Vasculitides are immune mediated diseases that affect blood vessels and become symptomatic due to end-organ ischemia.
They are usually classified according to:
1)The size of the blood vessel involved (small, medium or large)
2)Whether it is primary or secondary
3)Or if it is isolated to the peripheral nervous system.
General clinical peripheral presentations include:
1)A mononeuropathy
2)Multiple mononeuropathies
3)Distal symmetric polyneuropathy (often asymmetric by EMG evaluation).
In patients with mononeuropathy, additional specific nerves become involved over time that causes a pattern of asymmetric peripheral nerve dysfunction. If there is a pattern of overlapping mononeuropathies, specific nerves are involved bilaterally to varying degrees that leads to a generalized, asymmetric process. If the process is insidious with a gradual progression, patients may appear to have a symmetric polyneuropathy. Approximately 60% of patients present with a mononeuritis multiplex pattern and 40% with a distal symmetric polyneuropathy. Patients with mononeuropathies most often complain of burning pain in the affected nerve’s distribution. Neurologic examination reveals weakness and sensory involvement. Less frequently the presentation may be pure sensory. Muscle stretch reflexes are variably affected.
Laboratory evaluation usually demonstrates an inflammatory profile with an elevated sedimentation rate and C-reactive protein. Some of the vasculitides are associated with specific antibodies as exemplified by anti-neutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANAs) or cryoglobulins and rheumatoid factor. Leukocytosis and a moderate anemia are often concomitants. The affected nerves are enlarged and hypoechoic by ultrasound. Electrodiagnostic studies most often reveal absent or reduced motor and sensory amplitudes. The examination is most often asymmetric. Distal latencies may be normal or slightly prolonged. Conduction velocities are normal or only minimally slowed. Rarely, pseudoconduction block can be seen in affected nerves. Needle EMG shows asymmetric denervation.
Sensory nerve biopsy reveals asymmetric nerve fiber loss between and within individual nerve fascicles with primarily axonal degeneration. Immunostaining may reveal IgM or IgG, complement and membrane attack complexes on or within blood vessels. Mononuclear cells, epineurial, perineurial and endoneurial vessels may be positive for the receptor for advanced glycosylation end products, nuclear factor kappa Β. Interleukin 6 may be demonstrated along with CD4(+), CD8(+) and CD68(+) cells that invade the nerves. Blood vessels in muscle often demonstrate transmural inflammatory cell infiltration and necrosis. Matrix metalloproteinases, primarily MMP-9 are upregulated.
1.Temporal arteritis and Takayasu arteritis are the two large artery arthritides.
2.Peripheral neuropathy is only seen with temporal arteritis
1.Giant cell arteritis (GCA) affects medium and large caliber blood vessels that include the aortic arch, the internal and external carotid arteries and less frequently the vertebral arteries
2.Other cranial arteries than the temporal arteries can be involved in GCA which include:
a.Branches of the external carotid artery the most important of which are the posterior ciliary arteries that affect the optic nerve
b.Primary and secondary branches of the aorta
c.Lower extremity arteries (rare)
d.Mesenteric arteries (rare)
3.Typical clinical manifestations with temporal artery involvement:
a.Preceding symptoms of fatigue, weight loss, and in some patients a generalized muscle and joint ache
b.Headache (often burning) associated with scalp tenderness
c.Jaw and tongue claudication (rarely ischemic tongue and nasal septum ischemic lesions)
d.Sudden loss of vision from ischemic optic neuropathy
e.Peripheral nerve manifestations:
i.Occur in approximately 15% of patients and include:
1.Mononeuritis multiplex
2.Radiculopathy
3.Brachial and lumbosacral plexopathy
4.Generalized sensorimotor peripheral neuropathy
f.Peripheral tenderness of the temporal artery with nodularity (a cord) is apparent in less than 50% of patients
1.GCA demonstrates an inflammatory infiltration of the arterial wall by lymphocytes, macrophages and giant cells
2.Only approximately 50% of patients have multinucleated giant cells
3.The inflammation is characteristically at the transition from the adventitia to the muscularis or less frequently to the adventitia and rarely the vasa vasorum
4.The internal elastic lamina is fragmented and the lumen is distorted; inflammation is most often segmental
1.The ESR and CRP are elevated in 77 to 86% in the former (mean values approximately 90 mm/hr) and 95-98% in the latter (90 mg/dl).
2.Less than 5% of GCA have no increased serological inflammatory markers
3.Normochromic normocytic anemia, leukocytosis and or thrombocytosis are seen
4.Increased acute-phase proteins
5.Antiferritin autoantibodies are seen in approximately 90% of patients but also occur in other inflammatory and rheumatic diseases
1.Color-coded duplex sonography:
a.Inflammatory changes can be detected in the temporal arteries, extracranial vessels, the occipital and subclavian arteries
2.Edema of the vascular wall is seen as hypoechoic wall thickening (“halo” sign) often associated with stenosis and occlusions
3.Duplex sonography evaluates arterial flow that is accelerated in stenotic areas. The sensitivity of the technique is 85% and its specificity exceeds 90%. Reversal of flow through the temporal artery is a contraindication to temporal artery biopsy
4.The “halo” sign may disappear after 2-3 weeks of steroid therapy
5.High-resolution magnetic resonance imaging (MRI):
a.The scanners utilized are 1.5T to 3T:
i.Swollen wall segments from inflammation can be differentiated from unaffected vessels which may guide biopsy sites
b.MRA angiography to evaluate the aorta, supra-aortic arteries, visceral and extremity arteries if clinically indicated
c.18FDG-PET scan demonstrates GCA in arteries that are larger than 4mm in diameter
1.Approximately 15% of patients with PMR develop giant cell arteritis and 40-50% of patients with GCA have concomitant PMR
2.In the USA the incidence of PMR is 52.5 patients / 100,000 persons more than 50 years: the prevalence is approximately 0.5-0.7%
3.Caucasian patients are affected to a greater extent than other ethnicities, women are more affected than men and the disorder is rare in African-American individuals
1.Diagnostic criteria include:
a.Age of onset 50 years or older
b.Pain persisting for more than 1 month that involves at least two of the following areas: neck, shoulders and pelvic girdle
c.Absence of other disorders that may cause similar symptoms
d.Morning stiffness that lasts more than 1hr
e.Rapid response to prednisone (<20mg)
1.PMR is associated with the HLA-DR4 haplotype
2.IL-1 and TNFα gene polymorphisms are weakly associated with GCA and PMR
3.Absence of significant involvement of blood vessels
4.Synovitis, bursitis and tenosynovitis of the shoulder, hip, knee, wrist and metacarpal phalangeal joints may be seen
