The MUAP changes consisted of short duration, low amplitude and polyphasic MUAPs in the right pronator teres and brachioradialis muscles and polyphasic MUAPs in the right biceps, triceps, and deltoid muscles. Hence, multifocal pyomyositis should be added to the differential diagnostic list of necrotizing myopathy. In addition to the myopathic pattern, this patient had a severe axonal lesion of the median nerve best explained by the severe edema and infiltration of the right forearm. This likely caused a compartment syndrome with ischemic damage to the median nerve. Lastly, the theoretical risk of seeding infection by performing needle EMG on a patient with suspected infection must be considered. There is no evidence base, however, that can be used to quantify such risk, and the question of this theoretical risk is considered unresolved in the
literature.8 The clinical benefit of ascertaining a diagnosis clearly outweighed the this theoretical risk in our patient. REFERENCES 1. Agarwal V, Chauhan S, Gupta RK. Pyomyositis. Neuroimaging Clin N Am 2011;21:975–983. 2. Crum, NF. Bacterial pyomyositis in the United States. Am J Med 2004;117:420–428. 3. Chou H, Teo HE, Dubey N, Peh WC. Tropical pyomyositis and necrotizing fasciitis. Semin Musculoskelet Radiol 2011;15:489–505. 4. Al-Najar M, Obeidat F, Ajlouni J, Mithqal A, Hadidy A. Primary extensive pyomyositis in an immunocompetent patient: case report and literature review. Clin Rheumatol 2010;29:1469–1472. 5. Hassan FO, Shannak A. Primary pyomyositis of the paraspinal muscles: a case report and literature review. Eur Spine J 2008;(Suppl 2):S239–S242. 6. Soler R, Rodriguez E, Aguilera C, Fernandez R. Magnetic resonance imaging of pyomyositis in 43 cases. Eur J Radiol 2000;35:59–64. 7. Wilbourn, AJ. The electrodiagnostic examination with myopathies. J Clin Neurophysiol 1993;10:132–148. 8. El-Shekhlee A, Shapiro BE, Preston DC. Iatrogenic complications and risks of nerve conduction studies and needle electromyography. Muscle Nerve 2003;27:517–526.
SENSORY GANGLIONOPATHY WITH LIVEDOID VASCULOPATHY CONTROLLED BY IMMUNOTHERAPY JAMES J.P. ALIX, PhD, MRCP,1 MARIOS HADJIVASSILIOU, MD, FRCP,2 ROKIAHMAH ALI, MBBS, FRCPath,3 DAVID SLATER, MBChB, FRCPath,3 ANDREW G. MESSENGER, MD, FRCP,4 and D. GANESH RAO, DM, FRCP1 1
Department of Clinical Neurophysiology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, S10 2JF 2 Department of Neurology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, England 3 Department of Histopathology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, England 4 Department of Dermatology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, England Accepted 3 September 2014 ABSTRACT: Introduction: Livedoid vasculopathy is a rare dermatological condition characterized by painful ulceration, atrophic scarring, and persistent livedo reticularis. The pathogenesis is unclear. Methods: We report a patient with biopsyproven livedoid vasculopathy who developed a progressive sensory ganglionopathy with profound sensory ataxia. Serial nerve conduction assessments were undertaken. Results: Combined treatment with prednisolone and mycophenolate mofetil failed to control the ganglionopathy. After addition of rituximab, both symptoms and nerve conduction studies showed stabilization. Conclusions: Sensory ganglionopathies associated with autoimmune and inflammatory conditions may be characterized by a sub-population of “sick” dorsal root ganglia that can be rescued with aggressive immunotherapy. Muscle Nerve 51:296–301, 2015
Abbreviations: CIDP, chronic inflammatory demyelinating polyneuropathy; CMV, cytomegalovirus; EMG, electromyography; IV Ig, intravenous immunoglobulin; PCR, polymerase chain reaction; SNAP, sensory nerve action potential. Keywords: sensory ganglionopathy; immunosuppression; livedoid vasculopathy; nerve conduction studies; neuronopathy Correspondence to: J.J.P. Alix; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 8 September 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24452
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Ganglionopathy in Livedoid Vasculopathy
Livedoid vasculopathy is a rare cutaneous skin disorder characterized by recurrent purpuric lesions that over time progress into painful ulcerations of the lower limbs. After healing has taken place, areas of white, atrophied scars are left, known as atrophie blanche.1 The pathogenesis of the condition is not elucidated fully, and there is controversy over its designation as a vasculopathy or as an inflammatory disease.2 Overall, there seems to be an expanding literature in favor of its classification as a vasculopathy. Neurological involvement in the condition is rare; we describe a patient with livedoid vasculopathy who developed a functionally significant sensory ganglionopathy that responded to combined immunotherapy. CASE REPORT
A 32-year-old woman who worked as an occupational therapist was referred initially to the Rheumatology Clinic with a long-standing history of recurrent swelling and bruising over both ankles, as well as painful ulcers over both feet. Symptoms suggestive of Raynaud phenomenon were also MUSCLE & NERVE
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FIGURE 1. Livedo reticularis was present on the hands (a) and feet (b). Note the crusted ulceration on the sole of the foot (circled).
