Introduction: 

According to the definition in the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitis (CHCC2012), vasculitides that are not associated with any particular systemic disease or probable etiology are categorized on the basis of the size of the affected vessels. Because of the absence of large vessels in the peripheral nervous system, the relationship between neuropathy and vasculitis has been examined in medium- to small-vessel vasculitis. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a small-vessel vasculitis that predominantly affects the capillaries, venules, arterioles, and small arteries, particularly in the peripheral nervous system. This disorder comprises three main conditions: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, previously known as Wegener’s granulomatosis), and eosinophilic granulomatosis with polyangiitis (EGPA, previously known as Churg-Strauss syndrome), and according to previous large-scale studies, neuropathy was reported in MPA: 58%, GPA: 17%, and EGPA 77% of patients with these conditions, respectively. Although a recent large multinational observational case–control study reported lower frequency (23%) of vasculitic neuropathy in patients with MPA.

ANCA-associated vasculitis is one of the most important causes of vasculitic neuropathy from the standpoint of neurologists

The Chapel Hill Consensus Conference also classified vasculitis associated with systemic diseases (eg, rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE]) and vasculitis associated with other systemic disorders, including infections (eg, hepatitis B or hepatitis C), drug exposure (eg, minocycline), and malignancy, among others. 

Vasculitic Neuropathies: It is an immune-mediated disorder directed against blood vessels, which results in ischemia to end-organs supplied by the blood vessel and infarction of isolated peripheral nerves. A variety of blood vessels (from the aorta to the capillaries) and a variety of organs (including the lungs, heart, kidneys, gastrointestinal tract, skin, and nervous system

Etiologies:  

The Peripheral Nerve Society has also published a classification tailored to peripheral nerve vasculitis 

• Primary systemic vasculitides

  • Predominantly small vessel vasculitis

    • MPA  (ANCA associated)

    • Eosinophilic granulomatosis with polyangitis (CSS) or EGPA (ANCA associated)

    • Granulomatosis with polyangitis (Wegener granulomatosis) or GPA (ANCA associated)

    • Essential mixed cryoglobulinemia (non-hepatitis C virus)

    • IgA vasculitis (Henoch-Schonlein purpura)

  • Predominantly medium vessel vasculitis

    • PAN

  • Predominantly large vessel vasculitis

    • GCA

• Secondary systemic vasculitides associated with one of the following:

  • Connective tissue diseases: RA, SLE, Sjogren's syndrome, Systemic sclerosis, DM, MCTD.

  • Sarcoidosis

  • Behcet diseae

  • Infection (HBV, HCV, HIV, CMV, leprosy, Lyme disease, syphilis, TB, cryptococcosis, aspergillosis, RMSF, herpes zoster, and HTLV-1)

  • Hypersensitivity reaction (leukocytoclastic angitis)

  • Cryoglobulinemia

  • Malignancy

  • IBD

  • Hypocomplementeima urticarial vasculitis syndrome

• Nonsystemic/localized vasculitis: When it is rarely limited to peripheral nerves only, it is referred to as non-systemic vasculitis (see below).

  • Nonsystemic vasculitic neuropathy

    • Includes diabetic and nondiabetic radiculoplexus neuropathy

    • Includes some cases of Wartenberg migrant sensory neuritis

    • Post-surgical inflammatory neuropathy.

  • Diabetic radiculoplexus neuropathy

  • Localized cutaneous/neuropathic vasculitis

    • Cutaneous PAN

    • Others

Primary Vasculitides

GCA:  Temporal arteritis and Takayasu arteritis.  PN occurs in the setting of temporal arteritis only.  ~14% of patients develop neuropathies in the form of multiple mononeuropathies, multifocal neuropathy, radiculopathies, plexopathies, or a generalized sensorimotor peripheral neuropathy.

Polyarteritis nodosa:  Most common of the necrotizing vasculitides.  It is a systemic disorder and involves small and medium sized arteries in multiple organs.  

• Incidence: 2-9 per million; onset: 40-60 years.

• Nerve involvement is most frequent than other vasculitides: multifocal or multiple mononeuropathies.  Most frequent involvement: sciatic nerve and its branches (peroneal or tibial)

• Cranial nerves (facial and CN III) and CNS involvement is rare, occuring in <2% of patients. 

• Classification criteria were proposed by the American College of Rheumatology for research purposes.  Fulfilling three or more of the following 10 criteria is suggestive of polyarteritis nodosa: weight loss greater than or equal to 4 kg (8.8 lb), livedo reticularis, testicular pain or tenderness, myalgia, mononeuropathy or polyneuropathy, diastolic blood pressure greater than 90 mm Hg, elevated blood urea nitrogen or serum creatinine levels, presence of hepatitis B reactants in serum, arteriographic abnormality, and presence of granulocyte or mixed leukocyte infiltrate in an arterial wall on biopsy. These classification criteria were adapted for clinical use as well, but they have low sensitivity and specificity.  A 2008 diagnostic algorithm that suggests using positive and negative findings yields about 70% sensitivity and 90% specificity.  The positive findings include hepatitis B virus antigen or DNA in serum, arteriographic anomalies, and mononeuropathy or polyneuropathy.  The negative findings include one or more of the following: presence of ANCA; asthma; ear, nose, and throat signs; glomerulopathy; and cryoglobulinemia. This is based on the fact that patients with polyarteritis nodosa generally do not have glomerulonephritis and ANCA antibodies are negative.  In addition to hepatitis B virus, other viral infections may be present.  Neuropathy is seen in up to 70% of patients with polyarteritis nodosa and is more common in polyarteritis nodosa associated with hepatitis B virus.  Most patients also have systemic symptoms such as fever, weight loss, myalgia, and arthralgia. Patients also frequently have cutaneous and gastrointestinal manifestations and hypertension. Men frequently have testicular involvement.  Rarely, patients with polyarteritis nodosa have central nervous system involvement, including stroke. The latter is thought to be usually related more to thrombotic microangiopathy than to vasculitis.  Angiography of the visceral arteries can be highly suggestive of polyarteritis nodosa when arterial saccular or fusiform microaneurysms coexisting with stenotic lesions are demonstrated. Polyarteritis nodosa is usually a monophasic disease, with a relapse rate of just under 20%. About 25% of patients die within 5 years of symptom onset. 

• Abdominal angiograms can reveal a vasculitic aneurysms in renal, hepatic, or visceral blood vessels, a useful finding in patients with nondiagnostic biopsies. 

• Nerve biopsies are typical as in vasculitides except absence of granuloma which are seen in CSS and GPA.  Absence of eosinophilic infiltrate which is seen in case of CSS (EGPA)

• T-cell dependent process with secondary complement mediated vascular damage is the postulated pathogenic mechanism. 

Microscopic polyangiitis:

• It is a systemic non-granulomatous vasculitis that may affect arterioles, capillaries, and venules with minimal or no immune deposits in pathological specimens.  It clinically resembles PAN  and CSS, except that diffuse alveolar damage and interstitial fibrosis develops due to involvement of pulmonary capillaries and in 50% of cases there is concurrent rapidly progressive glomerulonephritis.  

• MPA is associated with ANCA directed against myeloperoxidase (MPO-ANCA) and necrotizing vasculitis with few or no immune deposits.

• The positivity rate of ANCA in sera from patients is approximately 80% in both MPA and GPA,

• Unlike PAN, there are few or no immune deposits on the blood vessels.  Kidney biopsies reveal focal segmental thrombosis and necrotizing glomerulonephritis.

• Palpable purpura are also more common in MPA than in classic PAN.  

• Average age of onset is 50 years and polyneuropathy complicates MPA in 14 to 36% of cases.

• Lab evaluation is remarkable for renal insufficiency, hematuria, and MPO/p-ANCA in most patients.  PR-3/c-ANCA can also occasionally be detected.  

Granulomatosis with polyangiitis:

• Formerly called Wegener granulomatosis (no more used as Wegener turned out to ba a Nazi official-high ranking physician who worked in a facility at Poland were inhumane and unethical medical experiments were carried out.)

• It is characterized by necrotizing vasculitis and granulomatosis involving the upper and lower respiratory tract and kidneys (glomerulonephritis).  

• Respiratory symptoms include nasal discharge, cough, hemoptysis, and dyspnea.  

• Half of the patients develop CNS or PNS involvement.  It can cause distal symmetric polyneuropathy, multifocal neuropathy, multiple mononeuropathies.  Neuropathy is more common in patients with severe renal involvement.  Cranial neuropathies, involving the 2nd, 6th, and 7th nerves, develop in approximately 5% to 10% of cases as a result of extension of the nasal and paranasal granulomas rather than vasculitis.  

• GPA is characterized by granulomatous inflammation of the respiratory tract and ANCA directed against proteinase 3 (PR3-ANCA) [8]. The positivity rate of ANCA in sera from patients is approximately 80% in both MPA and GPA.

• Most of the affected individuals have c-ANCA/PR-3 and this test as a specificity of 98% and sensitivity of 95%.

• Histological appearance is similar to PAN.  It involves medium and small sized blood vessels.  Additionally, granulomatous infiltration of the respiratory tract and necrotizing glomerulonephritis are also seen.  Peripheral eosinophilia, eosinophilic infiltrates on biopsy, and asthma is absent and does help distinguish granulomatosis with polyangiitis from CSS.

Eosinophilic granulomatosis with polyangiitis:

• Formerly called Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis).  Consider EGPA in any patient with neuropathy and peripheral eosinophilia with or without asthma.

• Signs and symptoms are similar to PAN except that respiratory involvement is common EGPA.

• Multifocal neuropathy/multiple mononeuropathies developing in as many as 75% of individuals.  