5.Putative recognition of an unknown antigen by dendritic cells or macrophages
6.There is systemic activation of both T and B cells; patients have an elevated IL-6 during exacerbations
1.Muscle biopsy and EMG are normal
2.The ESR is mildly elevated in 7-20% of patients; it is usually greater than 40mm/hr and rarely may exceed 100 mm/hr
3.The CRP is often elevated and parallels the ESR
4.Normocytic normochromic anemia is common as is an elevated platelet count
5.Antinuclear antibodies, complement, rheumatoid factor and anti-CCP are usually normal; IL-6 is elevated during exacerbations and follows disease activity; serum B-cell activating factor (BAFF) is also associated with disease activity
6.MRI:
a.Evaluation of the shoulder demonstrates subacromial, subdeltoid bursitis and glenohumeral joint synovitis; inflammation of the tendon sheaths in the hands has been described
7.18FDG PET has demonstrated inflammation of the subclavian arteries as well as uptake in the shoulders, hips and spinous processes of the cervical and lumbar vertebrae
1.PAN is the most common necrotizing vasculitis; its incidence ranges from 2 to 9 patients per million population
1.Mononeuropathy is the most common pattern of peripheral nerve involvement
2.The sciatic nerve itself or its peroneal or tibial branches are the most commonly involved
3.Cranial neuropathy or CNS vascular disease occurs in <2% of patients
4.Myalgias and arthralgias occur in 30-70% of patients
5.Constitutional symptoms of fatigue, weight loss and fever are common
6.Associated organ involvement includes:
a.Liver, kidney, gastrointestinal tract and skin
b.The lungs are usually spared
c.Abdominal pain, gastrointestinal bleeding and retroperitoneal hemorrhage occur
d.Skin lesions include:
i.Petechia and livedo reticularis
ii.Subcutaneous nodules
iii.Distal gangrene
1.Medium sized arteries are the most frequently involved although small arteries can be affected
2.Approximately 1/3 of patients have hepatitis B antigens; it is also seen concomitantly with hepatitis C and HIV
3.Nerve biopsy:
a.Supplying vessels demonstrate CD8+ T cell, macrophage and PML invasion associated with fibrinoid necrosis of the vessel wall
b.IgM, IgG, complement and membrane attack complexes are seen in the vessel walls
c.Thrombosis and ischemic damage of the vasa nervorum is seen
4.The pain in vasculitic neuropathy may be associated with an increased expression of nerve growth factor (NGF)
5.The ulnar nerve is most frequently involved in the upper extremity
6.Approximately 75% of PAN patients have a neuropathy
1.Electrodiagnosis:
a.A multifocal axonal neuropathy with decreased compound muscle action potentials (CMAP) amplitudes
b.Needle EMG:
i.A neurogenic pattern with spontaneous muscle fiber activity, polyphasic and high-amplitude MUAPs
2.Elevated sed rate
3.Other medium-sized vessel vasculitides include Kawasaki disease and thromboangiitis obliterans. They are not associated with peripheral neuropathy.
1.CSS is a vasculitis that affects small blood vessels and manifests with symptoms that are similar to PAN
2.It has an incidence of approximately 1/3 of PAN
3.In contradistinction to PAN the respiratory system is frequently involved but neurological symptomatology is equal
4.Patients usually have had a long preceding period of asthma and rhinitis which then evolve into an intermittent phase of primarily pulmonary eosinophilic infiltrates
5.Vasculitic manifestations involve the skin, gastrointestinal tract, sinuses, joints and peripheral nerves
1.Involvement of the peripheral nervous system occurs in approximately 75-80% of patients
2.The neuropathy is primarily that of mononeuropathy multiplex but can be a pure sensory or axonal sensorimotor neuropathy
3.Patients often present with late onset asthma (>35 years of age)
4.Systemic vasculitis occurs approximately 3 years after the onset of asthma
5.16-49% of patients develop a necrotizing glomerulonephritis in contradistinction to PAN which is on an ischemic basis
6.Patients have been described that were administered leukotriene antagonists
1.Sural nerve biopsy:
a.Necrotizing vasculitis with CD8+ cytotoxic T lymphocytes, CD4+ cells and slight eosinophilic infiltrates
b.Less frequently both intravascular and extravascular granulomas are demonstrated around affected blood vessels
c.Granulomatous vasculitis effects small and medium-sized arteries, arterioles, capillaries and venules
1.Serum reveals eosinophilia, leukocytosis, elevated ESR and C-reactive protein, rheumatoid factor and IgG and IgM
2.40-70% of patients have pANCA or myeloperoxidase antibodies
3.Approximately 50% of patients have positive pulmonary infiltrates on chest x-ray
4.EMG:
a.A multifocal axonal neuropathy
b.Mononeuropathy
1.Wegener’s granulomatosis has been recently renamed granulomatosis with polyangiitis
2.It is an autoimmune disease associated with granulomatous inflammation and anti-neutrophil cytoplasmic (ANCA) associated small vessel vasculitis
1.The prevalence of granulomatosis with polyangiitis is 5 patients per 100,000 of the population with its greater incidence being in northern Europe
2.GPA is seen in all ethnicities but its highest prevalence is in Caucasians
3.GPA granulomatosis is a necrotizing vasculitis that involves the upper and lower respiratory tract and causes glomerulonephritis
4.The early symptoms are nasal discharge, chronic cough, hemoptysis that evolves to dyspnea
5.Approximately 20-50% of patients develop neurological complications and include:
a.Mononeuropathy multiplex
b.Cranial neuropathies
c.Distal symmetric polyneuropathy
6.CNS manifestations:
a.Stroke
b.Pachymeningitis
c.Seizures
d.Reversible posterior leukoencephalopathy
7.Neuropathy occurs more frequently
8.The peak incidence occurs between 64-75 years of age
9.The most common cranial nerves affected are the II, VIth and VIIth nerves:
a.Cranial nerve involvement is seen in 5-10% of patients
b.Caused by extension of the nasal or paranasal granulomas rather than by vasculitis
1.GPA is a necrotizing vasculitis of arterioles, capillaries and venules
2.Clinical and experimental evidence has shown that myeloperoxidase (MPO), proteinase 3 (PR3) and lysosomal-associated membrane protein 2 (LAMP2) are major antigenic targets for ANCA in neutrophils
3.Tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 induce the translocation of proteinase 3 to the endothelial surface that causes the adherence of neutrophils to endothelial cells. This induces degranulation of the neutrophils which damages the endothelial surface of small blood vessels
1.The serum contains ANCA antibodies directed against proteinase-3 that has a specificity of 98% and a sensitivity of 95%
2.The absence of peripheral eosinophilia is a distinguishing point that differentiates the disorder from Chung-Strauss syndrome
3.Electrodiagnostic studies:
a.Multiple mononeuropathies
b.Symmetrical polyneuropathy
1.Microscopic polyangiitis (MPA) is a necrotizing vasculitis primarily affecting the lung and kidney capillaries