present in the hands. There was a family history of type-2 diabetes. Examination at the time revealed cold feet with blotchy discoloration and skin thickening over both lower legs. Initial blood tests, including full blood count, routine biochemistry, anti-nuclear antibodies, anti-double stranded DNA antibodies, extractable nuclear antigens, antineutrophil cytoplasmic antibodies, immunoglobulins, and the Schirmer test were unremarkable. A dermatological review raised suspicion of acrocyanosis; cold agglutin, cryoglobulins and lupus anticoagulant were tested and were all normal. She was prescribed nonsteroidal anti-inflammatory drugs and amitriptyline for pain. Symptoms plateaued for the following 4 years, at which point she developed livedo reticularis, first on her hands and then subsequently her feet (Fig. 1). Multiple small necrotic lesions also developed over the lower extremities that healed, leaving the appearance of atrophie blanche. A skin biopsy was undertaken and revealed extensive intravascular occlusion in dermal vessels with mild, focal inflammatory change around blood vessels (Fig. 2): a diagnosis of livedoid vasculopathy was made. There was no definite evidence of acute vasculitis on the skin histology. Repeat blood testing revealed no abnormality of coagulation and no evidence of systemic inflammation. Aspirin was commenced, which helped improve the appearance of her skin, but associated pain remained troublesome. Oral prednisolone was prescribed at a daily dose of 30 mg; this provided symptom relief, and the dose was weaned down gradually over the course of 1 year. Unfortunately, symptoms recurred, and oral steroids were restarted at a dose Ganglionopathy in Livedoid Vasculopathy
of 10–20 mg daily. Unsuccessful attempts to wean the steroids were made over the next 2 years, during which time aspirin was increased to 150 mg (single daily dose). After 2 years, azathioprine was commenced with a view to stopping oral steroids, however, it was discontinued quickly due to poor tolerance. By this time she was beginning to struggle with increasing pain from necrotic and hemorrhagic lesions over her lower legs to such an extent that she was unable to function in a clinical capacity in her job. Mycophenolate mofetil was tried but was stopped after 18 months due to a lack of effect and side effects. A hematologic review suggested anti-coagulants or anti-fibrinolytics; however, both therapies were declined. The patient was then referred to the Neurology clinic with a 1-year history of dysesthesia, which began in the feet and progressed to the hands. She had also begun to experience migraine headaches with aura. Examination revealed difficulty with tandem walking and disturbed sensation over her feet. Reflexes were preserved, and there was no weakness. Repeat blood tests showed no evidence of systemic inflammation, autoimmunity, or gluten sensitivity. Salivary gland imaging demonstrated no evidence of Sjogren syndrome. Nerve conduction studies revealed a slightly attenuated left sural sensory nerve action potential (SNAP) and an absent right fibular nerve SNAP (Fig. 3). Upper limb sensory studies and bilateral motor nerve conduction studies from median, ulnar, fibular, and tibial nerves, including F waves, were all within normal limits (not shown). Electromyography (EMG) of right fibularis tertius and vastus MUSCLE & NERVE
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FIGURE 2. Skin histology (320) demonstrating fibrin thrombi (arrows) within the dermal blood vessels.
