Differential Diagnosis in Neurology

10.12. Vasculitic Peripheral Neuropathy and Neuropathies Associated with Connective Tissue Disorders

• General features:
  • Most connective tissue diseases cause a secondary vasculitis (inflammation and necrosis of blood vessel walls)
  • Secondary vasculitis can occur secondary to an exogenous antigen, infection or drug
  • Neuropathy occurs as a comorbidity of the underlying disease (i.e. uremic neuropathy from renal failure in SLE, PAN, Wegener's granulomatosis, mixed connective tissue disease)
  • Entrapment neuropathy from diseases that induce a proliferation of connective tissue (rheumatoid arthritis, scleroderma, mixed connective tissue disease)
  • Comorbid drug toxicity (cyclosporin)
  • Inflammatory demyelination may occur concomitantly with SLE, Sjögren's and diabetes mellitus. Indistinguishable from autoimmune GBS or CIDP by EMG criteria
  • Cryoglobulinemia:
    • Frequently associated with all collagen vascular diseases
    • Type 1 (monoclonal Ig (light chains) associated with lymph proliferative disease)
    • Type II (monoclonal immunoglobulins; often IgM Kappa)
    • Type III (polyclonal IgG and IgM; associated with Sjögren's, rheumatoid arthritis, scleroderma, lymphoproliferative disease, glomerulonephritis, chronic liver disease and infection)
  • Microvascular thrombosis secondary to cytokines, vasospasms, endothelial cell proliferation, activation of clotting factors; a common mechanism in SLE with antiphospholipid antibodies
  • Autoantibodies: IgM monoclonal cryoglobulinemia is associated with MAG
• Clinical presentation:
  • General features common to all vasculitides:
    • Acute or subacute onset
    • Mononeuritis multiplex; sensory loss or weakness in the distribution of one or more nerves
    • 15–25% may have distal symmetric sensorimotor presentations
    • Median, ulnar, peroneal, femoral, and posterior tibial nerves affected (infarcted)
    • Rare isolated sensory involvement
    • Small modality sensation with burning pain occurs at some point in 80% of patients; all fiber sizes affected
    • Present in the context of systemic symptoms and signs of the specific disease
  • Non-systemic vasculitis:
    • No clinical or laboratory evidence of other organ system involvement
    • Approximately 1/3 of vasculitic neuropathy
    • Small and median sized arteries of the epineurium and perineurium are involved (vasovasorum)

Group I: Systemic Necrotizing Vasculitis

• Small and medium sized blood vessels are affected
• Pathology:
  • Leukotactic reaction; granulomatous and monocytic involvement of the blood vessel wall

Polyarteritis Nodosa

• General features:
  • Necrotizing vasculitis of small and medium sized blood vessels
  • Organs involved; long medullary arteries of the kidney; muscle, bowel, skin and testes; lobar liver infarction
  • Pulmonary circulation is spared
• Clinical presentation:
  • Hypertension; eosinophilia hepatic and testicular infarction: weight loss, fever similar to lymphoproliferative disease
  • Mononeuritis multiplex
  • Guillain Barré Syndrome
  • 10–20% suffer small vessel CNS strokes
• Laboratory:
  • Increased SED Rate
  • Rheumatoid factor (RF) noted
  • Decreased complement
  • Hepatitis B and C prior infection
  • ANCA antibodies in a small percentage of patients
• Pathology:
  • Necrotizing vasculitis of small and medium sized arteries
  • Mixed infiltrate of macrophages and neutrophiles

Microscopic Polyangiitis

• General features:
  • Glomerulonephritis in all patients
  • Involvement of lungs, GI tract in approximately 50%
  • Eye vascular involvement
  • Spleen and muscle involvement in 20–30%
  • Peripheral CNS involvement (rare)
• Clinical presentation:
  • Mononeuritis multiplex
  • Cortical stroke (rare)
• Laboratory:
  • ANCA (+), P > C in up to 90% of patients
  • RF noted in approximately 50% of patients
  • Rare decreased complement
  • Hepatitis B (-)
  • Rare microaneurysms noted on arteriography
• Pathology:
  • Necrotizing vasculitis
  • Neutrophilic and monocytic infiltrate