• EGPA typically presents with allergic rhinitis, nasal polyposis, sinusitis, and late onset asthma (after the age of 35 years).  Features of systemic vasculitis occur an average of 3 years after the onset of asthma and even longer after the onset of nasal symptoms.  Pulmonary infiltrates develop in conjunction with vasculitis affecting the pulmonary blood vessels. 

• 16% to 49% of patients with EGPA developed a necrotizing glomerulonephritis as opposed to ischemic nephropathy that can complicate PAN.  

• There is a strong association between EGPA and allergic diathesis, particularly asthma and eosinophilia. Although EGPA is also associated with ANCA, in which MPO-ANCA is predominant, the positivity rate is lower (only 30 - 40%).

• Several studies have shown differences in the clinical characteristics of patients with EGPA based on their ANCA status. Cardiac involvement is more frequent,whereas ear, nose, and throat manifestations, peripheral nerve involvement, and renal involvement are less frequent, in ANCA-negative EGPA patients when compared with ANCA positive EGPA patients.  

• Labs:  Eosinophilia, leukocytosis, elevated ESR, CRP, rheumatoid factor, and serum IgG and IgE levels.  Approximately two thirds of patients have MPO/p-ANCA.  The positivity of ANCA in EGPA is lower than in GPA and MPA. 

• Chest x-rays reveal pulmonary infiltrates and present in nearly half of patients.  

• Nerve biopsies shows features of necrotizing vasculitis and to a lesser extent eosinophilic infiltrates.  

• Additionally intravascular and extravascular granulomas are occasionally found in and around affected blood vessels.

Behcet disease:

• This disorder is characterized by recurrent oral and genital ulcerations, inflammation of the eye, arthritis, thrombophlebitis, skin lesions, and vasculitic lesions involving the small to medium size arteries.  CNS complications include brainstem strokes, meningoencephalitis, and psychosis.  Peripheral neuropathy is not as common as other neurological manifestations.

Clinical Features

• Subacute painful mononeuropathies or multiple mononeuropathies (mononeuritis multiplex); overlapping mononeuropathies, which confluence into distal symmetric polyneuropathies.  

  • Patterns:  60-70% of patients present with mononeuropathy or multiple mononeuropathies (multifocal), while 30-40% of patients present with distal symmetric polyneuropathy. 

    • Distribution of the affected peripheral nerve , preceded by pain, (foot drop, wrist drop).

    • Nerves most commonly involved in vasculitic neuropathies: 

      • Fibular: 90%, posterior tibial: 38%, ulnar: 35%, median: 26%, radial: 12%, femoral: 6%, and sciatic: 3%.

    • Random multiple mononeuropathies preceded by pain.

    • Asymmetric pattern of involvement in multiple nerves on both sides.

    • Gradual progression leading to confluent involvement of peripheral nerves resulting in distal symmetric polyneuropathy. 

• Pain is a predominant feature and is a complaint proferred by the patient.  In absence of significant pain (that is not-treated with analgesics) the diagnosis is of vascullitic peripheral neuropathy is called into question.  Pain can be burning or tingling in the distribution of the affected nerve(s); shooting, or lancinating. The symptoms suddenly develop in a single nerve territory followed by the gradual involvement of other nerves.

• Weakness and sensory loss are evident on examination.  Rarely only sensory signs.   MSR are normal or diminished depending on whether or not the affected nerve subserves the reflex arc. (sciatic nerve involvement > ankle reflex absent or hypoactive; median nerve involvement does not affect upper extremity reflexes).  The distribution of the sensory impairment tends to be similar to the pattern observed in mononeuritis multiplex, which reflects the focal lesions of the vasculitis. However, multiple lesions may yield a symmetric or asymmetric distally accentuated polyneuropathy pattern. According to studies focusing on neuropathic features of ANCA-associated vasculitis, mononeuritis multiplex occurred in approximately 70–90% of patients, whereas the others manifested symmetric or asymmetric polyneuropathy.

• Muscle weakness corresponding to the affected nerves might be evident, resulting in muscle atrophy. Therefore, patients with this disorder experience sensory or sensorimotor neuropathy, whereas pure motor neuropathy is an exclusion criterion for vasculitic neuropathy.  Deep tendon reflexes are reduced or absent depending on the affected nerves. The incidence of cranial neuropathy is low, except for GPA, in which granuloma formation in the cranial region is common.  It should be noted that central nervous system manifestations resulting from ischemia hemorrhage, or granuloma formation may occur and complicate neuropathic features in patients with ANCA-associated vasculitis.

Laboratory evaluation for Vasculitic neuropathy: 

• Lab findings:  

  • Routine Workup

    • Complete blood cell count (anemia or eosinophilia)

    • Serum protein electrophoresis

    • Creatinine, urea, electrolytes, urinalysis

    • Hemoglobin A1C, fasting blood sugar, 2-hour glucose tolerance test

    • Chest x-ray

    • Erythrocyte sedimentation rate, C-reactive protein

    • Hepatitis B surface antigen, hepatitis C antibodies

    • Antineutrophil cytoplasmic antibody

    • Cryoglobulins

    • Antinuclear antibody, double-stranded DNA, C3, C4

    • Rheumatoid factor

  •  Advanced Workup

    • Sinus x-ray

    • Chest CT

    • Anti-SSA/SSB, Schirmer test, salivary scan

    • Angiotensin-converting enzyme level

    • Porphyria screen

    • West Nile virus, Lyme disease, cytomegalovirus, HIV

    • Lumbar puncture for CSF analysis.  Cerebrospinal fluid protein levels and cell counts are usually normal. 

  • Potential Tests to Exclude Other Diagnoses

    • Citrullinated peptide antibodies

    • Lysozyme

    • Vascular endothelial growth factor

    • beta2-Microglobulin

    • Paraneoplastic autoantibodies

    • Lactate dehydrogenase

    • High-density lipoprotein cholesterol

    • DNA for PMP22 gene deletion associated with hereditary neuropathy with liability to pressure palsies

    • DNA for transthyretin gene

    • Gallium-67 scan

    • Visceral angiography

    • Body imaging for malignancy

  • EDX: Electrophysiological studies indicate the presence of axonal neuropathy characterized by a decrease in the compound muscle action potential and sensory nerve action potential but the preservation of the motor and sensory conduction velocities and distal motor latency.  These findings are predominantly observed in the lower extremities.

Secondary systemic vasculitides

Vasculitis associated with connective tissue disease

• Neuropathies are not uncommon in people with connective tissue diseases, although necrotizing vasculitis as the cause is infrequent.  

• Secondary vasculitis can complicate rheumatoid arthritis, SLE and Sjogren's syndrome, and, less frequently, systemic sclerosis.

• Clinical, histological, and electrophysiological features are similar to PAN.  

• Vasculitis may be seen in sarcoidosis.

Infection related vasculitis

• Vasculitic neuropathy can arise as a complication of a variety of infections.  HIV, hepatitis B and C, CMV, EBV, and herpes varicella-zoster.  

• HIV or cytomegalovirus infection related multifocal neuropathy or multiple mononeuropathies can occur in up to 3% of patients with AIDS.  

• Hepatitis B and C infections are associated with PAN and cryoglobulinemia.  

• Vasculitic neuropathy may also complicate Lyme disease.

• Patients with hepatitis B associated vasculitis are usually treated with antiviral medications, plasma exchange, and a short course of corticosteroids.

Malignancy related vasculitis 

• Rarely, cancers have been associated with vasculitic neuropathy.  Small cell lung cancer and lymphoma are the most common implicated malignancies, but leukemia, other myelodysplastic syndromes, renal cell carcinoma, bile duct, prostate, and stomach cancers have also been described.  

• Most reported cases are not associated with a necrotizing vasculitis, rather only nonspecific transmural or perivascular inflammation of small blood vessels without fibrinoid necrosis is seen on biopsy.  Several cases with vasculitic neuropathy associated with lung cancer and anti-Hu antibodies were reported as having vasculitis, although this disorder is not a true necrotizing vasculitis.  

• Multiple mononeuropathies or generalized neuropathy associated with lymphoma are often paraneoplastic in etiology or due to lymphomatous infiltration of the nerves.

Hypersensitivity Vasculitis

• Refers to a syndrome characterized by prominent cutaneous involvement and a leukocytoclastic reaction with sparing of vital organs.  The Chapel Hill International Consensus Conference on Nomenclature has suggested that the term "cutaneous leukocytoclastic angiitis" be used instead of hypersensitivity vasculitis for those cases with only cutaneous manifestations. 

• There is often a history of exposure to some precipitating antigen.  It  involves small diameter capillaries, arterioles, and venules. 

Drug-induced hypersensitivity vasculitis

• This can occur secondary to drug reaction and is a self-limited process as opposed to systemic necrotizing vasculitides.  

• Skin manifestations include petechiae.  

• Neuropathy is uncommon.  

• Minocycline may be an exception as it is reported to cause typical vasculitic neuropathy as a complication. 

•  Drugs of abuse (amphetamine, cocaine, opioids) also can cause vasculitis of the CNS or PNS.  

• ABx: sulfonamides, PCN, ciprofloxacin, ofloxacin, erythromycin, INH

• Antivirals: acyclovir, zidovudine

• Immunosuppressants: cyclophosphamide, methotrexate

• Other agents: granulocyte colony-stimulating factor, interferon-alpha, iodinated contrast agents.

• The pathogenesis more likely relates to a complement mediated leukocytoclastic reaction.

Vasculitis secondary to essential mixed cryoglobulinemia

• Cryoglobulins are circulating immune complexes consisting of immunoglobulins directed against polyclonal immunoglobulins.  These complexes precipitate out of solution when exposed to cold temperature but dissolve back into solution, thus the name cryoglobulin.  

• There are actually 3 types of cryoglobulins.  

