The Neuropathies of Vasculitis.

The term vasculitis refers to a pathologic condition defined by inflammatory cell infiltration and destruction of blood vessels. Systemic vasculitis is classified as primary (eg, polyarteritis nodosa, Churg-Strauss syndrome) or secondary, the latter associated with connective tissue disorders, infections, medications, and rarely, as a paraneoplastic phenomenon. Neuropathy is a common complication of systemic vasculitis and is related to ischemic nerve fiber damage with axon loss. Peripheral neuropathy may be the sole manifestation of vasculitis, a condition termed nonsystemic vasculitic neuropathy (NSVN). Treatment of vasculitic neuropathy requires long-term immunosuppressive therapies with potential side effects. The diagnosis of vasculitis should be established by tissue (preferably nerve) biopsy. High-dose prednisone is the standard platform therapy for patients with systemic and NSVN; for those with systemic vasculitis, at least 3 to 12 months of treatment with cyclophosphamide (monthly intravenous pulse or daily oral therapy) is also necessary to sustain remission and allow successful prednisone tapering. The use of cyclophosphamide in patients with NSVN is controversial, but recent retrospective data suggest that those treated with prednisone and cyclophosphamide from the outset fare better than those initially treated only with prednisone. If prednisone is administered as monotherapy, cyclophosphamide should be added after several months if there is no improvement or relapse occurs with tapering of prednisone. Intravenous pulse and daily oral cyclophosphamide probably offer similar efficacy, although the risk of complications is greater with oral therapy. Azathioprine can be safely substituted for cyclophosphamide after 3 months without an increased relapse rate. Azathioprine, methotrexate, intravenous immune globulin, mycophenolate mofetil, plasma exchange, and rituximab can be offered to patients who are intolerant or have a contraindication to cyclophosphamide. However, efficacy is unproven for any of these therapies. Interferon-alpha, sometimes combined with plasma exchange, is used to treat vasculitis associated with hepatitis B infection. Some patients also may improve with corticosteroids. The classification of diabetic lumbosacral radiculoplexus neuropathy as a vasculitic disorder remains controversial. However, there is compelling pathological evidence that this condition represents a T-cell-mediated microvasculitis. Some patients treated with intravenous corticosteroids may have greater recovery and improved pain control.

Clinicopathologic features of nonsystemic vasculitic neuropathy and microscopic polyangiitis-associated neuropathy: A comparative study

Polineuropatía y vasculitis de vaso pequeño con detección de p-ANCA identidad mieloperoxidasa

ObjectiveTo identify the most relevant antigens for monoclonal antibodies in lymphocytic infiltrates in non-systemic vasculitic neuropathy (NSVN).BackgroundCurrent immunosuppressive treatment for NSVN is insufficient. Monoclonal antibodies might be a treatment option,...

IntroductionNerve biopsy remains the gold standard to diagnose vasculitic neuropathy. Conversely, biopsy has imperfect sensitivity and entails risks associated with an invasive procedure. Methods to improve diagnostic accuracy remain important...

The term vasculitis incorporated a large group of clinically heterogeneous conditions that have the following characteristic pathologic features in common: inflammation and structural damage to blood vessel walls that leads to ischemic, hemorrhagic, and thrombotic damage to the tissues supplied by those vessels. Peripheral neuropathy is common in conjunction with most of these vasculitic syndromes, irrespective of whether vasculitis is the primary disease process, as in polyarteritis nodosa or Wegener’s granulomatosis, or is secondary to some other connective tissue disorder, such as rheumatoid arthritis or systemic lupus erythematosus. In patients with secondary vasculitides, it can occasionally be difficult to distinguish vasculitic neuropathy from other types of neuropathy (discussed in Chapter 13). The clinical and pathologic features of vasculitic neuropathy, however, are distinctive enough to merit separate discussion, particularly since neuropathy may be the first, and sometimes only, manifestation of vasculitis. Prompt diagnosis by the neuromuscular clinician is therefore crucial because of the significant potential for improvement with immunosuppressive treatment. In fact, vasculitic neuropathy represents one of the most treatable neuropathies encountered by clinicians.