Churg Strauss Syndrome

• General features:
  • Pulmonary involvement is prominent; sinus involvement in 25% of patients
  • Pituitary gland may be affected
  • Heart and kidney involvement in approximately 50% of patients
• Clinical presentation:
  • Asthma and eosinophilia
  • Acute painful dysesthesia and edema in dysesthetic portion of distal limbs
  • Early mononeuritis multiplex
  • Progression to asymmetrical polyneuropathy restricted to the limbs
  • EMG: decreased or absent amplitudes of SNAP and CMAP
• Laboratory evaluation:
  • Lung involvement (chest X-ray) in all patients
  • ANCA (p > c) in approximately 75% of patients
  • Eosinophilia in all patients
  • Increased IgE in 75% of patients
  • RF increased in one half of patients
• Pathology:
  • Intravascular and extravascular granulomatous eosinophilic tissue infiltrate
  • Necrotizing vasculitis of small and medium sized blood vessels
  • Infiltrate of CD8 positive suppressor/cytotoxic and CD4 positive helper T cells
  • Axonal degeneration

Wegener's Granulomatosis

• General features:
  • Granulomatous vasculitis of the upper and lower respiratory tract
  • Glomerulonephritis
  • Pulmonary involvement in greater than 75% of patients
  • Ocular vasculitis in 50% of patients
  • Dermatological lesions in approximately 50% of patients
• Clinical Presentation:
  • Cranial nerve involvement of V, IX, X
  • Mononeuritis multiplex
  • Symmetrical distal polyneuropathy (10–20%)
  • Ocular involvement in 50%
• EMG:
  • Positive sharp waves
  • Fibrillations
• Pathology:
  • Disseminated vasculitis of small and medium sized blood vessels
  • Granulomas of lung, kidney and sinuses
  • Capillaries, veins and venules are involved
• Laboratory:
  • RF in approximately 60
  • c-ANCA (epitope against proteinase 3)
  • p-ANCA (epitope is myeloperoxidase)

Rheumatoid Vasculitis

• General features:
  • All vessel sizes affected
  • Overwhelming joint involvement (small joints)
  • Systemic feature of anemia and weight loss in severely affected patients; adenopathy, pericarditis, intersitial lung disease, glomerulonephritis, skin serosal surfaces are involved
• Clinical presentation:
  • Peripheral neuropathy in 1–10% of patients
  • Entrapment neuropathy: median nerve (CTS); digital, ulnar, anterior and posterior interosseous nerves; ulnar nerve entrapment in the cubital tunnel or Guyon's canal, sciatic nerve entrapment in the posterior popliteal fossa; tarsal tunnel syndrome
  • Distal symmetric polyneuropathy:
    • Insidious onset of paresthesias and decreased sensibility in both upper and lower extremities
    • Minimal motor deficit
    • Hands often severely wasted
  • Mononeuritis or mononeuritis multiplex:
    • Acute or subacute onset; evolves into a severe distal sensorimotor neuropathy
    • Cranial nerve mononeuritis is rare
  • Severe distal sensorimotor neuropathy:
    • Rapid evolution
    • Multiple mononeuritis attacks evolving into symmetrical distal weakness and sensory loss
    • Seen in longstanding severe RA in a setting of systemic features of malaise, weight loss, skin involvement and rheumatoid nodules
    • Active disease with increased rheumatoid factor and decreased complement

SLE

• General features:
  • Prevalence of 1/1000 people; more common in women than men; black patients greater than white
  • Multiple susceptibility genes; complex II; deficiency of complex cascade have been implicated
  • Autoantibodies bind directly to specific antigens or form immune complexes
  • Concomitant systemic involvement of joints, serosal surfaces, heart, lung, kidney, skin and blood
  • Inflammatory demyelinating polyradiculopathy:
    • Acute to GBS presentation
    • CIDP form
    • Relapsing CIDP form
  • Cranial neuropathy:
    • Occurs in 5–10% of patients
    • II, V, VI, III, VII, laryngeal (X)
  • Rare neuropathies:
    • CTS
    • Acute sensory ataxic neuronopathy
    • Neuromyotonia
• EMG:
  • Overlapping mononeuritis
  • Severe generalized axonal neuropathy; positive sharp waves decreased CMAPs and SNAPs; often asymmetric; fibrillations in potential in weak muscles
• Laboratory:
  • ANA positive greater than 95%
  • Double stranded DNA positive in approximately 70% of patients
  • Smooth muscle antibodies
  • Ro and La antibodies greater >25% of patients ANCA greater than 10% of patients
  • RF + >75%
  • Cryoglobulins are found in 15%
• Pathology:
  • Necrotizing vasculitis; proliferative endarteritis; vasculopathy > vasculitis in cerebral vessels; small and medium sized vessel involvement; scattered perivascular inflammatory cells
  • Dorsal root ganglion biopsy; cytotoxic/suppressor CD8 T cells surrounding neurons
  • Involvement of small and medium sized vessels that includes arteries, arterioles, capillaries and venules