  • Type I cryoglobulin, are monoclonal immunoglobulins, usually IgM, directed against polyclonal IgG.  These are frequently associated with B-cell lymphoproliferative disorders, such as monoclonal gammopathy of undetermined significance (MGUS), Waldenström macroglobulinemia, chronic lymphocytic leukemia, B-cell non-Hodgkin lymphoma, and multiple myeloma. 

  • Type II cryoglobulins are composed of a combination of monoclonal IgM and polyclonal immunoglobulins directed against polyclonal IgG.  

  • Type III cryoglobulins are a mixture of polyclonal IgM, IgG, and IgA directed against polyclonal IgG.  

  • Type II and III cryoglobulins are seen in patients with so-called mixed cryoglobulinemia can also be associated with lymphoproliferative disorders but are mostly seen in patients with hepatitis C virus infection.  Patients with Sjögren syndrome, SLE, hepatocarcinoma, lymphoma, or hepatitis B virus may also have cryoglobulinemia.  Some cryoglobulinemias are idiopathic.  Patients with Sjögren syndrome and circulating cryoglobulins have more pronounced systemic involvement and are at a higher risk of developing lymphoma. 

  • Essential mixed cryoglobulinemia is a term used when mixed cryoglobulinemia is found in the absence of underlying disease.  

  • Not all patients with cryoglobulinemia develop vasculitis.  For example, up to 50% of patients with hepatitis C virus have circulating cryoglobulins, but only 5% develop vasculitis. 

  • Type II and type III cryoglobulins can engage with C1q on endothelial cells, which promotes inflammatory cell recruitment resulting in vasculitis. Type I cryoglobulins cause blood vessel occlusion and inflammation. The classic triad of generalized weakness, palpable purpura, and diffuse joint pain is present in up to 80% of patients. 

  • Peripheral neuropathy develops in 25 to 90% of patients with cryoglobulinemia of any type.  Neuropathy may present as a painful, distal, symmetric sensory or sensorimotor polyneuropathy; as multifocal or multiple mononeuropathies; or as a pure small fiber neuropathy.  

  • Other symptoms include livedo reticularis, cutaneous ulcers, gangrene,  Raynaud phenomenon, and glomerulonephritis.  Rarely, central nervous system manifestations may occur. 

  • The lack of local HCV replication in nerve biopsies suggest that HCV-mixed cryoglobulinemia associated neuropathy results from virus-triggered immune mediated mechanisms rather than direct nerve infection and in situ replication.  Neuropathy may arise due to ischemia from hyperviscosity or due to vasculitis related to immune complex deposition in small epineurial blood vessels.

  • Treatment of vasculitis associated with HCV mixed cryoglobulinemia

  • Treatment of mixed cryoglobulinemia requires removal of the antigen.  Patient with mixed cryoglobulinemia due to hepatitis C infection can be treated with alpha interferon and it appears to be effective.  Combination of alpha interferon and ribavirin also has yielded positive results though no randomized, control trials have been performed.  Use of high-dose corticosteroids and cyclophosphamide may allow the virus to persist and replicate, thus increasing the risk of liver failure.  Methotrexate is avoided due to the risk of direct hepatotoxicity.  A short course of corticosteroids has been used to control the initial manifestations of systemic vasculitis followed by plasma exchange and alpha interferon.  Rituximab may be beneficial in cryoglobulinemia vasculitis.  Current treatment preferences include plasma exchange followed by a combination of rituximab and antiviral therapy.

Pathological findings in Biopsy Specimens

The pathological findings of neuropathy resulting from vasculitis are characterized by the axonal degeneration of the nerve fibers and inflammation of the epineurial vessels accompanied by the destruction of vascular structures, such as the disruption of the vascular layers and/or obstruction of the lumen, with or without fibrinoid necrosis. Both myelinated and unmyelinated fibers are affected.  These findings are commonly observed in patients with MPA, GPA, and EGPA.  Although vessel wall inflammation accompanied by vascular structural damage is required for the pathological diagnosis of vasculitic neuropathy, the sensitivity of this finding is not high.  Furthermore, focal or asymmetric nerve fiber loss reflecting the region of the blood supply by the affected vessels is considered a supportive finding. After axonal degeneration, the debris is cleared by the macrophages; the macrophages can be seen penetrating the basement membrane, surrounding the myelinated fibers, and phagocytizing the myelin in the degenerated fibers. After the clearance of the myelin, subunits of Schwann cells indicative of remnants of the myelinated fibers (i.e., bands of Bungner) remain in the endoneurium. The macrophages that phagocytize the myelin during the process of axonal neuropathy are morphologically similar to those that participate in demyelination in patients with demyelinating neuropathies, such as Guillain-Barre´ syndrome and chronic inflammatory demyelinating polyneuropathy.  However, the structures in the axon, such as the neurofilaments and microtubules, are well preserved in patients with demyelinating neuropathies.

Diagnostic Criteria for Definite, Probable, and Possible Vasculitis 

Pathologically Definite 

• Findings suggestive of vasculitis are usually found in the epineurium and occur diffusely throughout the nerve trunk.  Nerve fiber degeneration resulting from ischemia is sometimes focal or asymmetric and tends to become conspicuous at the middle portion of the nerve trunk. The attachment of neutrophils to endothelial cells in the epineurial vessels is frequently observed in patients with ANCA-associated vasculitis; neutrophils play an important role in vascular inflammation by binding of ANCA.  

• ANCA.Active lesion: nerve biopsy showing collection of inflammatory cells in vessel wall AND one or more signs of acute vascular damage: 

  • Fibrinoid necrosis

  • Loss/disruption of endothelium

  • Loss/fragmentation of internal elastic lamina

  • Loss/fragmentation/separation of smooth muscle cells in media (can be highlighted with anti–smooth muscle actin staining)

  • Acute thrombosis

  • Vascular/perivascular hemorrhage

  • Leukocytoclasia 

• Chronic lesion: nerve biopsy showing collection of mononuclear inflammatory cells in vessel wall AND one or more signs of chronic vascular damage with repair: 

  • Intimal hyperplasia

  • Fibrosis of media

  • Adventitial/periadventitial fibrosis 

Pathologically Probable 

• Pathologic criteria for definite vasculitic neuropathy not satisfied AND perivascular inflammation accompanied by signs of active or chronic vascular damage OR perivascular/ vascular inflammation plus at least one additional class II or III pathologic predictor of definite vasculitic neuropathy: 

  • Vascular deposition of complement, IgM, or fibrinogen by direct immunofluorescence

  • Hemosiderin deposits (Perls Prussian blue stain for iron)

  • Asymmetric/multifocal nerve fiber loss or degeneration

  • Prominent active axonal degeneration; OR 

  • Myofiber necrosis, regeneration, or infarcts in concomitant peroneus brevis muscle biopsy (not explained by underlying myopathy) 

Pathologically Possible 

• Pathologic criteria for definite or probable vasculitic neuropathy not satisfied AND inflammation in vessel wall without other signs of definite vasculitic neuropathy OR one or more signs of active/chronic vascular damage or pathologic predictors of definite vasculitic neuropathy, without vessel wall or perivascular inflammation. 

Livedoid vasculopathy 

Livedoid vasculopathy is a rare cutaneous disease manifesting as recurrent ulcers on the lower extremities.  The ulceration results in atrophic, porcelain white scars termed as atrophie blanche.  The pathogenesis is yet to be understood with the main mechanism being hypercoagulability and inflammation playing a secondary role.  The important procoagulant factors include protein C and S deficiency, factor V Leiden mutation, antithrombin III deficiency, prothrombin gene mutation and hyperhomocysteinemia.  Histopathology of livedoid vasculopathy is characterized by intraluminal thrombosis, proliferation of the endothelium and segmental hyalinization of dermal vessels.  The treatment is multipronged with anti-thrombotic measures such as anti-platelet drugs, systemic anticoagulants and fibrinolytic therapy taking precedence over anti-inflammatory agents.  Colchicine, hydroxychloroquine, vasodilators, intravenous immunoglobulin, folic acid, immunosuppressive therapy and supportive measures are also of some benefit.  A multidisciplinary approach would go a long way in the management of these patients resulting in relief from pain and physical as well as psychological scarring. 

The main mechanism in the pathogenesis is hypercoagulability while inflammation plays a secondary role.  Autoimmunity has recently been found to be contributory.  It is a rare disorder with an estimated incidence of 1:100,000.  There is female preponderance in the ratio of 3:1.  Disease manifestations start either in late adolescence or middle age with the mean age of onset at 32 years.   There is occlusion in cutaneous capillary microcirculation leading to thrombosis, ischemia and infarction.  This explains the debilitating pain, muscle spasms, paresthesia and hyperesthesia experienced by affected patients.  The thrombotic effect results from defects either in the endothelial cell plasminogen activation, platelet dysfunction or enhanced fibrin formation.  Pericapillary deposition of fibrin and formation of thrombus act as a diffusion barrier impairing tissue oxygen supply causing ischemic infarction.  Low tissue perfusion leads to poor wound healing.  In sluggish circulation, there is ineffective killing of the microorganisms by leucocytes enhancing the chance of infection.  A vicious cycle of tissue destruction, edema and thrombosis develops, further jeopardizing tissue perfusion.  

The important causative associations of livedoid vasculopathy are as follows:

• Lupus anticoagulant and anticardiolipin antibodies is notable. 

• Increased level of PAI-1

• Low level of tissue plasminogen activator activity (<0.03IU/mL)

• Increased serum homocysteine level

• Protein C and protein S deficiency

• Antithrombin III deficiency

• Abnormalities in fibrinolytic pathways

• Antiphospholipid antibody syndrome

• Sickle cell disease

• Prothrombin G20210A gene mutation

• Factor V Leiden mutation.