2.Neuropathy occurs in 10-50% of patients
1.Mononeuritis multiplex is the most common peripheral manifestation
2.Similar to PAN and CSS; age at onset: 50 years
3.Skin purpura and abdominal pain
1.There is severe involvement of pulmonary capillaries that leads to alveolar hemorrhage and interstitial fibrosis
2.MPA is a necrotizing arteritis that involves small vessels (capillaries, venules, and arterioles). Rarely medium sized arteries are involved
3.There is scant immune deposition in vessels and granulomatous inflammation is absent
4.ANCA in MPA is directed against myeloperoxidase and rarely against proteinase 3; it is an antineutrophil cytoplasmic antibody associated vasculitis
5.The kidneys may be affected with a pauci-immune necrotizing and crescentic glomerulonephritis
1.Most often associated with p-ANCA and less commonly c-ANCA
2.Lung and kidney involvement
3.Electrodiagnosis:
a.Most frequently a mononeuritis multiplex
1.Behcet’s disease involves small and medium sized blood vessels
2.There is a relationship between HLA-B51; there is also a strong association with leukocyte antigen-B
1.Recurrent oral and genital painful ulcers; rarely sharply punched out skin ulcers are seen
2.There are inflammatory lesions of the eye, arthritis (often large joints), gastrointestinal lesions and thrombophlebitis of the hepatic venous and lower extremity systems
3.Neurologic complications:
a.CNS:
i.Headache
ii.Meningoencephalitis
iii.Stroke
iv.Cerebral venous thrombosis
v.Arterial aneurysms
vi.Myelitis (rare)
vii.Psychosis
b.Peripheral neuropathy is rare
1.A vasculitic disorder of small to medium sized blood vessels
2.Studies suggest a T-helper type 1 (TH1) predominant response to as of yet unknown stimulus
3.Increased CD4 and CD8 lymphocytes are found in the peripheral blood in association with IL-2 and interferon-γ (gamma)
1.HLA-B5 may be an associated genetic factor
2.Hypercoagulable state
3.Lower extremity Doppler ultrasonography:
a.Symmetric venous involvement of all deep and superficial veins of the lower extremities
1.Approximately 20% of SLE patients develop a neuropathy during the course of their illness
1.Distal-symmetric
2.Mononeuritis multiplex
3.Approximately 70 to 80% are axonal and 20% are demyelinating
4.One third of patients develop autonomic involvement
1.Approximately 30% of systemic sclerosis patients develop a neuropathy
1.Most often a predominant sensory neuropathy
2.Small fiber neuropathy
3.Autonomic neuropathy of the gastrointestinal tract
4.The “numb chin” syndrome (mental nerve involvement)
5.Carpal and tarsal tunnel syndrome
1.Incidence of neuropathy in both primary and secondary Sjogren’s syndrome varies widely (2 to 64%)
1.Symmetrical and asymmetric neuropathies
2.Small fiber neuropathy
3.Trigeminal nerve involvement
4.Autonomic neuropathy
1.Neuropathy is demonstrated in 15 to 50% of rheumatoid arthritis patients
2.Distal symmetric sensorimotor neuropathy
3.Associated carpal and tarsal tunnel compression is associated as is drug-induced neuropathy
1.The most common malignancies associated with paraneoplastic neuropathies are:
a.Small cell lung cancer
b.Gynecological cancer
c.Lymphoma
2.Less frequent malignancies are:
a.Carcinoma of the kidneys
b.Myelodysplastic syndromes
c.Leukemias
d.Bile duct
e.Prostate
f.Stomach
3.Lymphoma causes:
a.Mononeuritis multiplex
b.Generalized sensorimotor neuropathy
c.Direct nerve infiltration
1.Pure sensory neuronopathy:
a.Often burning quality
2.All forms of peripheral neuropathy have been described
3.High CSF protein and high sedimentation rate may be suggestive of paraneoplastic vasculitic neuropathy
4.Anti-Hu antibody may be seen in paraneoplastic vasculitic neuropathy from an underlying small cell lung cancer
1.Cryoglobulins are immunoglobulins that precipitate at temperatures <37oC
2.The cryoglobulins are often asymptomatic or can induce a small-vessel immune-complex-mediated vasculitis
3.Although most patients with hepatitis C infection develop cryoglobulinemia only 15% demonstrate vasculitis
4.Approximately 30-70% of patients develop:
a.Small fiber neuropathy (painful)
b.Mononeuritis multiplex
c.Sensorimotor neuropathy (often asymmetric)
d.Associations include:
i.Purpura of the skin (particularly severe in the distal extremities)
ii.Arthralgias
iii.Renal involvement
5.Other infections associated with vasculitic neuropathy include:
a.AIDs
b.Cytomegalovirus
c.Epstein Barr virus
d.Herpes varicella zoster
1.Sarcoidosis:
a.Mononeuritis multiplex
b.CIDP
c.VIIth nerve involvement
2.Inflammatory bowel disease:
a.Incidence of 0.7% of vasculitic neuropathy; most associated neuropathies are nonvasculitic
1.Hypersensitivity vasculitis is most often secondary to drug reactions:
a.Naproxen:
i.Rarely induces a leukoclastic vasculitis with neuropathy
b.Minocycline:
i.Induces a vasculitic neuropathy
c.Other drugs inducing a vasculitic neuropathy are:
i.Penicillin
ii.Cocaine
iii.Heroine
iv.Phenytoin
d.Vasculitis may involve the CNS
e.Petechiae are common
f.Pathogenesis may be a complement mediated leukoclastic reaction
1.Vasculitic neuropathy can occur without systemic involvement (NSVN)
1.NSVN is seen in 60% of vasculitic neuropathies primarily in adult patients
2.The neuropathy is insidious and progressive in 1/3 of patients
3.Patients develop mononeuritis multiplex or a generalized slightly asymmetric generalized sensorimotor neuropathy
1.Small and medium sized vessels are affected
2.Nerve biopsy:
a.Axonal neuropathy
3.Intramural infiltration of epineurium and perineurium with T cells
4.Increased MMPs 2 and 9 that are secreted from T and stromal cells that:
a.Destroy the subendothelial basement membrane
b.Disrupt the nerve-blood barrier
c.Allow inflammatory cell infiltration of the peripheral nerves
1.Elevated sedimentation rate; positive ANA titers in some patients
2.Electrodiagnosis:
a.EMG:
i.Mononeuritis multiplex
ii.Sight asymmetric sensorimotor neuropathy
1.The disorder is not associated with the severity of the diabetes and may affect patients in good glycemic control
1.Most patients have painful lower limb nerve roots, lumbosacral plexus and peripheral nerves
2.The disorder may develop acutely or insidiously
3.An upper limb variant has been described
1.Nerve ischemia due to a microvasculitis
1.Cryoglobulins:
a.Are circulating immune complexes that consist of immunoglobulins
b.They are temperature dependent and precipitate with a drop in temperature and redissolve upon warming
2.The incidence of essential mixed cryoglobulinemia is high in areas where there is low HCV infection prevalence
3.Cryoglobulin classification:
a.Type I:
i.Cryoglobulins are monoclonal immunoglobins, primarily IgMK, that are directed against polyclonal IgG immunoglobulins
ii.They are most often detected in patients with lymphoid malignancies exemplified by multiple myeloma
b.Type II cryoglobulins:
i.They are a mixture of monoclonal IgM and polyclonal immunoglobulins that are directed against polyclonal IgG antigens
c.Type III cryoglobulins:
i.Are composed of a mixture of polyclonal IgM, IgG and IgA that are directed against polyclonal IgG