Group 2: Hypersensitivity Vasculitis

• General features:
  • Involves capillaries arterioles and venules
  • Leukocytoclastic vasculitis
• Clinical presentation:
  • Cutaneous manifestations predominate
  • Peripheral nerve and internal organ involvement occurs
  • Self-limited
  • Glomerulonephritis; gastrointestinal and heart involvement occur concomitantly
• Laboratory:
  • Increased SED rate > 50%; rhF 10%
  • ANA positive in approximately 15%
  • Decreased complement rare

Sensory-Motor Neuropathy (Sjögren's)

• General features:
  • Sicca syndrome predominant
  • Arthritis (small joints)
  • Rare arteritis of CNS
• Clinical presentation:
  • Distal sensory or sensory motor neuropathy; approximately 75% of neuropathies in Sjögren's syndrome
  • Rare arm involvement
  • Greater than 50% minimal or no motor involvement
  • Rare autonomic involvement
  • Mononeuritis multiplex
  • Cranial neuropathy:
    • Trigeminal nerve is the most commonly affected; usual numbness of V2 and V3; 50% have bilateral symptoms; may have associated facial pain; usually is associated with generalized sensory neuropathy. This is differential point from other CTD with Vth nerve involvement, but no generalized sensory involvement
    • Rare involvement of I, II, oculomotor nerves and VIII. Rare recurrent cranial polyneuropathy is seen
    • Associated CIDP, carpal tunnel syndrome, primary autonomic neuropathy
• EMG:
  • Absent SNAP (in ataxic neuropathy form); low amplitude and decreased sensory conduction velocities in less affected nerves
  • F waves and MNC velocities are normal
  • Some denervation noted
  • Axonal neuropathy features of sensory motor neuropathy; decreased SNAPs and CMAs
• MRI:
  • Dorsal column increased T2 signal
• Pathology (sensory nerve biopsy):
  • Loss of large myelinated fibers
  • Arteriopathy greater than arteritis of CNS blood vessels

Henoch–Schönlein Purpura

• General features:
  • Erythematous macules that become papules; urticarial purpuric and necrotic; external portions of limbs and buttocks
  • Abdominal pain; joint and renal involvement
  • Most frequent in children following a streptococcal infection
• Clinical presentation:
  • Sensorimotor neuropathy (rare)
  • Cerebral vasculitis, small vessel (rare)
• Laboratory evaluation:
  • Increased sed rate in approximately 20% of patients
  • Increased IgA in approximately 50%
  • Decreased compliment (rare)
• Pathology:
  • Leukoclastic reaction in the skin; IgA vascular deposits noted
  • Arterial, capillaries and venules are affected