Non-systemic Vasculitic Neuropathy

Self-limiting nonsystemic vasculitic neuropathies include postsurgical inflammatory neuropathy, neuralgic amyotrophy (possibly), painful diabetic and nondiabetic radiculoplexus neuropathy (lumbosacral, thoracic, cervical, or in combination), and painless diabetic radiculoplexus neuropathy.  Self-limiting nonsystemic vasculitic neuropathies differ from the nonsystemic vasculitic neuropathies.  First, they usually fit a well-recognized syndrome, and the diagnosis can be made clinically without a nerve biopsy.  Second, they are typically self-limiting, tend to improve on their own, and tend not to recur.

NSVN is a the most commonly reported type of vasculitis affecting the PNS.  It affects the small or medium sized arteries in the epineurium and perineurium.  It may represent one of several localized vasculitic disease mediated by immune response directed against tissue-specific antigens.  MMPs, in particular MMP-2, and MMP-9 (gelatinase A and B), are upregulated in the peripheral nerves in patients with NSV.  T-cells are the predominant source of MMP-2 and MMP-9, although some stromal cells of the perineurium and endoneurium may also secrete MMP.  These enzymes digest the subendothelial basement membrane and thus facilitate inflammatory cells to penetrate the blood-nerve barrier.  It has a unique predilection for peripheral nerves.  It is usually seen in adults, but children can also be affected.  The neurologic signs and symptoms and nerve pathology are similar to PAN/MPA related neuropathy, but the clinic course is free of non-PNS involvement.  Those affected manifest multiple mononeuropathies or a generalized symmetric sensorimotor polyneuropathy.  Weight loss, constitutional symptoms.  Elevated ESR, ANA, anemia, leukocytosis, thrombocytosis, and autoantibodies occur in 20% to 40% of patients.  It is primarily a disorder of small and medium vessels. Muscle biopsies occasionally reveal coexisting muscle vasculitis and often show ischemic changes or inflammation.  Involvement of the skin later in disease.  The diagnosis has generally depended on sural nerve biopsy evidence of definite or probable vasculitis, with muscle involvement in patients.  Diagnostic criteria is as follows:

Inclusions

• Clinic evidence of neuropathy by history and examination

• EDX findings consistent with neuropathy

• Nerve or nerve/muscle biopsy diagnostic of or suspicious for necrotizing vasculitis

Exclusions

• Clinical, laboratory, radiologic, or pathologic evidence of organ involvement outside peripheral nervous system (except muscle)

• Identified etiologic agent (drug exposure or infection, especially hepatitis B, hepatitis C, HIV, CMV, or VZV)

• Underlying systemic condition predisposing to vasculitis (connective tissue disease, malignancy, DM, mixed cryoglobulinemia)

When patients develop vasculitis clinically restricted to the PNS, known as nonsystemic vasculitic neuropathy (NSVN), the most commonly encountered vasculitic neuropathy in pathologically based series:  Diabetic and nondiabetic radiculoplexus neuropathies are clinical variants of NSVN.   NSVN is clinically similar to systemic vasculitis-associated neuropathies except for reduced severity.   Patients most commonly present with progressive, stepwise pain, weakness, and numbness over multiple months.  Almost all exhibit a multifocal or asymmetric, distally accentuated pattern of involvement. The most commonly affected nerves are the common peroneal nerve in the leg and the ulnar nerve in the arm. Sedimentation rate is mildly to moderately elevated in 50%; other markers of systemic inflammation are generally normal. Electrodiagnostic studies reveal a predominantly axonal, asymmetric, sensorimotor polyneuropathy, but pseudo-conduction blocks may occur. Definite diagnosis requires biopsy evidence of vascular inflammation and signs of active or remote vascular damage. In biopsies lacking definite vasculitis, the diagnosis is suspected if axonal alterations are accompanied by perivascular inflammation and such supportive features as Wallerian-like degeneration, asymmetric fiber loss, hemosiderin, vascular immune deposits, neovascularization, myofiber necrosis/regeneration, focal perineurial damage, and endoneurial purpura. NSVN preferentially affects larger epineurial arterioles. Epineurial infiltrates are composed primarily of T cells and macrophages, suggesting that cellular cytotoxicity is the primary effector mechanism. Systemic vasculitides with progressive neuropathy are usually treated with cyclophosphamide and prednisone. No randomized controlled trial of therapy has been performed in NSVN, but data from retrospective cohorts suggest that combination therapy is more effective than steroid monotherapy. Once remission has been induced, cyclophosphamide should be replaced with azathioprine or methotrexate. Refractory patients can be treated with intravenous immunoglobulin, mycophenolate, rituximab, infliximab, or alemtuzumab. Although long-term outcome is reasonably good, more than one third of patients relapse, infrequent patients die from the disease or its treatment, and still others develop chronic pain. 

Postsurgical inflammatory neuropathy

Most neuropathy that occurred following surgery are felt to be due to stretching of compression of nerves.  Some neuropathies may be secondary to inflammation.  This is suspected to be an autoimmune neuritis.

Rituximab

Recently, rituximab was established as an effective treatment in patients with MPA and GPA and has been licensed for ANCA-associated vasculitis recently (RAVE trial).  RAVE

Rituximab is an anti-CD20 monoclonal antibody, targeting mainly B cells.   It  is considered as first-line treatment of ANCA-associated vasculitis.  In a recent study, rituximab was as effective as CYC in the treatment of ANCA-associated vasculitis (197 patients, more effective in induction of remission after relapse).   Rituximab was also effective in the treatment of cryoglobulinemic vasculitis.  Normal dosage is 375 mg/m2 four times every week.

Acetaminophen (TYLENOL) tablet 1,000 mg 03/24/20 1031 Given   Oral   1,000 mg   

DiphenhydrAMINE (BENADRYL) capsule 50 mg 03/24/20 1030 Given   Oral   50 mg   

RiTUXimab (RITUXAN) 1,000 mg in NS 250 mL infusion 03/24/20 1040 Start New Bag   IV Piggyback   1,000 mg Initial infusion: Start an infusion rate of 50 mg/hour (12.5ml/hour); if there is no infusion reaction, increase the rate by 50 mg/hour (12.5ml/hour) increments every 30 minutes, to a maximum rate of 400 mg/hour (100ml/hour).

Sodium chloride 0.9 % flush 3-10 mL.  Intravenous Flush   10 mL   

Plasma exchange is used in mixed cryoglobulinemia, since it is able to remove circulating cryoglobulins. However, no randomized controlled trials have been reported and only some of the patients seem to respond 

Management of ANCA-associated vasculitis

Multidisciplinary approaches are needed for the diagnosis and management of ANCA-associated vasculitis because of the systemic nature of the disorder.

EGPA, GPA, and MPA

1. First line treatment:

   • Induction (Standard therapy): 

     • IV MP, CYC, and prednisone as for NSVN

   • Maintenance (after remission):

     • Taper prednisone over 6-12 mo, and 

     • Continue CYC 2 mg/kg/day x 12 mo, then stop or taper by 25 mg q2-3 mo; or

     • Switch CYC to AZA 1-2 mg/kg/day x 18-24 mo; or

     • Switch CYC to MTX (methotrexate) 15-25 mg PO or IV qwk x 18-24 mo

2. Second-line option for refractory patients:

   • Replace oral CYC with pulse IV CYC: 0.5-1 gm/m2,  q3-4 wk x 12-24 mo

   • Replace CYC with MTX 14-25 mg PO or IV qwk x 24 mo

   • IVIg (see NSVN)

   • PE, 6-12 times

   • TMP/SMX 160/800 mg PO bid for WG

RAVE trial showed Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease.  

• Prednisone 1 to 1.5 mg/kg daily and rituximab is been recommended standard initial treatment of choice.  Rituximab is typically given at a dosage of 375 mg/m² weekly for 4 weeks.

• Alternative regimen: Rituximab 1000 mg IV x 1, repeat 14 days later, then 500 mg IV x 2 weeks apart,  q6 mo later

First line Treatment:

• Induction (Standard therapy):

  • IV methylprednisolone 15 mg/kg (1 gm/day) for 3-5 days, then transition to Prednisone 1 mg/kg/day, switched to qod after 2-4 weeks

  • Pulsed cyclophosphamide (CYC) in dosages 0.6– 0.75 g/m2 every 2–4 weeks x . To avoid bladder toxicity mesna should be added to treatment.

• Maintenance (after remission):

  • Taper prednisone over 6-12 months

    • Assuming that a patient begins prednisone at 60 mg/day and remains on this dose for four weeks, the following taper will require a total of 24 weeks (6 months) to reach a daily dose of 5 mg:

      • The prednisone dose is tapered by 10 mg each week until a dose of 40 mg/day is reached.

      • After one week on 40 mg/day, the prednisone dose is tapered by 5 mg each week until the dose reaches 20 mg/day

      • After one week on 20 mg/day, the prednisone dose is tapered by 2.5 mg each week until the dose reaches 10 mg/day.

      • After one week on 10 mg/day, the prednisone dose is tapered by 1 mg every two weeks until the dose reaches 5 mg/day.

    • Or:

      • Prednisone dose reduction of 5–10 mg every other week, until a maintenance therapy using 5–10 mg daily is achieved.   Osteoporosis prophylaxis should be initiated for every steroid treatment longer than 2 weeks. 

  • Continue cyclophosphamide for 6 months, or switch cyclophosphamide to azathioprine (start with 50 mg PO daily, increased to 1-2 mg/kg/day) for 18-24 months.  Methotrexate 5 mg/wk PO to start, increased to 10 mg/wk to 20 -25 mg/wk; may be given subcutaneous; reduce dosing in renal insufficiency.  Add folic acid supplementation of 5 - 10 mg/wk to reduce liver toxicity and GI intolerance.  In GPA patients, leflunomide can be used in the long-term treatment.

