations are caused by direct sensitization of peripheral C-fiber endings and changes induced in the central pain projecting neurons of the dorsal root ganglion, dorsal born and central pain systems.
Mechano allodynia (an innocuous mechanical stimulus is perceived as painful) is divided into static and dynamic subtypes. The former implies sensitization of C-fibers (lower threshold to fire) and the later in which a moving stimulus is painful (Aβ fibers). Dynamic allodynia is primarily a central process at the dorsal horn level. Small fiber neuropathies demonstrate spontaneous pain (ectopic firing near the DRG) as well as hyperalgesia (increased pain from a painful stimulus). Cold hyperalgesia is particularly suggestive of neuropathic pain. Hyperpathia (a higher threshold to fire pain fibers that once exceeded causes overwhelming pain that is not stimulus bound) requires central nervous system changes. This is most often associated with chronic regional pain syndrome I and II which is often secondary to peripheral C and A-delta fiber injury. Autonomic fiber symptomatology (1u unmyelinated) involves autonomic dysregulation that is seen as postural hypotension, obstipation, difficulty with sexual function, micturition, pupillary and sweating (hypo or hyperhidrosis) abnormalities. Characteristically small fiber neuropathies have decreased pain and temperature thresholds, minimal weakness and retained reflexes.
Large fiber neuropathies (12– 22 μ) have deficits in motor, vibratory and proprioceptive function. Patients demonstrate sensory ataxia, distal and proximal motor weakness, positive Romberg sign, poor balance and loss of reflexes.
In general, both large and small fibers are involved in neuropathies and demonstrate motor, sensory and autonomic features. Frequently sensory, phenomena are noted first with the gradual development of motor and autonomic phenomena, coldness of the affected extremities is the most commonly noted symptom of autonomic involvement in mixed peripheral neuropathy.
The distribution of the sensory loss is extremely important in differential diagnosis. Axonal metabolic dying back neuropathies (length dependent dying back neuropathy) affect the longest axons. Patients have deficits in the toes and legs. The hands become involved when the process crosses the knees. The center part of the chest loses sensation in what is known as a shield distribution. The maintaining dorsal root ganglia are in the thoracic spine and the most distal of their axons are in the central chest. Similarly the chin and midface may be affected before the C2 region, anterior to the ear. In general, these neuropathies progress symmetrically although initially they may be slightly asymmetric. Some polyneuropathies demonstrate a proximal symmetrical pattern of weakness. These include Guillain–Barré Syndrome, some patients with acute intermitted porphyria and chronic inflammatory demyelinating polyneuropathy. Rarely patients may have a proximal accentuation of weakness on a distal length dependent process such as occurs with diabetes and HIV.
Focal neuropathies are chronic with entrapments in the various tunnels, mononeuritis multiplex from infarction of nerves or compression. These may be genetic as is the case with hereditary neuropathy with compression palsy (deletion on chromosome 17) or mechanical from trauma, anesthesia, alcohol or coma. Mononeuritis multiplex has recently been described to present with a distal symmetric polyneuropathy. Monoradiculopathies, polyradiculopathies and plexopathies are distinguished by their characteristic patterns of involvement. Differential diagnosis becomes more complex in situations where there are several simultaneous processes. Older patients have some cervical and lumbar spondylosis particularly at C5–6 and L5–S1 levels. Shoulder injuries may damage the brachial plexus, individual nerves and nerve roots. Diabetic and HIV infected patients have pathology at root, nerve and plexus levels. Almost all patients with CRPS I/II have multiple nerve, plexus and root components that maintaining the process.
As a general rule, in the upper extremities root disease is primarily felt proximally and rarely radiates to the fingers. The exception is C6 which radiate to the lateral forearm, thumb and index fingers. C7–T1 almost never gets injured as this is a non-movement segment. Plexus and nerve problems radiate to the hand. In the lower extremity the reverse is true. Radicular pain frequently radiates to the foot while plexus problems are felt proximally. Nerve problems are experienced proximally and distally. At times, polyradiculopathies at L4–L5 and L5–S1 may simulate neuropathies. Most of the time patients have had back, buttock and posterior thigh radiations at some point in their course. The examination demonstrates the involved nerve roots. Multifocal neuropathies may have characteristic distributions such as cold parts of the body in leprosy (ear lobes, nose, and dorsal extremities) and a regional distribution in CRPS I.