Cryoglobulinemic Vasculitis

• General features:
  • Presence of protein in serum that precipitates on cooling
  • Usually IgG or IgM; mixed types occur IgM most often symptomatic
  • Mixed monoclonal and polyclonal gammopathies seen in CTD; may form immune complexes
  • Neuropathy is seen in 7% of patients with essential cryoglobulinemia
  • Secondary cryoglobulinemia associated with:
    • Monoclonal gammopathies (myeloma, macroglobulinemic, lymphoma, PAN and multiple myeloma)
    • Polyclonal gammopathies (connective tissue disease; mesothelioma and chronic infections)
• Clinical presentation:
  • General medical: Raynaud's phenomena; bleeding diathesis (platelet dysfunction); retinal hemorrhage; arthralgias, malaise; weakness; skin ulcers; blue cyanotic toes
  • Neuropathy:
    • Precipitated by cold
    • Pain and paresthesias of the distal extremities
    • Wasting and weakness of distal muscles; slowly progressive; may have an acute presentation
  • Rare small vessel vasculitis of CNS
• EMG:
  • Decreased sensory NCV's
  • Mild slowing of mNCVs
• Laboratory:
  • RF increased in approximately 80%
  • Decreased complement > 75%
  • Hepatitis C > 80%; Hepatitis B 5%
  • ANA elevated in approximately 20%
  • SM and ANCA elevated in approximately 5%
• Pathology:
  • Necrotizing vasculitis; occlusive microangiopathy; LCV in the skin
  • Involvement of small arteries, arterioles; capillaries and venules
  • Wallerian degeneration; perineuritis and perivascular mononuclear cell infiltration; center of nerve fascicle involved to a greater degree than peripheral involvement

Group III – Giant Cell Arteritis

• General features:
  • May involve the subclavian, brachial and aortic arch; occasionally origin of the carotid artery
  • Cause of the aortic arch syndrome
  • Blindness from infarction of the watershed between the central retinal artery and the posterior ciliary arteries from the external carotid system (at the optic nerve head)
  • Greater than 50% are associated with polymyalgia rheumatica
• Clinical presentation:
  • Infarction of the optic nerve head
  • Rare CNS conducting vessel stroke
  • Rare sensory motor neuropathy
  • Low grade headache with allodynic scalp (maybe seen with normal sed rate)
• Laboratory:
  • Increased Sed rate greater than 80% of patients
  • Arteriogram and biopsy positive external carotid artery in greater than 50% of patients
• Pathology:
  • Small arteries and arterioles involved
  • Necrotizing vasculitis
  • Epineural greater than perineurial involvement
  • Granulomas and giant cells are seen in approximately 50% of patients

Takayasu's Disease

• General features:
  • Worldwide distribution: Japan > Mexico > West
  • Aortic arch is primary area of involvement
  • Isolated subaortic and supravalvular pulmonary stenosis
  • Hypothyroidism (thyrosis cervical trunk collagen)
  • Systemic vessel occlusion
• Clinical presentation:
  • Intermittent claudication of vision (walking and with head position)
  • Large vessel stroke
  • Subclavian steal is frequent, but most often asymptomatic
  • Atrophy of soft tissue of the face
  • Early cataracts

Group IV: Localized Vasculitis

• General features:
  • Isolated granulomatous angiitis of the central nervous system
  • May involve the gall bladder, uterus, muscle and the skin
• Clinical presentation:
  • Mononeuritis multiplex
  • Distal symmetrical axonal sensorimotor neuropathy
• Laboratory:
  • Sed rate increased in greater than 50% of patients
• Pathology:
  • Small arteries and arterioles are involved
  • Necrotizing vasculitis; greater epineural than perineural involvement

Nonsystemic Vasculitic Neuropathy

• General features:
  • Incidence: 5 new cases/million people/year
• Clinical presentation:
  • Weakness; sensory loss and pain in isolated nerves (45% of patients)
  • Overlapping episodes of mononeuritis multiplex (40%)
  • Symmetrical distal neuropathy usually of the legs in 15% of patients
• EMG:
  • Denervation (positive sharp waves and fibrillation in affected muscles)
  • Decreased motor and sensory NCV's

Vasculitic Neuropathy Associated with Systemic Disease

• General features:
  • Incidence not determined
  • Major entities:
    • Polyarteritis nodosa
    • Wegener's granulomatosis
    • Churg–Strauss syndrome
    • SLE
    • rheumatic arthritis
    • mixed collagen vascular disease
    • scleroderma
    • cancer
    • hypersensitivity reaction
    • hepatitis B or hepatitis C infections
    • Lyme disease
    • HIV
• Clinical presentation:
  • Fever
  • Weight loss
  • Anorexia
  • Skin rash
  • Renal
  • Lung
  • Gastrointestinal disease
  • Clinical features noted for necrotizing vasculitides