Second-line options for refractory patients:

• Pulse IV cyclophosphamide, 0.5-1 gm/m2 q4 wk x 6 mo

• IVIg 0.5 g/kg/day x 4 days, then 0.5 g/kg/day q3-4 wk x 6-12 mo

• Replace cyclophosphamide with methotrexate 25 mg PO or IV qwk x 12-24 mo

Protocol for IV solumedrol + Cyclophosphamide IV (Vasculitic neuropathy)

• IV methylprednisolone 15 mg/kg (1 gm/day) for 3-5 days, followed by PO prednisone 60 mg.

• IV Cyclophosphamide 1000 mg IV qmo x 6 

• Azathioprine 200 mg qd. 

• Give Benadryl 50 mg IV x 1 prior to cyclophosphamide infusion

• Given mesna 200 mg IV q4h x 4 (start 1st dose just prior to cyclophosphamide infusion)

• Bactrim 160 mg PO qod

• Check CBC, CBC with diff, UA

Nucala (mepolizumab)

The efficacy of anti-interleukin-5 therapy (i.e., mepolizumab) was demonstrated in the case of refractory or relapsing EGPA. Several other new agents, including avacopan, vilobelimab, and abatacept, are under development for the treatment of ANCA-associated vasculitis.

HBV-associated PAN

1. First line treatment:

   • Prednisone 1 mg/kg/day x 2 week

   • PE 1-3/wk x 10 wk

   • INF-alpha, 3 million units or lamivudine 100 mg/day, until HBeAb seroconversion or x 9-12 months

2. Second-line option for refractory patients:

   • Higher doses of INF-alpha (as in hepatitis B): 10 million units tiw or 5 million U/day

   • Famciclovir 500 mg PO tid

   • Adefovir dipivoxil 10 mg/day

HCV-associated cryoglobulinemic vasculitis

1. First line treatment:

   • Induction:

     • Oral CYC 2 mg/kg/day

     • Prednisone 1 mg/kg/day, changing to qod after 2-4 week, then tapering

     • PE 1-3/wk x 9 wk

   • Maintenance (after remission):

     • PegINF-alpha2b 1.5 mcg/kg SC/wk and ribavirin 800 mg/day, or

     • PegINF-alpha2a 180 mcg SC/wk and ribavirin 1000-1200 mg/day x 48 wk

     • PE 1-3/wk x 9 wk

2. Second-line option for refractory patients:

   • See GPA

   • Rituximab 375 mg/m2 IV/wk x 4 wk

HIV-associated vasculitic neuropathy, CMV positive vasculitis

1. First line treatment:

   • Induction:

     • Ganciclovir, 5 mg/kg IV q12h x 3 wk

   • Maintenance:

     • Ganciclovir, 1000 mg PO tid

2. Second-line option for refractory patients:

   • Induction:

     • Foscarnet, 90 mg/kg IV q12 h x 3 wk

• Maintenance :

  • Foscarnet, 90 mg/kg/day IV

  • Prednisone 0.5-1 mg/kg/day, tapered over 6-12 mo

  • PE 1-3/wk x 10 wk

  • IVIG (see NSVN)

Cancer-associated vasculitic neuropathy

• Treat malignancy

• Standard therapy with prednisone and CYC (see NSVN/GPA)

Modifications of the Standard Regimen for CYC

The perceived need to administer a less toxic "standard" regimen of cyclophosphamide (CYC) has prompted many modifications.  One such modification that has gained popularity is as follows:

• Replacement of continuous PO CYC with a pulsed dose regimen:

  • Intermittent CYC IV pulses of 0.35 - 1 g/m2 BSA or 15 mg/kg q1-4 weeks for up to 2 years. 

    • This dosing strategy is designed to decrease the cumulative CYC dose and minimize the risk of bladder toxicity, myelosuppression, and cancer. 

    • Several RCT have shown that this strategy is as effective as continuous PO CYC dosing in inducing remission in primary systemic vasculitides, with similar mortality rate.  

    • EUVAS CYCLOPS trial regimen.

      • q2 weeks x 3 doses, then q3weeks x _______ more doses (Recommend: a minimum of 3 more doses for a total of 4 months to a maximum of 6 more doses for a total of 6 months; total duration depends on response 

Birmingham Vasculitis Activity Score

Vasculitis damage index

Microsoft Word - VDI form in word.doc (canvasc.ca) 

The VDI requires that disease manifestations be present for at least 3 months before being scored as damage rather than ongoing activity.  The minimum score is 0, which would raise doubts about the diagnosis of vasculitis, while the maximum score is 64.   Since “once positive always positive,” the score can only stay unchanged or increase; it can never decrease . 

Initiation of high-dose corticosteroids, maybe starting with 1 g of IV methylprednisolone times three, followed by 60 mg of prednisone daily 

 Initiation of cyclophosphamide either as IV pulse or a daily oral dose. 

PO CYC: Oral Cytoxan start at 50 mg a day x 1 weeks, if labs ok increase to 100 mg a day - goal 150 mg a day for 3 to 6 months

IV CYC 750mg/m2 with mesna

He will need gastric prophylaxis, PCP prophylaxis, osteoporosis prophylaxis, as well as surveillance labs and urinalysis for those treatments. The use of MESNA with cyclophosphamide should be considered 

Cytoxan (CYC) 50 mg daily for 2 weeks started on 2/10/2020, titrated up to 100 mg qd > WBC dropped > reduced CYC dose to 50 mg, then up to 75 mg qday.  3/31/2020 increased to 100 mg qd.  4/16/2020, increased ot 150 mg qday. 5/29/2020, reduced to 125 mg due to nausea.  Prednisone 7.5 mg a day.  July cytoxan 150 mg a day prednisone 7.5 mg a day -> tapered off oral cytoxan with plan for rituximab maintenance in August but did not start. 

Aug 2020 solumedrol pulse 1 gram x 5 doses and IVIG x 5 days

Cytoxan Eurolupus protocol (dose 1 August 28, dose 2 Sept 11, 2020, October 14th, October 28th and November 11) 

Rituxan 1 gram x 2 (dose 1 Sept 6, dose 2 October 1 , 2020) 

Cellcept started fall 2020

IVIG -HELD since Sept 2020 due to a new PE

Prednisone OFF since December 2020

Fall 2021 pulse steroids and PLEX, cellcept started 

TOTAL CYTOXAN ABOUT 20 GRAMS  

PLASMA EXCHANGE + IV CYCLOPHOSPHAMIDE PROTOCOL

Utility: This protocol is for use in patients with motor and anti-MAG neuropathies.

Treatment regimen: During each cycle of treatment patients receive plasma exchange (1.5 plasma volumes) with 5% albumin replacement on two consecutive days. This is followed by hydration (1 to 1.5 liters), then 1g/M2 of cyclophosphamide given intravenously over 3 to 4 hours, and, finally, further hydration (1 to 1.5 liters).

During a course of therapy this regimen is given 6 times, one every 4 weeks. The patient is treated with cyclophosphamide (Cytoxan), a total of 1.0 gm/M2 intravenously over a period of 3 hours. Patients should be otherwise healthy and without evidence of infection for the prior 1-2 weeks. The protocol should probably be modified in debilitated patients.

Precautions taken to avoid side effects include:

1. Fluid: Administration of 3-4 liters of fluid on the days of Cytoxan treatment.

   • This includes:

     • 1-1.5 liters of fluid before Cytoxan treatment

     • Fluid administered with Cytoxan treatment

     • The remainder of the fluid to be administered after Cytoxan treatment.

   • The IV fluid should be D5 0.5 NS administered at up to 150 cc/M2/hour.

   • Fluid load should be modified for patients with abnormal cardiac function or who are otherwise debilitated.

   • Some of the post-treatment IV fluid may be replaced by p.o. intake.

2. Antiemetics - Zofran (Ondansetron) 0.15 mg/kg over 15 minutes: Give

   • Prophylactically beginning 30 minutes prior to each cyclophosphamide dose

   • 4 and 8 hours after treatment

   • The patient should be sent home with enough antiemetics for 2-3 days.

3. Strict I&O should be kept during the patient's hospital stay.

4. Urine: During and 1 day after treatment
   
   

   • All urine should be evaluated for heme.

   • Microscopic analysis of the urine should be performed after each medication dose.

   • The specific gravity on all urines should be determined.

5. After administration of Cytoxan, IV tubing should be changed before resuming regular IV hydration.

6. Blood tests: Obtained before the first plasma exchange and at intervals thereafter.

   • Heme-8, differential, platelets (every month)

   • Comprehensive metabolic panel (CPT code 80053) (every month)

   • IgM vs GM1 or MAG (every 3 to 4 months): Send to

   • Neuromuscular Clinical Laboratory
     Box 8111 - Neurology
     660 South Euclid Avenue
     St. Louis, MO 63110
     Phone: 314-362-6981
     Fax: 314-362-2826

7. Follow-up - Return outpatient appointment is 1 to 2 months after the last treatment.

8. Nursing precautions should include:

   • Double gloving on handling urine because Cytoxan is excreted in the urine.

   • Double gloving when spiking Cytoxan mini bottles.

   • Post dose disposal of empty bottle in red bag.

Template case:

REASON FOR REFERRAL: Paresthesia.

HISTORY OF PRESENT ILLNESS:  PE is a 70-year-old, right-handed woman with history of strokes, seizures, cigarette smoking, and alcohol use COPD, hypertension, and hyperlipidemia is referred paresthesia with a specific question with regards to vasculitic neuropathy.