d.Mixed cryoglobulinemia:
i.Consist of type II and III cryoglobulins
ii.Encountered in connective tissue diseases and with infection by hepatitis B and C
iii.Essential mixed cryoglobulinemia is:
1.When mixed cryoglobulinemia occurs in the absence of an underlying disorder other than viral hepatitis
2.The majority of patients with essential mixed cryoglobulinemia have associated hepatitis C antigenemia
1.A peripheral neuropathy is encountered in 25-90% of patients with cryoglobulinemia of any type
2.The neuropathy of essential mixed cryoglobulinemia is manifest by:
a.Pain in a distal extremity distribution
b.A symmetric sensory or sensorimotor polyneuropathy
c.Mononeuropathy multiplex
d.Pure small fiber neuropathy (rare)
1.The mechanism suggested for the neuropathy is a virus triggered immune-mediated attack on nerves rather than direct nerve invasion as HCV replication in nerves has not been demonstrated
2.Putative mechanisms for the neuropathy include:
a.Ischemia from hyperviscosity
b.Vasculitis related to immune complex deposition in epineurial blood vessels
1.Electrodiagnosis:
a.NCS are similar to those of PAN
b.One patient has demonstrated conduction block on motor NCS
1.Most patients that develop CRPS have suffered either an injury to terminal twigs (peripheral fibers) of C and Aδ nociceptive afferents (type I CRPS) in soft tissue, or have a frank nerve injury (type II CRPS), bone fracture, or have undergone a surgical procedure. Cluster analysis reveals that the signs and symptoms of the syndrome may be separated into distinct factors
2.CRPS affects more females than males (relative risk 2:1-4:1)
3.Average age of onset 37-60 years
4.Type I (small fiber axonal injury) is far more common than type II (injury to a major nerve)
1.Continued regional pain:
a.Disproportionate to the inciting event
b.Most often burning in quality associated with a deep ache
c.Episodes of lancinating pain
2.Sensory signs and symptoms:
a.Mechanical hyperalgesia
b.Mechanical static and dynamic allodynia
c.Thermal hyperalgesia
i.Cold lowers pain thresholds more than warm
d.Pain spread from the initial area of injury most often distally to proximally
i.Rarely pain may be initially proximal to the area of injury
ii.Frequently over time the pain may be generalized to envelop the entire body
e.After sensations:
i.Pain continues after the stimulus is withdrawn. It is not stimulus bound
f.Mirror pain:
i.The pain is experienced in a similar distribution contralaterally to the injury
g.Vasomotor motor dysfunction:
i.Temperature asymmetry
ii.Skin color changes:
1.Livedo reticularis
iii.Sweating asymmetry
h.Sudomotor dysfunction and edema:
i.Swelling due to fluid in the body’s tissue
ii.Hyper or hypohidrosis
iii.Sweating asymmetry
i.Motor and trophic alterations:
i.Decreased range of motion
ii.Motor dysfunction:
1.Weakness
2.Dystonia
3.Myoclonus
4.Rapid tremor
iii.Dystrophic changes:
j.Hair:
i.Early in the course of illness, there is hypertrichosis; the hair is thicker and more curly than normal. Over time patients lose hair in affected areas
k.Nails:
i.Become ridged and brittle
l.Skin is frequently erythematous, thickened and demonstrates livedo reticularis
m.Bones are demineralized and fracture easily
The clinical diagnosis requires at least one symptom in each of the factors and one sign in at least two of the factors. CRPS I and CRPS II manifest similar symptoms and signs. Multiple studies have demonstrated that the spread of CRPS is a common phenomenon with time in refractory patients. Mirror spread and contiguous extremity spread are the most common patterns. Rapid new contiguous spread has also been described. A study of the natural history of CRPS demonstrated that 92% of 656 patients reported the spread of pain in some pattern over the course of their illness. CRPS spreads and may encompass the entire body surface in a significant portion of long standing refractory patients.
1.Peripheral afferent and efferent and central involvement that causes neurogenic inflammation (secretion of substance P and calcitonin gene related peptide) from injured nerve terminals
2.Activation of the immune system that causes an exaggerated inflammatory response
3.Maladaptive plasticity in both the central and peripheral nervous systems
4.Central sensitization is likely to play a role in contiguous spread, ipsilateral involvement and the generalized spread of CRPSII. It is manifested by:
a.Spontaneous pain at the site of injury and beyond its spatial extent
b.Mechanical pain hypersensitivity (AΒ fiber dynamic mechano-allodynia) and punctate and pressure hyperalgesia
c.Temporal summation (“windup”)
5.Mechanisms include:
a.Enhanced membrane excitability, increased synaptic efficacy of pain projections and disinhibition of PTNs (pain transmission neurons). Increases of previously subthreshold synaptic afferent input to nociceptors above and below the affected segments (carried by Lissauer’s tract in the spinal cord) discharges PTNS and increases their receptive field size. PTNs also receive small amplitude low threshold mechano-afferent (AΒ input) and nociceptive inputs outside of their receptive fields that become functional during central sensitization that further decreases receptive field threshold, increases receptive field size, and amplifies temporal summation.
b.It has been recently demonstrated that generalized whole body allodynia and hyperalgesia can be produced by a migraine attack. Functional magnetic resonance imaging in migraine patients with generalized mechanical allodynia demonstrated acute thalamic activation to dynamic mechano-allodynia and heat stimuli. The authors postulated that central sensitization of thalamic neurons with total body receptive fields occurs or that there is pain-facilitation from “on” cells of the rostral medullary nucleus that project to the thalamus or descend to the spinal cord and induce hyperexcitability of PTNs at all spinal levels
6.Pain facilitation by central sensitization may also occur from neuro-immune interactions that cause:
a.Activation of microglial cells and support their role in the initiation of neuropathic pain and that of astrocytes in its maintenance
b.Nerve injury:
i.Has been implicated in the disruption of the blood-spinal cord barrier that:
1.Results in an influx of inflammatory mediators
2.The segmental spinal recruitment of T-cells and monocytes. The chemokines CCL2 and CCL20 are pivotal in this process
c.There is support for the mechanism that neuro autoantibodies initiate a spreading inflammatory response throughout the neuroaxis. Radiolabelled PK11195, a biomarker of microglial activation, has demonstrated activation at the first dorsal horn synapse and in a minority of patients, trans synaptic activation in the thalamus
d.An autopsied patient with long standing generalized CRPS demonstrated significant posterior horn cell loss and activation of both microglia and astrocytes, most prominently at the index level (L5) but extending throughout the spinal cord.