Neuropathy Associated with Rarer Connective Tissue Diseases

Scleroderma

• General features:
  • Fibrosis of the skin and visceral organs from proliferation of extracellular matrix proteins and collagen
  • Scleroderma limited to the skin, rarely causes neuropathy (linear scleroderma, morphea, diffuse cutaneous scleroderma)
  • Incidence of 10–15 patients per million people; ethnic differences are important
  • Peak incidence is third to fifth decade
  • Women to men, 3:1
  • Microvascular changes in the skin may predate fibrosis
  • CREST (sub variant):
    • Calcinosis
    • Raynaud's phenomenon
    • Esophageal dysmotility
    • Sclerodactyly
    • Telangiectasia
  • CREST:
    • Associated with vasculitic neuropathy
• Clinical presentation:
  • Raynaud's phenomenon in 95% of patients
  • Slowly progressive skin and systemic signs over years
  • Trigeminal inflammatory ganglionitis:
    • Affects 3% of scleroderma patients
    • Bilateral and asymmetrical in 60% of patients
    • Rare involvement of other cranial nerves
  • Entrapment neuropathies:
    • Carpal tunnel syndrome is seen in 10% of patients; often most prominent in the early inflammatory stage of the disease
    • Pressure palsies of the other major nerves occur
  • Sensory motor neuropathy:
    • Asymmetric at onset
    • Later stages symmetric, distal polyneuropathy
    • Vasculitic neuropathy; asymmetric multifocal, sensory motor neuropathy
    • Motor greater than sensory involvement; <10%
    • Distal weakness predominant in some patients
• EMG:
  • Primarily axonal features
• Laboratory:
  • Positive anti-Scl-70 and anticentromere in >60% of patients
  • Anti nucleolar antibodies-anti-RNA polymerase I, II, and III; anti ribonucleoprotein (RNP)
• Pathology (nerve biopsy):
  • Nonvasculitic form:
    • Loss of myelinated fibers with axonal atrophy
    • Increased endoneurial and perineurial tissue
    • Endoneurial microvasculopathy
    • Vasculitis (rare)

Mixed Connective Tissue Disease (Overlap Syndromes)

• General features:
  • Clinical overlap of SLE, scleroderma and polymyositis
  • ANA titers against RNP-V1
  • Women > men
  • 3rd to 4th decade at onset
  • Fatigue, sclerodactyly, arthralgia early in the disease;
  • Later rash, GI, renal and muscle involvement;
  • Severe pulmonary hypertension a cause of death in some patients
• Clinical presentation:
  • Trigeminal sensory neuropathy
  • Symmetric sensory polyneuropathy
  • CTS (carpal tunnel syndrome)
  • Acute autonomic neuropathy
  • CIDP presentation
• EMG:
  • Polyradiculopathy presentation
  • Demyelinating or mixed axonal-demyelinating features
• Pathology:
  • Enhancement of cauda equina on MRI
  • Primarily axonal alterations

Behçet's Disease

• General features:
  • Oral and genital ulcers
  • Ocular involvement
  • Large and small vessel vasculitis
  • Middle East, India and Japan have highest incidence
  • Men greater than women; presents in young adults
  • Painful oral aphthous ulcers greater than genital ulcers; anterior or posterior uveitis; retinal vasculitis
  • Associated; erythema nodosum, thrombophlebitis, arterial aneurysms, CNS manifestations (sinus thrombosis; aseptic meningitis, stroke)
• Clinical presentation:
  • Central nervous system manifestations of vasculitis:
    • Dementia syndrome
    • Brainstem presentations
    • Purely ocular inflammation
    • Stroke
  • PNS:
    • Sensorimotor neuropathy
    • Mononeuritis multiplex (vasculitis)
    • Motor predominant poly radiculoneuropathy
    • Lumbosacral polyradiculitis
    • Distal sensorimotor demyelinating neuropathy (rare)
• Pathology:
  • Mixed neutrophilic and lymphocytic large and small vessel vasculitis

Relapsing Polychondritis

• General features:
  • Inflammation and progressive destruction of cartilage
  • Peak incidence in fifth decade
  • Trachea, nose greater involvement than ear lobe; joint, cardiac valve; eye (episcleritis, conjunctivitis, uveitis, keratitis) involvement
• Clinical presentation:
  • Optic neuritis
  • Sensory neural hearing loss greater than 30%
  • Vestibular involvement greater than 30%
  • Rare involvement of III, IV, VI and V
  • Rare sensory motor neuropathy and mononeuritis multiplex
  • Rare central nervous system vasculitis with stroke