medialis muscles was normal. At this time possible diagnoses considered included an early sensory neuropathy or, due to the asymmetry, a ganglionopathy. Over the course of the following year, patchy sensory loss to all modalities over both arms and legs developed. Sensory ataxia worsened and caused difficulty with walking and manipulating objects such as keys. Notably, her handwriting deteriorated. Examination demonstrated pseudoathetosis, a Romberg sign, impaired joint position sense throughout, and impaired vibration sense in the legs. Mycophenolate mofetil was again prescribed, and she tolerated a dose of 1.5 g twice daily. Repeat nerve conduction testing 10 months later demonstrated worsening of SNAPs from the right arm and leg (Fig. 3a; January 2012). Of note, marked decrements in sensory potential amplitudes were observed for the right median and radial nerves. Following this, skin disease remained under control and there were no significant issues with painful cutaneous lesions. However, sensory ataxia continued to worsen; by this time she was walking with a stick and required occupational therapy to facilitate activities of daily living, such as the use of cutlery. Neuro-imaging of the brain and spine was normal with no evidence of T2 signal change in the dorsal cord, which can sometimes be the case in sensory ganglionopathies.3 Whole body positron emission tomography imaging was normal. A decision was made to introduce rituximab, in addition to 1 g twice daily of mycophenolate mofetil and 15 mg daily prednisolone, on the basis of a possible inflammatory component to the underlying livedoid vasculopathy. Nerve conduction studies were repeated and continued to show evidence of disease progression; on this occasion involving the ulnar nerve (Fig. 3a, January 2013 study), however, other studies remained stable. All motor studies remained nor298
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mal with no significant change relative to previous examinations. Blink reflex studies were also normal (not shown). No issues with infection were encountered at this stage. Combination immunotherapy was continued, and symptom progression appeared to halt. Further nerve conduction testing 15 months after starting rituximab demonstrated no evidence of further deterioration of sensory responses; in fact, improvements in SNAP amplitudes were observed (Fig. 3; November 2013). Neurological examination remained stable. Unfortunately she developed diarrhea due to cytomegalovirus (CMV) colitis, most probably secondary to long term immunosuppression. A good response to anti-viral treatment with intravenous gangcyclovir, followed by oral valgangcyclovir was achieved, leading to cessation of gastrointestinal symptoms and a negative CMV polymerase chain reaction (PCR) result. A decision was made to stop mycophenolate but to continue with low dose prednisolone and rituximab, and PCR for CMV was performed before administration of subsequent rituximab infusions. A repeat colonoscopy excluded an underlying inflammatory bowel disorder. Despite stopping mycophenolate, clinical symptoms and sensory nerve conduction abnormalities remained stable. The patient continues to be followed on this treatment. DISCUSSION
Livedoid vasculopathy is a rare skin disorder characterized by painful, recurrent ulceration, and livedo reticularis. Controversy exits as to whether the condition is inflammatory in nature or is an occlusive vasculopathy.2 The primary features on histological examination are fibrin deposition and thrombosis in dermal blood vessels, and the condition has been reported in association with hypercoagulable states such as hyperhomocysteinemia, protein C and S deficiency, and anti-phospholipid syndrome. As a result therapies such as aspirin, warfarin, and pentoxifylline, which reduce blood viscosity, have been used with some success.4–6 Other authors argue that there is also an autoimmune component to the condition. For example, the disorder may be seen in association with systemic connective tissue disorders,1,2 and immune staining has revealed the presence of IgM and complement in vessel walls.7 In the field of occlusive vasculopathies, the best described neurological complication is most probably stroke in the context of systemic lupus erythematosus and the anti-phospholipid syndrome (independent of cerebral vasculitis), Moyamoya disease, and sickle cell anemia.8–10 Sickle cell anemia can also be associated with peripheral nerve injury, typically the mental and mandibular nerves MUSCLE & NERVE
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FIGURE 3. a: Table detailing the neurophysiological findings at various time points. The first examination was undertaken 6 years after the histological diagnosis of livedo reticularis. Note the persistent asymmetry and non–length-dependent pattern of the abnormalities. b,c: Percentage change in median (b) and sural (c) SNAPs. Following addition of rituximab to mycophenolate and prednisolone, improvement and stabilization were observed.