As per the referring clinician, patient had left sural and gastrocnemius muscle biopsy (8/3/2023): Report not available for review.  As per the referring clinician, Bradley H Gould (PA) Telephone communication note (8/9/2023): "D/w U ofM Pathologist that nerve biopsy is suggestive of necrotizing vasculitis and muscle biopsy prelim suggests neuropathic changes.  Reviewed course and labs.  Pt is indicated for urgent follow up with Rheumatology and Neuromuscular Neuro.  Will reach out to Rheum (urgent referral order also placed) and try to expedite Neuromuscular Neuro eval.  Attempted to call pt multiple times to explain this but goes to voicemail and her voicemail box is full."

xx states that she had developed feeling of numbness in her right foot around November last year.  Since then it has progressed to the left foot.  She notes occasional pins and needle and burning sensation across the dorsum of her toes and midfoot.  She was started on gabapentin by her PCP at 300 mg p.o. 3 times daily but notes it has not helped alleviate her symptoms.  She was also started on OxyContin which helped relieve her pain but made us sleep excessively.  As per chart review, she was also trialed on amitriptyline without benefit and with adverse effects.

As per chart review and clinic notes of the referring clinician (7/18/2023), she was admitted to the hospital on December 8, 2022 for further evaluation.  The reason for her admission was worsening peripheral paresthesias, numbness, and pain as well as new onset perioral numbness.  She also developed fever, worsening chronic productive cough, fatigue, and reduced appetite.  She presented with leukocytosis, fever, tachycardia, hypertension, and elevated WBC suggesting sepsis in the setting of worsening cough.  Elevated transaminases: AST and ALT of 535 and 580, respectively; hypomagnesemia with serum magnesium of 1.6, CRP: 13.2, ESR: 93, procalcitonin: 21.14.  Hepatitis work-up revealed elevated HBV core IgM and therefore HBV DNA was ordered which later on was not detectable/negative.  Patient was started on IV ceftriaxone and azithromycin for acute interstitial pneumonia and then transition to oral Ceftin and azithromycin on discharge.  Pulmonology also started patient on steroids and Bactrim.  Patient endorses having had an extensive work-up while in the hospital.  Of note, MRI of the brain (12/9/2022) revealed multiple small acute to subacute ischemic strokes, including bilateral thalamus, left posterior limb of internal capsule and left frontal lobe.  For neuropathic pain patient received Lyrica 50 mg p.o. 3 times daily and lidocaine gel.  Patient was discharged on 2/18/2023 with appropriate follow-up recommendations with different subspecialties. 

EMG/NCS of right upper and lower extremities was performed by Dr. xxx Normal study.

Since then she has had several ED visits and hospital admissions as noted (3/29/2023, admitted: 5/24/2023 and discharged on 5/26/2023).  At her 5/24/2023 admission neurology was consulted for generalized weakness, difficulty walking, somnolence and confusion.  There was history of jerky movements in her extremities which was new.  Patient had started using a walker due to weakness in her legs resulting in falls.  Reportedly as per documentation (5/24/2023) by neurology consult patient was reportedly drinking the day prior.  She denied any alcohol withdrawal seizures in the past.  Patient is a chronic alcohol drinker and drinks 1 pint to 1/5 of alcohol about 4-5 times a week, as per report.  Of note, ethanol levels and UDS were checked on 5/24/2023 and were normal.  She was started on Keppra 1 g p.o. twice daily since EEG showed findings suggestive of generalized epilepsy.  She was also put on long-term cardiac monitoring with Zio patch which did not show any evidence of atrial fibrillation; LINQ placement was recommended by neurology as outpatient.

As per clinic note by referring clinician (7/18/2023), patient was evaluated by rheumatology Dr. xx, who had a concern about ANCA vasculitic process.  She was started on prednisone.  Patient reports she took the prednisone for approximately a month and has stopped since a month.  She underwent left sural nerve (not fibular) and gastrocnemius (not fibular tertius muscle) muscle biopsies.  She complains of pain and tenderness over the left lateral malleolus (sural nerve biopsy site).  Preliminary report as per referring clinician is suggestive of necrotizing vasculitis.  

Patient reports that she continues to have burning paresthesias across both feet but more so over the surgical incisional sites.  She complains of cramps in her toes.  She has been using a cane over the past 6 months.  She reports her balance is unsteady if she does not use a cane for support.

She denies any history of wrist or foot drop.  No history of skin rashes around the ankles or limbs.  No history of hematuria.  No history of hemoptysis.  No history of epistaxis.  No GI bleed.  No history of paralysis of face or limbs.

REVIEW OF PRIOR LABORATORY AND DIAGNOSTIC STUDIES:

Lab Results

Component Value Date

WBC 9.7 05/26/2023

HGB 12.4 05/26/2023

HCT 37.3 05/26/2023

PLT 240 05/26/2023

CHOL 186 05/25/2023

TRIG 80 05/25/2023

HDL 77 05/25/2023

ALT 7 (L) 05/24/2023

AST 16 05/24/2023

NA 137 05/26/2023

K 4.1 05/26/2023

CL 102 05/26/2023

CREATININE 0.70 05/26/2023

BUN 9 05/26/2023

CO2 28 05/26/2023

TSH 1.89 05/24/2023

INR 1.0 05/24/2023

HGBA1C 4.7 02/16/2023

Labs (2/16/2023): ANCA (p-ANCA and c-ANCA).  This patient has a positive ANA that interferes with a titer of ANCA.  Because of this, please use the anti-MPO EIA to follow this patient.  The anti-PR-3 EIA was negative.

Component

    Latest Ref Rng 12/8/2022 2/17/2023

Myeloperoxidase Ab

    <=20 UNITS 27 (H) 16 

Legend:

(H) High

Labs (2/16/2023): ANA: Positive (1: 320) homogeneous.  SS-A and SS-B antibodies: Negative.  SCL-70-ab: Negative/unremarkable.  Histone-Ab and centromere antibody: Negative.  CCP: Negative.  RA: Positive (2580 <1280).  Glomerular basement membrane, C3, C4: Negative.  ESR: 93.  CRP: 13.2.

CSF studies (12/9/2022): Paraneoplastic autoantibody evaluation: Negative.  CSF protein: 66 mg/dL.

Component

    Latest Ref Rng 3/30/2023 5/24/2023 5/25/2023 5/26/2023

Magnesium

    1.7 - 2.5 mg/dL 1.4 (L) 1.6 (L) 2.0 1.7 

Magnesium

     1.6 (L)

Legend:

(L) Low

Component

    Latest Ref Rng 11/21/2022 2/16/2023

Hemoglobin A1C

    4.0 - 5.6 % 5.7 (H) 4.7 

Mean Bld Glu Estim.

    62 - 140 mg/dL 117 88 

Legend:

(H) High

Labs (5/24/2023): CK, TSH, ethanol: Normal.  UDS-7 (5/24/2023): Negative.

Component

    Latest Ref Rng 2/16/2023

Hepatitis C Antibody

    Nonreactive Nonreactive 

Hepatitis B Surface Ag

    Negative Negative 

Hepatitis A Antibody IgM

    Negative Negative 

Hep B Core IgM

    Negative POSITIVE ! 

Hepatitis C Virus RNA Qualitative

    Not detected IU/mL TNP 

Hepatitis C Virus RNA Quantitative

    IU/mL TNP 

HCV Quantitative Log

    Log (10) IU/mL TNP 

HCV Interpretation

    Not detected No HCV antibody detected 

Legend:

! Abnormal

Labs (2/7/2023): Hepatitis B virus DNA (qualitative/quantitative) unremarkable/not detected.

Component

    Latest Ref Rng 5/24/2023

Glucose, Urine

    Negative mg/dL Negative 

Color, Urine

    Amber, Colorless, Yellow, Straw Straw 

Clarity, Urine

    Clear Clear 

Specific Gravity, Urine

    1.005 - 1.030 1.010 

pH, Urine

    5.0 - 7.0 pH 7.0 

Leukocytes, Urine

    Negative Negative 

Nitrite, Urine

    Negative Negative 

Protein, Urine

    Negative mg/dL Negative 

Ketones, Urine

    Negative mg/dL Negative 

Urobilinogen, Urine

    Normal mg/dL Normal 

Bilirubin, Urine

    Negative Negative 

Blood, Urine

    Negative eryth/mcL Negative 

EMG/NCS of right upper and lower extremities was performed by xx: Normal study.

Vascular ultrasound (arterial Doppler) lower extremities (12/8/2022): Normal bilateral ABIs.  Slightly diminished bilateral toe brachial indicis suggestive of mild peripheral small vessel disease.

Vascular ultrasound duplex (venous) left lower extremity (12/7/2022): No sonographic evidence of DVT in left lower extremity.

CT chest without contrast for ILD, RA factor >1200 (11/7/2022): Chronic interstitial lung disease with areas of fibrosis and honeycombing.

MRI brain with and without contrast for left face paresthesia, right facial droop; lower extremity weakness (12/9/2022)-images reviewed: Multiple hemispheric small acute ischemic foci, including involvement of bilateral thalami.  Extensive chronic, microangiopathic white matter ischemic disease.  No evidence of hemorrhage.

MRI of the cervical spine with or without contrast (12/19/2022)-images reviewed: Multilevel degenerative disc disease most severely at C4-C5 with spinal canal stenosis and moderately severe to right neuroforaminal narrowing.  Broad-based posterior disc protrusion at C5-C6 more severe on the right than left.  

CTA of head and neck with and without contrast (12/9/2022): Prominent calcified plaque within the cavernous and supraclinoid segments of the right ICA with up to 70 to 80% stenosis.  Scattered atherosclerotic occasion within the carotid vasculature.  Right suprahilar soft tissue fullness noted.  CT of the chest was recommended (ordered by Dr. James Passinault) - pending. 