Differential Diagnosis of Vasculitic Neuropathy by Vessel Size

• Systemic necrotizing vasculitis (small and medium sized arteries):
  • Polyarteritis nodosa (PAN)
  • Allergic angiitis granulomatosis
  • Wegener's granulomatosis
  • Vasculitis of connective tissue disease
  • Polyangiitis overlap syndrome
• Hypersensitivity vasculitis (small vessels; capillaries arterioles and venules):
  • Henoch–Schönlein Purpura
  • Vasculitis with infections disease
  • In association with some drug reactions
  • Connective tissue disease
  • Neoplasm
• Localized vasculitis:
  • Isolated peripheral nerve vasculitis (localized form of PAN)

Differential Diagnosis of Vasculitis and Malignancy (malignancy and hypersensitivity vasculitis)

• More common in myelo and lympho proliferative disease
• Rare in association with solid tumors
• Prominent in hairy cell leukemia
• Chédiak-Higashi disease

Differential Diagnosis of Unusual Vasculitis of Peripheral Nerves in Association with:

• Cryoglobulinemia
• Sjögren's disease
• Relapsing polychondritis
• Reiter's disease
• Hypereosinophilia syndrome

Differential Diagnosis of Vasculitis Neuropathy by Signs and Symptoms

The suspicion of a systemic vasculitic neuropathy occurring in the face of known vasculitis is raised with the onset of an asymmetric neuropathy that may evolve over time into a symmetric distal motor sensory neuropathy due to overlapping infarction or inflammation of specific peripheral nerves. Trigeminal nerve involvement early and mononeuritis multiplex are seminal feature of these diseases. The specific features of each entity lead to the underlying cause of the vasculitis.

In SLE the neuropathy occurs in the face of established disease. Central nervous system features usually predominate with stroke, seizures, psychosis as major signs. Transverse myelitis usually at T4–T6 (dropped cervical level) in many instances may be confused with neuropathy if bladder involvement is not prominent. Serosal surface, arthralgia, joint and skin manifestations are usually prominent when sensorimotor neuropathy begins. The major differential points at this stage are ruling out toxic metabolic or nutritional causes (and usually immune suppressive drugs such as D-penicillamine or cyclosporine. A GBS picture that may emerge in this context is more characteristic of PAN. The differential considerations are cervical myelitis or severe vasculitic neuropathy. In later stages of the illness a CIDP presentation may be noted and has to be differentiated from lymphoma, HIV, Castleman's disease, graft versus host disease, osteosclerotic myeloma and monoclonal neuropathy. The vasculitic sensorimotor neuropathy is suggested by an asymmetric onset, stuttering course and significant motor involvement.

The major differential features that are problematic for making the diagnosis of Sjögren's syndrome are distinguishing it from other processes associated with the SICCA complex. These are sarcoid, graft versus host disease, amyloidosis; hepatitis C, HIV and HTLV-1 disease. In sarcoid, bilateral VIIth nerve involvement rather than Vth nerve is classic. Dural enhancement associated with intracranial lesions in the posterior hypothalamus and pituitary regions are diagnostic. Severe mucous ulcerative inflammation is characteristic of graft versus host disease whereas Sjögren's is primarily glossitic and conjunctival symptomatology. Dissociated sensory loss (small fiber modality loss) and autonomic neuropathy in association with a primary uveal veil, cardiac and renal disease suggests amyloid neuropathy. HTLV-1 is a long standing myelopathy with prominent spasticity and bladder involvement associated with neuropathy. Hepatitis C is suspected in the face of a cryoglobulinemic neuropathy. HIV most commonly has parotid hypertrophy (cyst formation on MRI) prominent myelin atrophy on CNS MRI with distal burning symmetrical neuropath (late stages).