e.A possible mechanism for both symptom spread and neuronal loss is activated glial secretion of pro-inflammatory cytokines, nitric oxide, excitatory amino acids, prostaglandins and adenosine triphosphate
f.Reorganization of the somatosensory cortex occurs after peripheral nerve injury; demonstrated by functional MRI:
i.The pain matrix which encompasses discriminative, affective, motivational and inhibitory components is modulated in CRPSII that may have a major effect on both the development and maintenance of widespread pain
g.Increased levels of proinflammatory cytokines that include TNF-α , interleukin 1-Β, IL-2 and Il-6 and decreased levels of anti-inflammatory cytokines IL-4 and IL-10 have been identified in the plasma and cerebrospinal fluid and within affected extremities of CRPS II patients
1.Quantitative sensory testing
2.EMG and NCS to evaluate the peripheral nerve injury
3.Triple phase bone scan
4.Plain radiographs:
a.Generalized osteopenia, bone lakes and periarticular osteopenia
1.Fibromyalgia is a disorder of widespread pain and tenderness that has been continuous for at least 3 months
2.The pain is on both sides of the body, above and below the waist and includes the axial spine
3.The 2010 ACR criteria require:
a.Fatigue
b.Sleep disorder
c.Cognitive dysfunction
4.The physician assessment:
a.Physicians to evaluate patients by questions to determine scores on a widespread pain index (WPI) and a symptom severity (SS) scale
i.The WPI is a 0-19 scale that assesses pain in 19 different body regions that include:
1.Shoulder girdle
2.Hip
3.Jaw
4.Upper arm
5.Upper leg
6.Lower arm and lower leg
7.Upper and lower back
8.Chest
9.Neck
10. Abdomen
ii.The pain is evaluated over the past week
iii.The SS scale quantifies symptom severity in a 0-12 scale for:
1.Cognitive dysfunction
2.Fatigue
3.Unrefreshed sleep
1.Painful tender points as detailed by the manual tender point survey (MTPS) method
2.Other than the tender points outlined in the MTPS the physical examination is negative
3.The tender points are evaluated over the:
a.Cervical spine
b.Trapezius ridge
c.Arcade of Frohse
d.Medial scapular border
e.LS vertebra
f.Mid to lower back
g.Medial knee
h.Anterior chest
1.Structural brain changes in patients with fibromyalgia have demonstrated:
a.Moderate evidence that central sensitization is correlated with gray matter volume loss in the anterior cingulate and prefrontal cortex
b.Global gray matter volume is unchanged
2.Functional MRI has demonstrated that brain activity is response to a nociceptive stimulus:
a.Is similar in pattern to activation of the pain matrix but has greater activation than normal controls
b.Some evidence for decreased functional connectivity in the descending pain-modulating system in FM patients
c.Functional MRI evidence that the default mode network to insula connectivity is associated with spontaneous pain in fibromyalgia patients
d.Altered fMRI activity in FMS has also been demonstrated:
i.Between the DMN and the anterior mid cingulate cortex, the right parahippocampal gyrus, left superior parietal lobule and the left inferior temporal gyrus
ii.Reduced functional connectivity between the DMN and the right parahippocampal gyrus has been demonstrated by correlation analysis to be associated with longer duration of disease
e.The translocator protein is upregulated during glial activation in chronic pain patients and is:
i.The rate-limiting step in neurosteroid synthesis
ii.Modulates synaptic transmission
iii.Related serotonergic mechanisms determine if pro- or anti- nociceptive neurosteroids are synthesized
iv.Fibromyalgia patients with the high TSPO (translocator protein) affinity binding genotype:
1.Have higher pain intensity and more severe fibromyalgia as compared to patients with mixed / low affinity binders
2.The effects are modulated by interaction with the serotonin transporter gene
f.A subset of patients with fibromyalgia have a large fiber demyelinating neuropathy similar to chronic inflammatory demyelinating polyneuropathy (CIDP)
g.There is mounting evidence to support a contribution of small fiber neuropathy to a subgroup of patients with FMS
1.There is no consistent or characteristic abnormality on laboratory testing for fibromyalgia
2.Diagnostic evaluation is to rule out diseases with similar manifestations or to diagnose concomitant disorders
3.Skin biopsy to evaluate epidermal nerve fiber density
1.Definition:
a.A small fiber neuropathy is a structural abnormality of small nerve fibers that is characterized pathologically by degeneration of the distal small fiber nerve endings
b.Small fibers are unmyelinated C-fibers (1μ) and Aδ fibers (1-4μ) that traverse the dermis to innervate cutaneous structures. Both types of fibers terminate as free endings in the skin
c.Aδ fibers carry epicritic fast pain, well localized and lancinating in quality as well as cold sensation
d.C-fibers transmit innocuous warm and possibly innocuous cold sensibility as well as nociception from high threshold mechanical, thermal and chemical stimuli
e.There is active interplay between fiber types on pain transmission neurons that also result in specific sensations as exemplified by the thermal grill illusion
f.Small fibers are a major component of the autonomic nervous system:
i.Thinly myelinated fibers are preganglionic
ii.C-fibers contribute to postganglionic fibers that innervate sweat glands, blood vessels and the heart
g.Nerve growth factor interacts with and is trophic for these small fiber neurons
h.Mutations in both NGF or its high-affinity receptor NTRK1 cause:
i.Degeneration of nociceptors and sympathetic neurons
ii.The cause of autonomic neuropathy type V (nociceptors) and type IV (sympathetic neurons)
i.Incidence and prevalence of SFN has not been established
1.Symptoms are variable both in severity and progression in patients with SFN
2.Symptoms usually start in the feet and progress proximally in a length-dependent manner. When the neuropathy crosses the knees patients note hand involvement. The pattern is that of stocking and glove sensory abnormality
3.Pain may be the presenting symptom. It is characterized by:
a.Spontaneous (stimulus independent) but can be evoked by mechanical stimuli
b.It is most often described as burning or prickling and in some patients has a pruritic element
c.Pain attacks triggered by exercise or temperature suggest:
i.Nav1.7 mutations
ii.Fabry’s disease