TTE (12/9/2022): LVEF: 56%.  No significant valvular dysfunction noted.

cVEEG (5/25/2023 at 03:17 to 5/26/2023 and 01:00) for encephalopathy and muscle jerks: Abnormal awake and sleep continuous EEG monitoring indicative of generalized epilepsy.  No electrographic seizures seen.  Paroxysmal high amplitude (up to 150 UV) generalized spike/polyspike and wave discharges (2-3 HZ, polyspike up to 19 HZ) are seen maximum in bilateral fronto-central regions with more consistence and prominence in the right fronto-central region (F4-C4), lasting 0.5 to 3 seconds with the frequency of 1 per 15-60 seconds throughout the record. No visible movement/jerk was noticed through the recorded video. 

Left sural and gastrocnemius muscle biopsy (8/3/2023): Report not available for review.  As per the referring clinician, Bradley H Gould (PA) Telephone communication note (8/9/2023): "D/w UofM Pathologist that nerve biopsy is suggestive of necrotizing vasculitis and muscle biopsy prelim suggests neuropathic changes.  Reviewed course and labs.  Pt is indicated for urgent follow up with Rheumatology and Neuromuscular Neuro.  Will reach out to Rheum (urgent referral order also placed) and try to expedite Neuromuscular Neuro eval.  Attempted to call pt multiple times to explain this but goes to voicemail and her voicemail box is full.

ALLERGIES:  Ace inhibitors, Aspirin, Caffeine, Margesic (propoxyphene), Tylenol [acetaminophen], and Valsartan

MEDICATIONS:  

Current Outpatient Medications

Medication Sig Dispense Refill

• amLODIPine (NORVASC) 10 mg tablet Take 1 tablet (10 mg total) by mouth 1 (one) time each day. 90 each 3

• aspirin 81 mg chewable tablet Chew 1 tablet (81 mg total) 1 (one) time each day. 90 each 3

• atorvastatin (LIPITOR) 40 mg tablet Take 1 tablet by mouth 1 (one) time each day. 30 each 11

• Combivent Respimat 20-100 mcg/actuation inhaler INHALE 1 PUFF BY MOUTH FOUR TIMES DAILY (BULK) (Patient taking differently: Inhale 1 puff 4 (four) times a day if needed.) 4 g 11

• cyanocobalamin (VITAMIN B-12) 1,000 mcg tablet Take 1 tablet (1,000 mcg total) by mouth 1 (one) time each day.

• diclofenac (VOLTAREN) 1 % topical gel Apply 2 g topically 2 (two) times a day. Apply to feet in tender area 50 g 0

• fluticasone propionate (FLONASE) 50 mcg/actuation nasal spray SHAKE LIQUID AND USE 1 SPRAY IN EACH NOSTRIL 1 TIME EACH DAY 16 g 0

• levETIRAcetam (KEPPRA) 1,000 mg tablet Take 1 tablet (1,000 mg total) by mouth 2 (two) times a day. 180 each 1

• meloxicam (MOBIC) 15 mg tablet Take 1 tablet by mouth 1 (one) time each day. 30 each 0

• montelukast (SINGULAIR) 10 mg tablet TAKE ONE TABLET BY MOUTH DAILY AT 9 PM AT BEDTIME 30 tablet 11

• omeprazole (PriLOSEC) 40 mg DR capsule TAKE 1 CAPSULE BY MOUTH 1 TIME EACH DAY 60 capsule 0

• pyridoxine (B-6) 50 mg tablet Take 1 tablet (50 mg total) by mouth 1 (one) time each day. 30 each 11

• thiamine (VITAMIN B-1) 100 mg tablet Take 1 tablet (100 mg total) by mouth 1 (one) time each day. 30 tablet 0

• venlafaxine XR (EFFEXOR-XR) 75 mg 24 hr capsule Take 3 capsules (225 mg total) by mouth 1 (one) time each day. Take with food. 90 each 11

• lidocaine 2 % Apply 20 mL topically 1 (one) time each day if needed (Mild pain). Apply to feet and hands when in pain (Patient not taking: Reported on 7/18/2023) 20 mL 0

• mometasone-formoterol (DULERA 200) 200-5 mcg/actuation inhaler Inhale 2 puffs 2 (two) times a day. Rinse mouth with water after use to reduce aftertaste and incidence of candidiasis. Do not swallow. (Patient not taking: Reported on 5/25/2023) 1 each 0

• nicotine (Nicoderm CQ) 14 mg/24 hr Place 1 patch on the skin 1 (one) time each day at the same time. 30 each 0

• nicotine polacrilex (COMMIT) 4 mg lozenge Dissolve 1 lozenge (4 mg total) in the mouth every 2 (two) hours if needed for smoking cessation. 100 lozenge 0

• oxyCODONE (ROXICODONE) 5 mg immediate release tablet Take 1 tablet (5 mg total) by mouth every 6 (six) hours if needed for severe pain. Max Daily Amount: 20 mg (Patient not taking: Reported on 8/14/2023) 6 each 0

No current facility-administered medications for this visit.

(Not in a hospital admission)

MEDICAL HISTORY:

Patient Active Problem List

Diagnosis

• Seasonal allergic rhinitis

• Essential hypertension

• Generalized anxiety disorder

• GERD (gastroesophageal reflux disease)

• Lumbosacral radiculopathy due to degenerative joint disease of spine

• Mixed hyperlipidemia

• Osteoarthritis of hip

• Primary insomnia

• Primary osteoarthritis of both knees

• Tobacco user

• Tobacco dependence syndrome

• Inflammatory disease of vagina and vulva

• Allergic conjunctivitis of both eyes

• Osteopenia

• COPD (chronic obstructive pulmonary disease) (CMS/HCC)

• Lichen sclerosus et atrophicus

• Age-related cataract of both eyes

• Chest pain

• Arthritis of knee

• Cough

• Pulmonary nodules

• Restrictive lung disease

• Decreased diffusion capacity

• Pneumonia due to infectious organism, unspecified laterality, unspecified part of lung

• Generalized pain

• Hypomagnesemia

• Generalized weakness

• Peripheral polyneuropathy

• Prediabetes

• Ischemic stroke (CMS/HCC)

• Weakness of both lower extremities

• Hypokalemia

• Vision changes

• Nonintractable epilepsy without status epilepticus (CMS/HCC)

• Generalized epilepsy (CMS/HCC)

• Abnormal finding on CT scan

• Stenosis of right carotid artery

• Decreased appetite

• Right foot pain

• Irregularly irregular pulse rhythm

• Healthcare maintenance

• Nodule of skin of both feet

Past Medical History:

Diagnosis Date

• Age-related cataract of both eyes 01/20/2021

• Anxiety

• Arthritis

• Cigarette smoker

• COPD (chronic obstructive pulmonary disease) (CMS/HCC)

• Difficulty sleeping

• GERD (gastroesophageal reflux disease)

• Hyperlipidemia

• Hypertension

• Postmenopausal state

• Seasonal allergic rhinitis

• Seizures (CMS/HCC)

• Stroke (CMS/HCC)

SURGICAL HISTORY:

Past Surgical History:

Procedure Laterality Date

• BUNIONECTOMY Left

• COLONOSCOPY

• D&C FIRST TRIMESTER / TX INCOMPLETE / MISSED / SEPTIC / INDUCED ABORTION

• LIPOMA RESECTION

FAMILY HISTORY:

family history includes Alcohol abuse in her father; Asthma in her mother; Breast cancer in an other family member; Colon cancer in an other family member; Lung cancer in her mother; Ovarian cancer in an other family member; Thyroid disease in her mother; Uterine cancer in an other family member.

SOCIAL HISTORY:  

Tobacco use:   reports that she has been smoking cigarettes. She has a 12.50 pack-year smoking history. She has never used smokeless tobacco.

Alcohol use:   reports current alcohol use.

Drug use:  reports that she does not currently use drugs after having used the following drugs: Methamphetamines.

Work and Living situation: Patient lives with her daughter.

PHYSICAL EXAMINATION:

VITAL SIGNS:  

Visit Vitals

BP 115/89 (BP Location: Left arm, Patient Position: Sitting, BP Cuff Size: Large adult)

Pulse 98

Ht 1.499 m (59")

Wt 60.9 kg (134 lb 3.2 oz)

BMI 27.11 kg/m²

OB Status Postmenopausal

Smoking Status Every Day

BSA 1.56 m²

General: Awake, no acute distress.  

Skin: Discoloration/hyperpigmentation of the skin over the dorsum of both feet in a patchy distribution.

CV: Regular rate and rhythm, normal S1, S2 auscultated, no murmurs. 

Lungs: Clear to auscultation.

Extremities: No cyanosis, no edema.  Incisional scar over the lateral aspect of left ankle behind the mid lateral malleolus and incisional scar over the left upper calf (biopsy sites); tender and painful to touch.

Skeletal: No joint or skeletal deformities noted. 

Neurological Exam:  Patient is alert and oriented to person, place, and time.  Speech is clear, spontaneous and fluent.  Language function is preserved.  MoCA: not tested.  Thought process is organized, sequential, and goal-direct.  Olfaction is not tested.  Visual fields are full to confrontation and visual acuity is intact to finger counting, OU.  Pupils are equal, round and reactive to direct and consensual response to light. There is no RAPD.  Extraocular movement are with normal fixation, ductions, versions, smooth pursuits, and saccades and no nystagmus.  Strength of masticatory muscles are normal, bilaterally. Normal facial sensation, symmetry, and strength.  Normal hearing to finger rub, bilaterally.  Palatal elevation is symmetrical.   Tongue protrusion in midline and lateral thrust is normal, no atrophy or fasciculations.  Neck flexion/extension/lateral rotation strength: 5/5.  Shoulder shrug: 5/5, bilaterally. 

Motor exam is normal muscle bulk and tone.  No adventitious movement noted.  Motor testing reveals no drift and full strength: 5/5 in all muscle groups in upper and lower extremities, bilaterally.  