due to occlusion of the vasa nervorum.11 Reports of neurological manifestations in livedoid vasculopathy are few, but a large case series of 70 patients found 9% had evidence of peripheral neuropathy on clinical examination and nerve conduction studies, although detailed data were not provided.4 In all previous reports of livedoid vasculopathy where neurological symptoms have been detailed, the symptoms reported have been entirely sensory.4,5,12,13 Despite this, Toth et al. described occasional positive sharp waves and enlarged motor unit potentials in extensor digitorum brevis and first dorsal interosseous muscles, together with long duration, high amplitude motor unit potentials in abductor pollicis brevis.12 Motor nerve conduction studies were normal, while SNAPs were reduced asymmetrically. The authors concluded that the underlying neurological disorder was mononeuritis multiplex and suggested that occlusion of the vasa nervorum and subsequent nerve infarction were the cause. Of interest, their serial sensory studies demonstrated either outright abnormality or a significant, progressive attenuation of SNAP amplitudes in 6 of 10 nerves tested12; similar results were obtained in our patient before disease control. Lim et al., also described a patient with purely senGanglionopathy in Livedoid Vasculopathy
sory symptoms in the right ulnar distribution and both feet.13 Matching abnormal sensory nerve conduction abnormalities were accompanied by reduced compound muscle action potentials of the fibular and tibial nerves. EMG findings were not reported. Abnormalities similar to those detailed by both Toth et al. and Kim et al. have also been reported in sensory ganglionopathies associated with other conditions, such as Sjogren syndrome and paraneoplastic disease, and can cause diagnostic confusion.14,15 In recognition of this, the thoughtful criteria of Camdessanche et al. score the presence of motor conduction abnormalities in less than 2 lower limb nerves in favor of a ganglionopathy diagnosis.16 In our experience, extensive serial nerve conduction studies are often required to secure the diagnosis. In our patient, the asymmetrical, non–lengthdependent abnormalities in sensory nerves only, together with the clinical findings of patchy sensory loss and sensory ataxia would favor primary sensory ganglionopathy.16 Furthermore, all motor nerve and EMG studies were normal over 3 years of serial testing, and it would seem unlikely that neurovascular thrombosis would affect sensory fibers in isolation. Lastly, nerve infarction and the axonal degeneration that follows would not show MUSCLE & NERVE
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evidence of potential recovery in the time frame of our nerve conduction studies, and immunomodulatory treatments would be ineffective. It would, therefore, seem most likely that, in this instance, the sensory ganglionopathy was driven by an immune mediated/inflammatory pathogenesis. Sensory ganglionopathies are rare in comparison to typical large fiber peripheral neuropathies and are often difficult to diagnose; as a result the disorder is likely to be under-recognized. The etiologies of acquired sensory ganglionopathies are varied and include immune-mediated conditions such as Sjogren syndrome and gluten sensitivity, infective causes such as human immunodeficiency virus, paraneoplastic disease, and some rare hereditary neurological disorders such as Friedreich ataxia.17,18 In many patients no cause is identified. Treatment often has limited success, but reports of improvement following treatment with infliximab or intravenous immunoglobulin (IVIg) have been documented in patients with Sjogren syndrome.19,20 We have also reported improvement of symptoms in patients with gluten-related sensory ganglionopathy following institution of a glutenfree diet.17 In paraneoplastic cases, early treatment of the underlying neoplasm tends to improve neurological outcome,21 although a good response to a combination of immunoglobulins, cyclophosphamide, and methylprednisolone has been described.22 Use of rituximab for sensory ganglionopathy has been reported with good effect in anti-Hu associated paraneoplastic disease23 but this remains an otherwise unexplored area. In the context of neuropathy, rituximab has been used in IgM antimyelin associated glycoprotein neuropathies,24–26 multi-focal