4.SFN may present with a patchy loss of sensation that involves the face or trunk which suggests an autoimmune cause
5.Autonomic dysfunction manifests with:
a.Constipation and diarrhea
b.Impotence
c.Postural hypotension:
i.If severe, amyloid neuropathy may be causative
6.Trophic changes:
a.Dry, cracked, erythematous and shiny skin (particularly prominent in CRPSI)
7.Motor function is normal
8.Reflexes are normal but in a subset of patients may be slightly hyperactive
9.Cerebellar and sensory coordinative function is normal
10. Large fiber sensory modalities of vibration, proprioception and light touch are normal
11. A distal loss of pin-prick or thermal sensation (easily tested with a cold tuning fork) are diminished. A subset of patients has punctate mechanical hyperalgesia and dynamic mechanical allodynia (pain evoked from lightly brushing the skin)
12. Resting tachycardia with a postural drop in blood pressure suggests autonomic fiber involvement
13. Diagnostic criteria for SFN in diabetes mellitus include:
a.Possible - length-dependent symptoms and / or clinical signs (hypoesthesia in small fiber modalities)
b.Probable – length dependent symptoms, clinical signs of small fiber damage and normal nerve conduction studies
c.Definite – length dependent symptoms, clinical signs of small fiber damage, normal nerve conduction studies, and altered intra-epidermal nerve fiber density at the ankle and / or abnormal quantitative sensory testing of thermal thresholds at the foot
1.Skin biopsy:
a.A skin punch biopsy 3 mm in diameter is usually obtained 10 cm proximal to the lateral malleolus; alternatively, the biopsy site is the proximal thigh 20 cm below the iliac spine. In combination with the distal biopsy site may help in the differential between a neuropathy and neuronopathy
b.Morphometric analysis:
i.Bright field immunochemistry or indirect immunofluorescence are the techniques utilized for routine diagnostics (bright field immunohistochemistry is most commonly utilized)
ii.The biopsy is stained for the PGP9.5 antigen a ubiquitin hydrolase that is found in all nerve fibers
iii.Intra-epidermal nerve fiber density measurements quantify the number of nerve fibers that cross the dermal-epidermal junction per millimeter of epidermal surface
iv.Values below the fifth quartile compared to age and gender matched controls are diagnostic of a SFN
v.Qualitative assessments of small nerve fibers include:
1.Axonal swelling, a marker of predegenerative change
2.Weaker PGP9.5 staining
vi.In vivo corneal confocal microscopy can measure Aδ and C-fibers that originate in the ophthalmic division of the Vth nerve; corneal nerve bundle density inversely correlates with the severity of neuropathy
1.The specific biomarkers of the disorders that cause SFN
2.Quantitative sensory testing
a.Detection thresholds, pain thresholds (for mechanical and thermal stimuli) and stimulus-response functions (exemplified by “wind up”) are evaluated
b.Thermal detection and pain thresholds are most important for SFN
3.Electrodiagnostic evaluation:
a.NCS primarily assess large myelinated fibers (AΒ fibers 12-22μ ) and are unable to measure small fibers
b.Conventional NCS are utilized in SFN workup to rule out a large fiber component (would suggest an autoimmune etiology)
c.Laser evoked potentials:
i.Lasers can stimulate Aδ –fibers and their evoked cortical potentials allow evaluation of the somatosensory pathways from Aδ-fiber terminals in the skin to cortical terminations (SI, SII, insular cortex among others)
d.Microneurography:
i.Recording microelectrodes are inserted into nerve fascicles that allow multiple small fiber recording. The function of small fibers can be directly determined but at the moment this is a research tool
e.Autonomic nervous system testing:
i.The Ewing protocol for cardiovascular reflex testing
ii.Sympathetic skin response
iii.Quantitative sweat testing
1.In these rare inherited conditions small fibers are dysfunctional but structurally intact
2.Inherited erythromelalgia (IE):
a.IE is caused by mutations of the SCN9A gene that maps to chromosome 2q24.3 and is AD
b.The gene encodes the Nav1.7 sodium channel
1.Episodes of symmetrical burning pain of the feet or legs associated with erythema
2.There is usually a family history but sporadic patients are seen
3.The usual onset is in the first two decades of life: late onset patients, in the sixth decade have been described with minimal ion channel dysfunction
4.The attacks may be triggered by a mildly warm stimulus or exercise and may be ameliorated by cooling (some patients place their affected extremities in ice-water)
1.There have been 20 gain of function mutations in the Nav1.7 channel that cause IE
2.The mutations lower pain projection neuron firing thresholds which allows the channel to be activated by smaller depolarizations
3.Slow deactivation kinetics which keep the channel open longer once it is activated
4.Dorsal root ganglia pain projecting neurons are hyperactive
1.Molecular genetic testing to delineate the specific SCN9A mutation
1.The mutation is in the SCN9A gene that encodes Nav1.7 that maps to chromosome 2q24.3
1.These patients suffer paroxysmal attacks of pain in the lower body, often the rectum
2.Pain may be experienced in the eyes, jaw and is often associated with flushing of the affected site
3.Attacks may be precipitated by defecation, crying or yawning or occur spontaneously
1.The SCN9A mutations that are seen in PEPD impair inactivation of the Nav1.7 channel that causes an enhanced persistent current
1.Molecular genetic analysis to delineate the SCN9A gene mutation that leads to the mutated Nav1.7 channel
1.Recently described in one Columbian family
1.Severe upper body pain that begins in infancy
2.Upper body pain that is triggered by fasting or fatigue, illness, cold or exercise
1.It is an autosomal dominant mutation in the TRPA1 gene that maps to chromosome 8q21.11
2.Encodes a non-selective cation channel that is expressed in a sub-population of nociceptors that can be activated by endogenous ligands or extreme cold
3.The biophysical kinetics of the TRPA1 channel are altered which increases current flow when the channel is activated
4.The mutation causes a single substitution in the S4-S5 region of the receptor which increases chemical sensitivity of TRPA1 but does not change its voltage sensitivity
5.This R852A mutation causes:
a.Increased basal channel activity
b.A loss of Ca (2+) - induced potentiation