Sensory exam is notable for increased sensitivity to pinprick and cold temperature sensation over the dorsum of both feet.  She has exquisite tenderness over the incisional sites over the left lateral malleolus as well as left calf.  Vibration sensation is normal at both halluces in feet and both index fingers in hands.  Semmes Weinstein monofilament testing: Right foot: 9/10.  Left foot: 8/10.  Romberg present.  She is able to stand up from the chair with some effort.  Gait is wide-based, slow cadence, short stride length but symmetrical.  She is able to walk better, steadier, slightly faster with using a cane.  She is unable to perform forced walking maneuvers.  Coordination is intact to FNF, bilaterally but demonstrates mild intention tremor on approaching the target (left > right).

MSR are 2+ in upper extremities, 2+ knees, and absent ankle reflexes, bilaterally.  Plantars are downgoing (flexor), bilaterally. 

ASSESSMENT:

70-year-old, right-handed woman with history of strokes, seizures, cigarette smoking, and alcohol use COPD, hypertension, and hyperlipidemia is referred paresthesia with a specific question with regards to vasculitic neuropathy.  Neurological examination is notable for sensory dysfunction to small fiber sensory modalities with increased sensitivity to pinprick sensation over the dorsum of both feet, mild sensory ataxia, absent ankle reflexes, bilaterally.

1. Paresthesias 

2. Dysesthesia 

3. Vasculitic neuropathy (CMS/HCC) 

4. Ischemic stroke (CMS/HCC) 

5. Seizures (CMS/HCC) 

6. Generalized weakness 

Paresthesia/dysesthesia/Vasculitic neuropathy.  Chronic onset paresthesias in both feet with a subacute worsening.  Exam is notable for sensory dysfunction to small fiber sensory modalities in a distal to proximal gradient with absent ankle reflexes, localizes to the peripheral nerves in particular small fiber nerves.  Onset of symptoms were asymmetrical with initial involvement in right foot around November, 2022 and since then it has progressed to the left foot and confluent.  No motor deficit such as foot drop or wrist drop.  Her risk factors for- neuropathy based on history include alcohol use.  EMG/NCS of right upper and lower extremities did not demonstrate involvement of the large nerve fibers.  She had left sural nerve biopsy which based on preliminary report is notable for necrotizing vasculitis.  If so she has pathologically definite vasculitic neuropathy.

Patient has history of paresthesias/dysesthesias and pain with worsening course; multiple ischemic embolic strokes felt due to ICAD (artery to artery) but unclear, with encephalopathy, abnormal EEG suggestive of epilepsy, constitutional symptoms including fever, worsening chronic productive cough, fatigue, and reduced appetite.  She also has history of pulmonary dysfunction including COPD (attributed to smoking cigarettes).  Serology is positive for ANA and suggestive of ANCA positivity with specificities to anti-MPO. anti-PR-3 EIA was negative.  RA positive with elevated ESR and CRP.  CSF studies were unremarkable other than slightly elevated CSF protein at 66 mg/dL.  CT chest without contrast (11/7/2022): Chronic interstitial lung disease with areas of fibrosis and honeycombing.  Repeat CT of the chest which was ordered is still pending.   MRI brain with and without contrast for left face paresthesia, right facial droop; lower extremity weakness (12/9/2022)-images reviewed: Multiple hemispheric small acute ischemic foci, including involvement of bilateral thalami.  Extensive chronic, microangiopathic white matter ischemic disease.  No evidence of hemorrhage.  No history of skin rashes around the ankles or limbs.  No history of hematuria.  No history of hemoptysis.  No history of epistaxis.  No GI bleed.  No history of paralysis of face or limbs.

Given the history and evolution of her clinical features and the results of current work-up findings, there is a concern for systemic vasculitis, likely ANCA associated vasculitis; small vessel vasculitis -MPA except that there is no diffuse pulmonary or renal involvement.   Secondary causes of systemic vasculitides such as RA and MCTD is a possibility.  

Vasculitis Damage Index (VDI) Score: 6

Impaired lung function

Diastolic BP ? 95 or requiring antihypertensives

Cognitive impairment

Seizures

Cerebrovascular accident

Peripheral nerve involvement (based on result of left sural nerve bx - as reported)

I discussed with the patient the concerns regarding systemic vasculitis.  I discussed treatment options including cyclophosphamide (EUVAS CYCLOPS regimen) and SE profile.  Patient and her daughter are concerned about side effects profile of CYC and not amenable to this option.  I discussed Rituximab (RAVE trial) and explained that Rituximab therapy was not inferior to cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease.  She is amenable to this option.  I will ask my office to try and obtain the nerve biopsy report.  I will repeat EMG/NCS of bilateral lower extremities (scheduled with me) to be expedited.  She will require direct admission to treat her expeditiously as there is a increased likelihood of accruing increased morbidity.

Following admission:  Start IV Solu-Medrol 500 mg intravenous infusion twice daily for 3 days, followed by prednisone 60 mg p.o. daily (a.m. dose) for 4 weeks, then based on stability response and assessment may be tapered to 50 mg p.o. for two weeks, then 40 mg p.o. for 4 weeks, then 30 mg p.o. for 4 weeks, then 25 mg p.o. for 4 weeks, then 20 mg p.o. daily and eventually tapered to 10 mg p.o. daily for up to 6 months.  Concomitant treatment with Tavenos (avacopan) may facilitate the use of an even shorter, reduced-dose glucocorticoid regimen.  Caution: Monitor baseline LFTs prior to starting avacopan and monitor LFTs as clinically indicated.

For prednisone: 

Check CBC, CMP: monthly, check HbA1c every 3 months, DEXA.  

Calcium 1200mg daily.  

Vitamin D 800 units daily

GI bleeding: Avoid ASA and NSAIDs.

GI prophylaxis: Taking omeprazole or Famotidine.

Lasix use with prednisone  worsens hypokalemia 

Referral to dietician for dietary precautions on steroids: Low sodium, low-carbohydrate, high protein diet and to avoid excessive weight gain, while on steroids. 

PCP to monitor blood pressure

Ophthalmology evaluation to check for glaucoma.  Patient has had cataracts removed.

Induction to begin after completion of IV solumedrol 3rd dose (Inpatient): Rituximab (375 mg/m2 per week for four weeks) intravenous infusions.

Maintenance:  For patients treated with rituximab for induction of remission, maintenance therapy typically begins between months 4 and 6 after the last induction dose with Rituximab 1000 mg IV infusion given 2 weeks apart OR an "on-demand" dosing strategy, in which peripheral B lymphocyte (CD19-positive cells) counts, which are depleted by rituximab, and ANCA titers are monitored and the drug is redosed when B lymphocytes reconstitute and the ANCA titer becomes positive.  Recheck hepatitis-B prior to repeat dosing with Rituximab. 

Prevention of opportunistic infection vaccinations.  Bactrim DS p.o. thrice weekly (for  P. jirovecii pneumonia).  Influenza/pneumonia and COVID 19 vaccinations, up-to-date.

Check TB qunatiferon (IGRA) - prior to starting Rituximab.  

PLAN:

EMG/NCS of bilateral lower extremities (scheduled with me) to check for polyneuropathy.  Please expedite.

Obtain the report of left sural nerve biopsy for review.

Patient may need direct admit as inpatient to start therapy expeditiously.

Follow up in about 3 months (around 11/14/2023) for Dr. Melanie Taylor..

Cyclophosphamide in Vasculitis

CycloPHOSphamide (CYTOXAN) 1,160 mg in sodium chloride 0.9 % 333 mL infusion 

1,160 mg (rounded from 1,164 mg = 600 mg/m2 per DOSE × 1.94 m2 Treatment plan ideal BSA), Intravenous, ONCE, 1 dose, On Wed 10/2/24 at 1130, Infuse over 60 minutes after first dose of Mesna IV is complete. CHEMOTHERAPY. 

Infuse: 1,160 mg at 333 mL/hr

Indications: Vasculitis 

dexAMETHasone (DECADRON) tablet 20 mg 

20 mg, Oral, ONCE, 1 dose, At least 30 minutes prior to cyclophosphamide. (If methylprednisolone is ordered, hold decadron)., On Wed 10/2/24 at 1115 

Indications: Vasculitis 

dextrose 5 % - sodium chloride 0.45 % IV 

150 mL/hr, Intravenous, CONTINUOUS, Starting on Wed 10/2/24 at 1115, Until patient discharged. (Hold IV hydration during cyclophosphamide infusion.) 

Indications: Vasculitis 

Infuse:  150 mL/hr

diphenhydrAMINE (BENADRYL) capsule 50 mg 

50 mg, Oral, ONCE, 1 dose, At least 30 minutes prior to cyclophosphamide., On Wed 10/2/24 at 1115 

Indications: Vasculitis 

LORazepam (ATIVAN) tablet 1 mg 

1 mg, Oral, ONCE, 1 dose, At least 30 minutes prior to cyclophosphamide., On Wed 10/2/24 at 1115 

Indications: Vasculitis 

mesna 200 mg in dextrose 5% 57 mL infusion 

200 mg, Intravenous, ONCE, On Wed 10/2/24 at 1115, For 1 dose, Infuse over 15 minutes. Give first IV dose immediately before Cyclophosphamide. 

Indications: Vasculitis 

mesna 200 mg in dextrose 5% 57 mL infusion 

200 mg, Intravenous, ONCE, On Wed 10/2/24 at 1415, For 1 dose, Infuse over 15 minutes. Administer three hours after initiation of mesna. 

Indications: Vasculitis 

ondansetron (ZOFRAN) tablet 8 mg 

8 mg, Oral, ONCE, 1 dose, At least 30 minutes prior to cyclophosphamide., On Wed 10/2/24 at 1115 

Indications: Vasculitis