Peripheral Nerve Vasculitis: Classification and Disease Associations

Predictors of Patient-Reported Recovery From Motor or Sensory Deficits Two Years After Acute Symptomatic Lumbar Disk Herniation

Vasculitic neuropathy remains challenging to diagnose and monitor because of its heterogeneous clinical and laboratory presentation. Blood‐based biomarkers indicating nerve damage could serve as an additional diagnostic tool to ensure early diagnosis, precise therapeutic monitoring, and a more targeted anti‐inflammatory treatment. A potential marker for this purpose is neurofilament light chain (NfL), a marker of neuroaxonal damage that is used as a biomarker in several diseases of the central and peripheral nervous system. NfL has also been suggested to reflect disease activity in patients with vasculitic neuropathy. However, its biodynamics and link to degeneration of peripheral nerve tissue remain unconfirmed. To investigate the usefulness of NfL as a marker of peripheral nerve damage in this context, we retrospectively assembled a cohort of 35 patients undergoing sural nerve biopsies (including patients with vasculitic neuropathy and other neuropathies). We then measured NfL in serum samples cryoarchived at the time of biopsy and correlated NfL levels with histological parameters. For our histological analysis, we quantified parameters of acute axonal degeneration and chronic axonal loss using a combination of manual, threshold‐based, and supervised learning‐based analyses. We found a significant positive correlation between parameters of acute axonal degeneration and serum‐NfL levels that persisted after adjusting for age and concomitant central nervous system disease. We did not find a similar correlation with parameters of chronic axonal loss quantified in nerve biopsies. These findings support the value of NfL as a marker for acute axonal degeneration in patients with vasculitic neuropathy.

ObjectiveReported prevalence of vasculitic neuropathy (VN) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is highly variable, and associations with other organ manifestations have not been studied systematically while accounting for diagnostic certainty of VN.MethodsData of all patients with AAV within the Diagnostic and Classification criteria for primary systemic VASculitis study were analyzed cross-sectionally. VN was categorized as definite (histology proven), probable (multiple mononeuropathy or nerve biopsy consistent with vasculitis), or possible (all others). Associations with other organ manifestations were compared in patients with and without VN.ResultsNine hundred fifty-five patients (mean age 57 years, range 18–91 years, 51% female) were identified. Of these, 572 had granulomatosis with polyangiitis (GPA), 218 microscopic polyangiitis (MPA), and 165 eosinophilic granulomatosis with polyangiitis (EGPA). The prevalence of VN was 65% in EGPA, 23% in MPA, and 19% in GPA. Nerve biopsy was performed in 32/269 (12%) patients, demonstrating definite vasculitis in 17/32 (53%) of patients. VN was associated with myeloperoxidase-ANCA positivity (p = 0.004) and skin (p < 0.001), musculoskeletal, (p < 0.001) and cardiovascular (p = 0.005) involvement. Patients with VN were less likely to have renal (p < 0.001), eye (p < 0.001), and gastrointestinal (p = 0.023) involvement.ConclusionsOur study provides comprehensive insights into the prevalence and organ associations of VN in a large, systematically collected AAV cohort. VN is most commonly associated with skin, musculoskeletal, and cardiovascular manifestations. In routine clinical practice, diagnosis of VN is infrequently confirmed by the gold standard of nerve biopsy but rather supported by the clinical setting of active systemic AAV.