c.Accelerated Ca (2+) - dependent inactivation
d.Putatively, the inter-subunit salt bridges between adjacent S4-S5 regions stabilize the conformations associated with the chemical and voltage gating of the channel
1.Molecular genetic analysis to delineate the mutation of the TRPa1 gene
1.The mutation in Nav1.9 was discovered by exome analysis with 12 affected and nine unaffected members in 2 families
2.Two missense mutations were identified in the SCN11A gene that maps to chromosome 3p22
3.Nav1.9:
a.Is a tetrodotoxin (TTx) – resistant channel that is expressed in nociceptors
b.It has hyperpolarized voltage-dependent activation that is close to the resting membrane potential
c.It inactivates slowly which leads to a persistent current
d.Mutations in Nav 1.9 have caused both gain of function and loss of function channel kinetics that cause painful and painless peripheral neuropathy and autonomic symptoms
1.A childhood onset; a subset of patients have onset of pain in infancy
2.In some patients, painful episodes decrease in adolescence
3.There are 3 subtypes of clinical manifestations with SCN11A missense mutations:
a.Loss of pain (L811P)
b.Painful small fiber neuropathy
i.G699R, L1158P and 1381T variants
ii.Cause painful small fiber symptomatology
iii.Late onset – the fifth or sixth decade
iv.Associated with:
1.Skin discoloration
2.Burning pain
3.Autonomic dysfunction manifested by:
a.Dry eyes
b.Diarrhea
c.Urinary alterations
d.Palpitations
e.Orthostatic dizziness
4.Familial episodic pain:
a.Early infantile onset of episodic pain
b.Gradual amelioration in adolescence
c.Pain is primarily in the lower extremities
d.Induced by cold and barometric pressure changes
e.Relief of pain with anti-inflammatory medication and by warming the affected extremities
1.In Japanese patients, all subjects had mutations at the arginine amino acid in position 222
2.Experimental evidence suggests that the mutation may impair axonal channel components that are important for AP firing, channel localization and distribution
1.Molecular genetic analysis of the SCN11A gene to delineate the mutation
1.Nav 1.7 mutations
2.Nav 1.8 mutations
3.Nav 1.9 mutations
1.Is caused by mutations in the TTR gene that maps to chromosome 18q12.1
2.Greater than 100 missense mutations in the TTR gene have been delineated worldwide (not all are amyloidogenic). The variants are primarily seen in single individuals or within a few families
3.TTR-FAP has a prevalence of 1 in 100,000 individuals in the USA and Europe; it is endemic in northern Portugal, Sweden, Cyprus, Majorca and Japan
4.It is heterogeneous as regards to signs and symptoms among individuals and between geographic locations
1.The most common form of familial amyloid polyneuropathy
2.Most often symmetric, distal neuropathy that begins in the lower extremities, progresses to the arms and then to the proximal extremities and trunk
3.Upper extremity involvement is predominant in the TTR184s and TTR L58H variants
4.Patients may complain of pain and small fiber symptomatology
5.Autonomic dysfunction is manifested as impotence and urinary dysfunction
6.Late onset progressive transthyretin-related amyloid neuropathy
7.All late-onset TTR-mutant patients manifest:
a.Distal weakness
b.Sensory loss to all modalities
c.Loss of deep tendon reflexes
d.Sensorimotor hand involvement
e.Sensory-ataxic gait (92% of patients)
f.TTR may manifest with congestive heart failure and postural hypotension
1.TTR is a transport protein for thyroxine in plasma and retinol (Vitamin A)
2.TTR circulates as a tetramer of four identical subunits; it is synthesized by the liver and the choroid plexus
3.TTR mutations:
a.Accelerate TTR amyloid formation
b.Most mutations are associated with cardiac and/or nerve involvement
c.Variably involved are:
i.The gastrointestinal tract
ii.Vitreous
iii.Lungs
iv.Carpal tunnel ligaments
d.The described single point mutations cause destabilization of the quaternary structure into Β-plated sheet predominant insoluble and inactive forms
e.Tetramer dissociation is a required and rate-limiting process in the formation of amyloid fibrils
f.Amyloidogenic mutations:
i.Destabilize the quaternary and tertiary TTR structure
ii.Induce conformational changes that lead to dissociation of the tetramers that then reassemble into partially unfolded species that form amyloid fibrils that deposit into the peripheral nerves and heart
1.Skin biopsy
2.QST
3.Molecular genetic analysis to delineate the mutation in the TTR gene
1.Fabry’s disease is an X-linked lysosomal storage disease due to a lack of alpha-galactosidase A
2.Its incidence is 1 patient in 40,000 males
3.Heterozygous females may be asymptomatic or due to lyonization or random X-inactivation may be severely affected
1.A large proportion of patients present with burning or lancinating pain in their distal extremities
2.Angiokeratomas:
a.Reddish or purple maculopapular lesions are found:
i.In the bathing suit distribution (scrotum, inguinal and perineum)
ii.The umbilicus
3.Angiectasias:
a.Small red lesions may occur in the nail beds, conjunctiva and oral mucosa
4.Associated medical complications:
a.Small vessel cerebrovascular disease with stroke
b.0.0167% of all causes of end stage renal disease
c.Hypertension
d.Atherosclerosis with myocardial infarction
e.Patients succumb by the fifth decade
1.Sural nerve biopsy:
a.Decreased small myelinated (1-4μ) and unmyelinated C-fibers (1-μ)
2.Glycolipid granules in DRG cells of the peripheral and sympathetic nervous system
3.Skin biopsy:
a.Decreased epidermal nerve fiber density
4.The disease is caused by mutation of Xq21-22 that leads to decreased α-galactosidase and the consequent accumulation of ceramide trihexoside in peripheral nerves and vascular endothelial cells of organs
1.Α-galactosidase deficiency can be demonstrated in leukocytes and cultured fibroblasts
2.Molecular genetic analysis to delineate the mutation
3.NCS:
a.Decreased amplitudes of motor and sensory nerves
4.QST:
a.Increased temperature detection thresholds
1.Tangier disease is caused by homozygous or compound heterozygous mutation in the ABCA1gene that maps to chromosome 9q81; it is autosomal recessive
2.Families have been described from Chesapeake Bay, Missouri and Kentucky
1.Major presentations include:
a.An asymmetric mononeuropathy multiplex
b.A slowly progressive symmetric polyneuropathy affecting the legs > arms. Remitting and relapsing in some patients.