Paraneoplastic sensory neuropathy can present with a severe sensory ataxia. Prominent dorsal column large fiber proprioceptive and vibratory defects are common. Many paraneoplastic neuropathies have some small fiber burning components associated with autonomic features. Idiopathic chronic ataxic neuropathy does not have autonomic involvement which is common in both Sjögren's and paraneoplastic neuropathy. Anti-Hu antibodies are found in the majority of paraneoplastic syndromes. Other immune mediated ataxic sensory polyneuropathies are:

• Miller Fisher variant of GBS
• MAG (myelin associated glycoprotein)
• Pure sensory CIDP
• Immunoglobulin associated paraproteinemias
• Anti-sulfatide antibodies
• Syphilis
• HZ
• SICCA complex

The hypersensitivity vasculitides are diagnosed by their characteristic leukocytoclastic skin reactions. Most cryoglobulinemic neuropathies are secondary to hepatitis C and B or are in association with other collagen vascular diseases. Patients have severe Raynaud's phenomenon and extreme cyanosis of the extremities often associated with bleeding that is clearly temperature dependent. Henoch–Schönlein purpura occurs primarily in children in association with GI pain and arthralgias as well as the seminal purpura. The sensorimotor neuropathy is a minor part of the complex. Hypersensitivity vasculitis most often occurs from an autoimmune reaction to sulfa drugs or penicillin and may present with dramatic swelling and burning of the fingers and toes. Temporal arteritis usually presents with headache and involvement of the external carotid vascular system affecting the watershed of the posterior ciliary arteries and the central retinal artery with concomitant loss of vision. Elderly patients with several months of fatigue, polymyalgia rheumatica and weight loss are usually affected. Rarely the arch of the aorta, carotid and subclavian arteries may be affected. Sensorimotor peripheral neuropathy and mononeuritis multiplex may be seen in this context.

Polyarteritis nodosa in the majority of patients strikes the peripheral nervous system. It should always be suspected in a middle aged man who has developed late onset asthma, eosinophilia, liver, kidney or testicular infarction. Microaneurysms of the long medullary arteries of the kidney are diagnostic. In this setting vasculitic involvement of the brachial and lumbosacral plexus, it presents as subacute GBS . Raised palpable infarction of skin arterioles of the quadriceps should be sought. Mononeuritis multiplex is common. Central nervous systems stroke is rare. Microscopic polyangiitis is a subvariant of PAN and strikes the kidneys primarily, but vasculitis may also be seen in the eyes, lung, muscle and rarely the brain. ANCA antibodies (p > c) are seen in up to 90% of patients. A sensorimotor neuropathy in the face of severe renal involvement should suggest this diagnosis. Decreased complement and increased rheumatoid factor are supportive. The lungs are involved in approximately 50% of patients and the neuropathy is not burning in the feet, which separates it from uremic neuropathy.

Churg–Strauss sensorimotor neuropathy is suggested in patients with eosinophilia and interstitial lung disease. The pituitary may be involved. IgE is increased in the serum in 75% of patients and ANCA antibodies are present (p > c) in 50–75%) of patients.

Wegener's granulomatosis invariably attacks the sinuses (greater than 90% of patients). It is also associated with granulomatous lung disease and chronic sinusitis. Orbital and Vth nerve involvement occur. Mononeuritis multiplex is more common than an asymmetric, stuttering, slowly progressive distal predominant sensorimotor neuropathy.

Rheumatoid arthritis invariably involves the carpal tunnel and less commonly the tarsal tunnel. Differential diagnosis must entertain hand paresthesias from subluxation at C1–C2. Severe intrinsic hand muscle atrophy out of proportion to the arthropathy is common. High sed rate and RF are seen in greater than 90% of patients. Low level eosinophilic ANA and ANCA antibody response with decreased complement are supportive. Rarely mononeuritis and asymmetric peripheral vasculitis occurs.

Scleroderma is easily diagnosed from its distinctive physical findings. Often not recognized is its penchant for trigeminal involvement which may be bilateral. Carpal tunnel syndrome is common in its early inflammatory stages. Later a subtle sensorimotor neuropathy develops. It should always be suspected in patients with early severe Raynaud's phenomena. The CREST syndrome (calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly and telangiectasia is associated with a sensorimotor neuropathy. Raynaud's is often severe in SLE and rheumatoid arthritis. Scleroderma presents no difficulty in differentiation from other CTD or vasculitic neuropathies. Realizing that Vth nerve, carpal tunnel, tarsal tunnel and a vasculitic neuropathy may occur is what is overlooked.