motor neuropathy,27,28 and chronic inflammatory demyelinating polyneuropathy (CIDP).29 Reports differ as to the degree of improvement, and it is interesting to note recent work that suggests this may be due, at least in part, to leukocyte IgG receptor polymorphisms.30 Systematic analyses of immunomodulatory treatments for CIDP indicate the need for adequately powered randomized controlled studies to fully assess the efficacy of such therapeutics.31,32 In the combined context of skin disease and neuropathy, rituximab has been used successfully in cryoglobulinemic vasculitis.33–35 It is also noteworthy that a recent multi-center analysis of the effect of rituximab on peripheral nervous system involvement in primary Sj€ ogren syndrome included a patient with a purely sensory polyneuropathy and ataxia who responded to treatment.36 The proponents of an autoimmune etiology for livedoid vasculopathy point to the success of immunomodulatry therapies such as IVIg, steroids, aza300
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thioprine, and cyclophosphamide as evidence of an underlying autoimmune process.4,37 Here, the mild electrophysiological improvement and clinical stabilization followed addition of rituximab to mycophenolate mofetil and prednisolone. Skin disease was under control by this time, but rituximab has been used successfully for classical cutaneous livedoid vasculopathy in which high dose steroids, azathioprine, and methotrexate have all failed.38,39 The success of rituximab in these cases and our patient suggest that inflammatory pathways may play a role in livedoid vasculopathy, at least in some individuals. While such strong immunomodulatory treatments have inherent risks in patients with aggressive and disabling disease, the risk:benefit ratio may be tipped toward intervention. The mild improvement in some nerve conduction parameters observed in our patient is beyond that which might be expected due to technical variability (Fig. 3). These observations are of interest and raise several questions about the nature of the electrophysiological changes observed in ganglionopathy. Given the permanent deficits experienced by our patient and others reported in the literature, it is possible that the inflammatory milieu to which the dorsal root ganglia are exposed causes significant cell death, as has been reported in pathological studies of ganglionopathies.40–42 Improvement could rely theoretically on rescue of a subpopulation of “sick” dorsal root ganglia that are unable to support the distal axon. In such circumstances, axonal transport and energy production would be impaired leading to conduction failure in the segments tested with routine nerve conduction studies. Metabolic derangements in axons secondary to inflammation have also been reported and can result in conduction block.43,44 Theoretically, a multi-focal, immune mediated, reversible conduction block could have occurred in the distal axon, as is proposed to occur in acute ataxic sensory neuropathies and can show rapid resolution of neurophysiological abnormalities.45 Local changes in skin tissues might also influence results, however, in our patient, nerve conduction results continued to worsen after the skin disease had been brought under control. In summary, we report a patient with profound sensory ganglionopathy in the context of livedoid vasculopathy. Although no evidence of systemic autoimmunity was found, the patient’s skin disease and neurological symptoms were stabilized by combination immunotherapy. While reports of successful treatment for sensory ganglionopathies are limited, we propose that, at least for those associated with autoimmune and inflammatory conditions, aggressive intervention might save a subpopulation of “sick” ganglia, or relieve MUSCLE & NERVE