The temporal profile of a neuropathy may be divided into:
- Acute (progressing over days to weeks)
- Subacute (6 months to one year)
- Chronic (6 months to years)
Within this time frame the process may be:
- Monophasic
- Intermittent
- Progressive
Acute neuropathies are generally autoimmune, toxic exposures, critical care or acute intermittent porphyria. Subacute neuropathies may be autoimmune, paraneoplastic, metabolic or vitamin deficiencies. Chronic neuropathies are often hereditary or metabolic (uremia, diabetes, liver failure). Axonal neuropathies are characterized by distal muscle weakness, atrophy and fasciculation whereas demyelinating neuropathies demonstrate weakness and loss of deep tendon reflexes out of proportion to atrophy.
In type I and type III hereditary sensory motor neuropathy, large nerves may be palpated.
Hereditary neuropathies are suggested by pes cavus, a fore shortened foot and intrinsic foot muscle atrophy. The insertion of the gastrocnemius muscles in the lower extremities is too high and there is distal 1/3 of the quadriceps muscle atrophy. The forearm flexor muscles may also have a proximal insertion which causes thin wrists and ankles. Patients may have associated kyphoscoliosis , ataxia, cardiomyopathy and other dysmorphisms. The process is extremely slow. Patients may note that it was always difficult for them to stand in one place without shifting weight due to deep ache in the legs. They may have had difficulty running and were clumsy in their adolescent years. 10% of patients with hereditary neuropathies have abnormally flat or "rocker bottom feet". Most of these patients have little sensory loss. They suffer an undue number of twisted ankles due to peroneal muscle weakness. Family members are often affected, but are unaware of the condition.
Almost all neuropathies that are acquired have a seminal feature that allows a clinical diagnosis. The following differential diagnosis of peripheral neuropathy will concentrate on the specific history and physical examination that allow a clinical diagnosis.
Sensory Neuropathy
As noted in the general review of differential diagnosis of neuropathy, sensory neuropathy may be divided into those that affect:
- Large fibers
- Small fiber
- Dorsal root ganglion (large neurons)
- Proximal dorsal root ganglion (DRG) root components
These may further be divided into those with specific autoimmune epitopes on large and small fibers as well as the DRG to which antibodies are made. Other causes include: demyelinating sensory neuropathies, inherited, infectious, toxic/metabolic and sensory neuropathy associated with systemic disease. Ataxic sensory polyneuropathy, idiopathic sensory neuropathy and chronic painful neuropathies may have a predominant DRG pathology.
A-delta fibers (1–4 μ ) mediate lancinating shooting pain and cold sensations. They may also be involved in deep muscle ache. C-fibers mediate burning pain, heat, and some deep muscle pain. Burning pain, lancinating pain, amhidrosis and autonomic dysregulation with intact strength, large fiber sensation and reflexes are characteristic of small fiber neuropathies. Blended sensations such as cold-pain also suggest small fiber involvement. The nervi nervorum that innervate plexus and nerve sheaths are also small fibers and often are activated at the site of injury from released inflammatory cytokines (TNF- alpha, IL1 and IL6). The nerves so involved are hypersensitive throughout their course. This pattern is frequently described as fibromyalgia as the entrance points of the trunks and nerves of the plexus are sensitive to pressure (Tinel's signs) as they enter the extremity. Careful examination of the pupils for poor response to light, light near dissociation (constrict to near response greater than light), anhidrosis , severe constipation or nocturnal diarrhea, postural hypotension, (abnormalities of the RR interval on EKG (indicative of a cholinergic deficit) and sexual dysfunction make a diagnosis of autonomic neuropathy. Autonomic neuropathy can be both acute, and chronic as well as being a component of sensorimotor neuropathy.
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