Mixed connective disease has features of scleroderma, SLE and polymyositis. It is the most common connective tissue disease that presents with trigeminal neuropathy. Rarely, a sensorimotor neuropathy is present. High (antibody titers of ANA antibodies to extractable nuclear RNP ribonuclease-V1 are present).

Behçet's disease primarily affects the CNS with anterior and posterior uveitis, optic neuritis, a brainstem syndrome or vasculitic stroke. Its seminal feature is aphthous ulceration of the mouth and genitals. Occasionally patients have a well demarcated extra genital, erythematous ulcer on the body that is extremely painful. Large joint and GI involvement occurs. Venous thrombosis of the cortical veins is increasingly recognized. Rarely, patients have a concomitant distal predominant sensorimotor polyneuropathy.

Relapsing polychondritis may present with a painful swollen ears. Ochronosis and uremia may also involve the pinna. This inflammatory autoimmune disease of cartilage causes tracheal stenosis, saddle nose deformity and heart valve inflammation. The central nervous system features of optic neuritis, vestibulopathy and conductive hearing loss from eustachian tube involvement are the seminal central features. Rarely mononeuritis multiplex and a sensorimotor polyneuropathy are seen concomitantly.

The major differential diagnostic problems occurring in the diagnosis of vasculitic neuropathy is not in differentiating one connective diseases from another in which it may occur, but rather diagnosing it in the absence of systemic features. The differential diagnosis includes an infectious etiology such as Lyme disease, multifocal demyelinating neuropathy, multiple lumbar plexopathy, neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsy. The non-systemic vasculitic neuropathies may present as mononeuropathy, multiple mononeuropathy or mononeuropathy multiplex in addition to an asymmetric distal sensorimotor polyneuropathy which may occur from overlap of infarction of large nerves.

Differential Diagnosis of Mononeuropathy or Multiple Mononeuropathy

• Pressure palsy
• Multiple entrapments
• Traumatic
• Electrical injury
• X-RT
• Immunization
• Herpes Zoster
• Carcinomatous infiltration
• Lymphoma
• Diphteritic wound infection with neuropathy (local toxin production)
• Diabetes
• Collagen vascular disease
• Monomeric sensory neuropathy
• Sensory perineuritis
• Cholesterol emboli syndrome
• Idiopathic thrombocytopenic purpura
• Tangier disease
• AIP and variegate porphyria
• Drug induced neuropathies
• Subacute bacterial endocarditis
• Leprosy
• CMV
• Leptospirosis
• Mycoplasma pneumonia
• Ascaris
• Plasmodium falciparum
• Sarcoid
• HIV
• HTL-V-1
• Sarcoidosis
• Diabetes mellitus

Differential Diagnosis of Mononeuropathy Multiplex

Axonal

• Vasculitis (non-systemic)
• Vasculopathy (vessel wall abnormalities)
• Necrotizing vasculitis:
  • PAN
  • Microscopic polyangiitis
  • Churg–Strauss syndrome
  • Wegener's granulomatosis
  • Rheumatoid arthritis
  • Systemic Lupus erythematosus
  • Sjögren's syndrome
• Hypersensitivity vasculitis:
  • Penicillin
  • Sulfonamide
  • Henoch–Schönlein purpura
  • Cryoglobulinemic vasculitis
• Temporal arteritis
• Cocaine
• Heroin
• Amphetamine
• Sarcoid
• Mixed cryoglobulinemia
• Relapsing polychondritis
• Behçet's disease
• Mixed connective tissue disease
• "Overlap Syndromes"
• Leprosy
• Cytomegalovirus (AIDS patients)
• Diabetes
• Neurofibromatosis

Demyelinating Neuropathies

• CIDP
• Hereditary liability to pressure palsy (HNPP)
• Hereditary polyneuropathies (HSMN) I, III, V with superimposed neuropathy (DM; chemotherapy)

Differential Diagnosis of Vasculitic Neuropathy by Category

• Inflammatory or immune mediated
• Ischemic
• Drug induced
• Infectious
• Genetic (systemic collagen vascular disease)
• Malignancy
• Related to systemic disease (non collagen vascular):
  • Cholesterol emboli
  • Bleeding into nerve sheaths