c.A pseudosyringomyelia presentation with dissociation between loss of pain and temperature with maintenance of large fiber modalities of vibration and position sense in the arms
2.Large, yellow-orange tonsils
3.Enlarged liver, spleen and lymph nodes
1.Tangier disease patients have elevated plasma triglyceride concentrations and almost absent HDL that result from mutations in the ATP binding cassette transporter A1(ABCA1)
2.The ABCA1 transporter:
a.Facilitates the efflux of cellular phospholipid and free cholesterol to aggregate with apolipoprotein A-1 (apoA-1) to form HDL particles
3.Plasma deficiency or absence of HDL, apolipoprotein A-1 (apoA-1, the major HDL apolipoprotein) causes the accumulation of cholesteryl esters in many body tissues
4.Nerve biopsy:
a.Axonal degeneration with both de- and re-myelination
b.Electron microscopy:
i.Abnormal accumulation of cholesteryl esters in Schwann cells including those associated with thinly or unmyelinated nerve fibers
5.Skin biopsy:
a.Decreased intradermal small fiber density
1.Plasma HDL concentration of less than 5mg/dl
2.Low total plasma cholesterol (below 150mg/dl)
3.Normal or high plasma triglycerides
4.Electrodiagnosis:
a.Motor and sensory NCS are normal or have moderate decreased amplitudes, prolonged distal latencies and slow conduction velocities
1.Idiopathic small fiber neuropathy:
a.In approximately 50% of patients with SFN no specific etiology can be determined
2.Sulfoglucuronosyl paragloboside epitopes
3.TTR met 30
4.Sulfatide epitopes
5.GALOP epitopes
6.Familial amyloid neuropathy
1.Burning mouth syndrome is also named stomatodynia, glossodynia
2.Definition:
a.Any form of burning or stinging sensation in the mouth in association with a normal mucosa in the absence of local or systemic disease
1.The intra-oral burning or dysesthetic sensation recurs daily for more than 2h / day for more than 3 months
2.Most often encountered in perimenopausal or menopausal aged women
3.There is a female / male ratio of 7:1
4.The anterior 2/3 of the tongue is most commonly affected
5.Taste alterations and dryness are associated
1.Putatively a neuropathic condition; possible small fiber neuropathy
1.Neurotransmitter positron tomography has demonstrated hypofunction of the dopaminergic system of the basal ganglia:
a.Spatial and temporal brain responses to noxious heat thermal stimuli are different in burning mouth syndrome as compared to controls
1.Ehlers-Danlos syndrome may be caused by mutation in:
a.The alpha-1 (V) gene COL5A1 that maps to chromosome 9q34
b.Alpha-2 (V) gene COL5A2 that maps to chromosome 2q31
c.Alpha-1(1) gene COL1A1 gene on chromosome 17q
2.There are 6 major EDS variants the most common of which are:
a.Hypermobility (hEDS)
b.Chronic (cEDS)
c.Vascular (vEDS)
3.There is a recently described overlap between hEDS and the joint hypermobility syndrome (JHS)
1.Pain is common in the various EDS types particularly in JHS/hEDs and manifests with:
a.Recurrent / migratory onset of arthralgias in childhood
b.An evolution by slow progression to a widespread chronic pain syndrome in adults and elderly patients
2.Patients experience:
a.Burning pain (hands and feet)
b.Dysesthesia
c.Paresthesias
d.Mechanical allodynia
e.Cramps
f.Diffuse myalgias
3.Most EDS patients have moderate to severe autonomic dysfunction
1.Skin biopsy:
a.A decrease of IENFD as compared with age and sex-matched controls
1.Sural SNAP and conduction velocities are normal
1.Approximately 50% of small fiber neuropathies are idiopathic (no specific underlying etiology can be determined)
2.Approximately 50% of idiopathic SFN have abnormal 2-hour glucose tolerance tests or an abnormal fasting glucose which may be seen despite a normal glycosylated hemoglobin
3.Risk factors for the development of SFN:
a.All of the features between prediabetes and metabolic syndrome:
i.Hyperlipidemia
ii.Hypertension
iii.Obesity
iv.Insulin resistance
1.Symptoms vary widely that often start as vague unpleasant sensations in the feet
2.Cold like pain, tingling and a pins and needle sensation that evolves into burning pain
3.The pain may be persistent but varies in intensity throughout the day
4.Lancinating electric shock-like pain, that lasts for seconds, may be superimposed on persistent pain
5.Symptoms may increase at night and during periods of inactivity
6.Mechanical hyperesthesia and dynamic and static allodynia may affect the lower extremities
7.Autonomic dysregulation may manifest as:
a.Dry eyes and dry mouth
b.Postural lightheadedness, presyncope and syncope
c.Hypo or hyperhidrosis
d.Erectile dysfunction
e.Urinary frequency, nocturia and difficulty voiding
f.Gastrointestinal manifestations:
i.Nausea and vomiting
ii.Constipation or diarrhea
iii.Early satiety
8.Motor and coordinative function is usually normal
9.Large fiber modalities of sensation that include proprioception, vibration and light touch are intact
10. Affected extremities have decreased thermal sensitivity and “pin-prick” sensitivity; a subset have mechanical hyperalgesia and allodynia
11. Some patients demonstrate dystrophic skin changes
1.No specific etiology can be determined
2.Skin biopsy:
a.Decreased intraepidermal small nerve terminal fibers (A-delta and C-fibers); lowest quartile
b.Terminal axonal swelling and often abnormalities of sweat glands
1.QST:
a.Heat or heat-pain detection thresholds may be the most specific for SFN
2.Contact heat evoked potentials (CHEPs):
a.Provides rapid cycles of heat that produce evoked cortical potentials that are linearly correlated between CHEP amplitude and cutaneous nerve fiber density
3.Quantitative Sudomotor Axon Reflex Testing (QSART):
a.A measure of postganglionic sympathetic cholinergic function
b.QSART is abnormal in approximately 75% of patients with SFN and sudomotor dysfunction can precede neuropathic signs and symptoms
c.Other tests for autonomic sweat testing include:
i.Sweat imprint
ii.Thermoregulatory sweat testing
iii.Quantitative direct and indirect sudomotor tests
1.Idiopathic SFN
2.Burning mouth syndrome
3.Fibromyalgia
4.Significant number of patients with glucose intolerance
1.Nav 1.7 mutations:
a.Inherited erythromelalgia
b.Paroxysmal extreme pain disorder
2.Nav 1.8:
a.Severe pain
b.Brugada syndrome
3.Nav 1.9:
a.Familial episodic pain syndrome
b.Infantile pain episodes
1.Fabry’s disease
2.Tangier’s disease
3.Ehlers-Danlos
4.TTR met 30
5.Sulfoglucuronosyl paragloboside (SGPG)
6.Sulfatide
7.GALOP
1.Impaired glucose tolerance
2.Diabetes mellitus
3.Rapid glycemic control “insulin neuritis”
4.Vitamin B12 deficiency
5.Dyslipidemia
6.Hypothyroidism
7.Chronic kidney disease
8.Hepatitis
1.HIV
2.Hepatitis C
3.Influenza
4.Erythromelalgia-related poxviruses
5.Idiopathic autonomic neuropathy (often preceded by upper respiratory or gastrointestinal infections)
6.Epstein-Barr virus-associated acute autonomic neuropathy
7.Chagas disease (chronic phase)
8.Mycoplasma infection
1.Anti-retrovirals:
a.CART therapy
2.Antibiotics:
a.Metronidazole
b.Nitrofurantoin
c.Linezolid
3.Chemotherapeutic agents:
a.Bortezomib
b.Bortezomib-thalidomide (used in the treatment of multiple myeloma)
4.Other Causes:
a.Flecainide
b.Statins
c.Alcohol
d.Vitamin B6 toxicity
1.Guillain-Barre syndrome (a component of the immune attack)
2.Chronic inflammatory demyelinating polyneuropathy (a component of the neuropathy)
3.Celiac disease
4.Sarcoid
5.Sjogren’s syndrome
6.Systemic lupus erythematosus
7.Peripheral Nerve Vasculitis:
a.Primary Vasculitides:
i.Periarteritis nodosa
ii.Chung-Strauss syndrome
iii.Granulomatosis with polyangiitis
iv.IgG4-related disease
v.Microscopic polyangiitis
b.Secondary Systemic Vasculitides:
i.Systemic lupus erythematosus
ii.Systemic sclerosis
iii.Sjogren’s syndrome
iv.Rheumatoid arthritis
v.Paraneoplastic vasculitic neuropathy
vi.Hepatitis C cryoglobulinemia
vii.Vasculitis without any systemic involvement (NSVN)
viii.Inflammatory bowel disease
ix.Paraneoplastic neuropathies
x.Amyloid
xi.Monoclonal gammopathy
xii.Mixed cryoglobulinemia
1.Critical illness
2.Complex regional pain syndrome type I (CRPS I)