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inflammation-driven conduction block. This may in turn lead to symptom stabilization and perhaps even improvement. We would, therefore, advocate early consideration of such treatments in suitable patients. REFERENCES 1. Hairston BR, Davis MD, Pittelkow MR, Ahmed I. Livedoid vasculopathy: further evidence for procoagulant pathogenesis. Arch Dermatol 2006;142:1413–1418. 2. Khenifer S, Thomas L, Balme B, Dalle S. Livedoid vasculopathy: thrombotic or inflammatory disease? Clin Exp Dermatol 2010;35: 693–698. 3. Lauria G, Pareyson D, Grisoli M, Sghirlanzoni A. Clinical and magnetic resonance imaging findings in chronic sensory ganglionopathies. Ann Neurol 2000;47:104–109. 4. Gan EY, Tang MB, Tan SH, Chua SH, Tan AW. A ten-year retrospective study on livedo vasculopathy in Asian patients. Ann Acad Med Singapore 2012;41:400–406. 5. Osada S, Kimura Y, Kawana S. Case of livedoid vasculopathy with peripheral neuropathy successfully treated with low-dose warfarin. J Dermatol 2010;37:98–101. 6. Alavi A, Hafner J, Dutz JP, Mayer D, Sibbald RG, Criado PR, et al. Livedoid vasculopathy: an in-depth analysis using a modified Delphi approach. J Am Acad Dermatol 2013;69:1033–1042.e1031. 7. Schroeter AL, Diaz-Perez JL, Winkelmann RK, Jordan RE. Livedo vasculitis (the vasculitis of atrophie blanche). Immunohistopathologic study. Arch Dermatol 1975;111:188–193. 8. Webb J, Kwiatkowski JL. Stroke in patients with sickle cell disease. Expert Rev Hematol 2013;6:301–316. 9. Kassim AA, DeBaun MR. Sickle cell disease, vasculopathy, and therapeutics. Annu Rev Med 2013;64:451–466. 10. Shah NM, Khamashta MA, Atsumi T, Hughes GR. Outcome of patients with anticardiolipin antibodies: a 10 year follow-up of 52 patients. Lupus 1998;7:3–6. 11. Ballas SK, Darbari DS. Neuropathy, neuropathic pain, and sickle cell disease. Am J Hematol 2013;88:927–929. 12. Toth C, Trotter M, Clark A, Zochodne D. Mononeuropathy multiplex in association with livedoid vasculitis. Muscle Nerve 2003;28: 634–639. 13. Kim JE, Park SY, Sinn DI, Kim SM, Hong YH, Park KS, et al. Ischemic neuropathy associated with livedoid vasculitis. J Clin Neurol 2011;7:233–236. 14. Griffin JW, Cornblath DR, Alexander E, Campbell J, Low PA, Bird S, et al. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sj€ ogren’s syndrome. Ann Neurol 1990;27:304–315. 15. Lauria G, Pareyson D, Sghirlanzoni A. Neurophysiological diagnosis of acquired sensory ganglionopathies. Eur Neurol 2003;50:146–152. 16. Camdessanche JP, Jousserand G, Ferraud K, Vial C, Petiot P, Honnorat J, et al. The pattern and diagnostic criteria of sensory neuronopathy: a case-control study. Brain 2009;132(Pt 7):1723–1733. 17. Hadjivassiliou M, Rao DG, Wharton SB, Sanders DS, Gr€ unewald RA, Davies-Jones AG. Sensory ganglionopathy due to gluten sensitivity. Neurology 2010;75:1003–1008. 18. Sghirlanzoni A, Pareyson D, Lauria G. Sensory neuron diseases. Lancet Neurol 2005;4:349–361. 19. Takahashi Y, Takata T, Hoshino M, Sakurai M, Kanazawa I. Benefit of IVIG for long-standing ataxic sensory neuronopathy with Sj€ ogren’s syndrome. IV immunoglobulin. Neurology 2003;60:503–505. 20. Caroyer JM, Manto MU, Steinfeld SD. Severe sensory neuronopathy responsive to infliximab in primary Sj€ ogren’s syndrome. Neurology 2002;59:1113–1114. 21. Graus F, Keime-Guibert F, Re~ ne R, Benyahia B, Ribalta T, Ascaso C, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124(Pt 6):1138–1148. 22. Keime-Guibert F, Graus F, Fleury A, Ren e R, Honnorat J, Broet P, et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 2000;68:479–482. 23. Coret F, Bosca I, Fratalia L, Perez-Griera J, Pascual A, Casanova B. Long-lasting remission after rituximab treatment in a case of anti-Hu-
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literature.8 The clinical benefit of ascertaining a diagnosis clearly outweighed the this theoretical risk in our patient. REFERENCES 1. Agarwal V, Chauhan S, Gupta RK. Pyomyositis. Neuroimaging Clin N Am 2011;21:975–983. 2. Crum, NF. Bacterial pyomyositis in the United States. Am J Med 2004;117:420–428. 3. Chou H, Teo HE, Dubey N, Peh WC. Tropical pyomyositis and necrotizing fasciitis. Semin Musculoskelet Radiol 2011;15:489–505. 4. Al-Najar M, Obeidat F, Ajlouni J, Mithqal A, Hadidy A. Primary extensive pyomyositis in an immunocompetent patient: case report and literature review. Clin Rheumatol 2010;29:1469–1472. 5. Hassan FO, Shannak A. Primary pyomyositis of the paraspinal muscles: a case report and literature review. Eur Spine J 2008;(Suppl 2):S239–S242. 6. Soler R, Rodriguez E, Aguilera C, Fernandez R. Magnetic resonance imaging of pyomyositis in 43 cases. Eur J Radiol 2000;35:59–64. 7. Wilbourn, AJ. The electrodiagnostic examination with myopathies. J Clin Neurophysiol 1993;10:132–148. 8. El-Shekhlee A, Shapiro BE, Preston DC. Iatrogenic complications and risks of nerve conduction studies and needle electromyography. Muscle Nerve 2003;27:517–526.