Chapter 7 - Peripheral nervous system involvement in vasculitis

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a common and clinically relevant side effect of chemotherapy. Approximately 50% of all leukemia, lymphoma, colorectal- and breast cancer patients are affected.CIPN is induced by neurotoxic chemotherapeutic agents and can manifest with sensory and/or motor deficits. It is associated with significant disability and poor recovery. Common symptoms include pain, altered sensation, reduced or absent reflexes, muscle weakness, reduced balance control and insecure gait.These symptoms not only affect activities of daily living, subsequently reducing patients’ quality of life, they have far more become a decisive limiting factor for medical therapy, causing treatment delays, dose reductions, or even discontinuation of therapy, which can affect the outcome and compromise survival. To date, CIPN cannot be prevented and its occurrence presents a diagnostic dilemma since approved and effective treatment options are lacking.Promising results have recently been achieved with exercise. We have revealed that sensorimotor training (SMT) or whole body vibration (WBV) can reduce the symptoms of CIPN and attenuate motor and sensory deficits. We furthermore detected a tendency that it may also have a preventive effect on the onset of CIPN.MethodsWe are therefore conducting a prospective, multicentre, controlled clinical trial involving 236 oncological patients receiving either oxaliplatin (N = 118) or vinca-alkaloid (N = 118) who are randomized to one of two interventions (SMT or WBV) or a treatment as usual (TAU) group. Primary endpoint is the time to incidence of neurologically confirmed CIPN. Secondary endpoints are pain, maintenance of the functionality of sensory as well as motor nerve fibres as well as the level of physical activity. The baseline assessment is performed prior to the first cycle of chemotherapy. Subsequent follow-up assessments are conducted at 12 weeks, after completion of chemotherapy, and at a 3-month follow-up. Patients who develop CIPN receive an additional assessment at this time point, as it represents the primary endpoint.DiscussionWe hypothesize that SMT and WBV prevent the onset or delay the progression of CIPN, decrease the likelihood of dose reductions or discontinuation of cancer treatment and improve patients’ quality of life.Trial registrationDeutsche Register Klinischer Studien (DRKS00006088, registered 07.05.2014).

Background: Vasculitic neuropathies are an uncommon heterogeneous group of nerve disorders characterized by inflammation of the vasa nervorum, which may be either systemic vasculitic neuropathy (SVN) or non-SVN (NSVN). Settings and Design: This is a retrospective, observational study. Materials and Methods: Nerve biopsy-proven cases of vasculitic neuropathy (VN) from January 2011 to December 2017 were included in the study. Results: Twenty-five percent (40/156) patients had vasculitis on biopsy, 62.5% were male and the mean age was 52.8 ± 14.9 years. The median (interquartile range) duration of symptoms before diagnosis was 75 (345) days. Thirty (75%) patients had NSVN and 10 (25%) patients had SVN. The clinical pattern of peripheral nervous system involvement was as follows: 20 (50%) had polyneuropathy, 13 (32.5%) had mononeuritis multiplex, and 7 (32.5%) had polyradiculoneuropathy. Twenty-three (57.5%) patients received immunomodulatory therapy. Conclusion: VN has a wide spectrum of clinical presentation. High index of suspicion followed by nerve biopsy is needed for diagnosis. Early treatment may improve prognosis in this group of patients.

Mild traumatic brain injuries can lead to long-lasting cognitive and motor deficits, increasing the risk of future behavioral, neurological, and affective disorders. Our study focused on long-term behavioral deficits after repeated injury in which mice received either a single mild CHI (mCHI), a repeated mild CHI (rmCHI) consisting of one impact to each hemisphere separated by 3 days, or a moderate controlled cortical impact injury (CCI). Shams received only anesthesia. Behavioral tests were administered at 1, 3, 5, 7, and 90 days post-injury (dpi). CCI animals showed significant motor and sensory deficits in the early (1–7 dpi) and long-term (90 dpi) stages of testing. Interestingly, sensory and subtle motor deficits in rmCHI animals were found at 90 dpi. Most importantly, depression-like behaviors and social passiveness were observed in rmCHI animals at 90 dpi. These data suggest that mild concussive injuries lead to motor and sensory deficits and affective disorders that are not observed after moderate TBI.

Nonsystemic vasculitic neuropathy: Presentation and long-term outcome from a French cohort of 50 patients