SENSORY GANGLIONOPATHY WITH LIVEDOID VASCULOPATHY CONTROLLED BY IMMUNOTHERAPY JAMES J.P. ALIX, PhD, MRCP,1 MARIOS HADJIVASSILIOU, MD, FRCP,2 ROKIAHMAH ALI, MBBS, FRCPath,3 DAVID SLATER, MBChB, FRCPath,3 ANDREW G. MESSENGER, MD, FRCP,4 and D. GANESH RAO, DM, FRCP1 1
Department of Clinical Neurophysiology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, S10 2JF 2 Department of Neurology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, England 3 Department of Histopathology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, England 4 Department of Dermatology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, England Accepted 3 September 2014 ABSTRACT: Introduction: Livedoid vasculopathy is a rare dermatological condition characterized by painful ulceration, atrophic scarring, and persistent livedo reticularis. The pathogenesis is unclear. Methods: We report a patient with biopsyproven livedoid vasculopathy who developed a progressive sensory ganglionopathy with profound sensory ataxia. Serial nerve conduction assessments were undertaken. Results: Combined treatment with prednisolone and mycophenolate mofetil failed to control the ganglionopathy. After addition of rituximab, both symptoms and nerve conduction studies showed stabilization. Conclusions: Sensory ganglionopathies associated with autoimmune and inflammatory conditions may be characterized by a sub-population of “sick” dorsal root ganglia that can be rescued with aggressive immunotherapy. Muscle Nerve 51:296–301, 2015
Abbreviations: CIDP, chronic inflammatory demyelinating polyneuropathy; CMV, cytomegalovirus; EMG, electromyography; IV Ig, intravenous immunoglobulin; PCR, polymerase chain reaction; SNAP, sensory nerve action potential. Keywords: sensory ganglionopathy; immunosuppression; livedoid vasculopathy; nerve conduction studies; neuronopathy Correspondence to: J.J.P. Alix; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 8 September 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24452
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Ganglionopathy in Livedoid Vasculopathy
Livedoid vasculopathy is a rare cutaneous skin disorder characterized by recurrent purpuric lesions that over time progress into painful ulcerations of the lower limbs. After healing has taken place, areas of white, atrophied scars are left, known as atrophie blanche.1 The pathogenesis of the condition is not elucidated fully, and there is controversy over its designation as a vasculopathy or as an inflammatory disease.2 Overall, there seems to be an expanding literature in favor of its classification as a vasculopathy. Neurological involvement in the condition is rare; we describe a patient with livedoid vasculopathy who developed a functionally significant sensory ganglionopathy that responded to combined immunotherapy. CASE REPORT
A 32-year-old woman who worked as an occupational therapist was referred initially to the Rheumatology Clinic with a long-standing history of recurrent swelling and bruising over both ankles, as well as painful ulcers over both feet. Symptoms suggestive of Raynaud phenomenon were also MUSCLE & NERVE
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FIGURE 1. Livedo reticularis was present on the hands (a) and feet (b). Note the crusted ulceration on the sole of the foot (circled).
present in the hands. There was a family history of type-2 diabetes. Examination at the time revealed cold feet with blotchy discoloration and skin thickening over both lower legs. Initial blood tests, including full blood count, routine biochemistry, anti-nuclear antibodies, anti-double stranded DNA antibodies, extractable nuclear antigens, antineutrophil cytoplasmic antibodies, immunoglobulins, and the Schirmer test were unremarkable. A dermatological review raised suspicion of acrocyanosis; cold agglutin, cryoglobulins and lupus anticoagulant were tested and were all normal. She was prescribed nonsteroidal anti-inflammatory drugs and amitriptyline for pain. Symptoms plateaued for the following 4 years, at which point she developed livedo reticularis, first on her hands and then subsequently her feet (Fig. 1). Multiple small necrotic lesions also developed over the lower extremities that healed, leaving the appearance of atrophie blanche. A skin biopsy was undertaken and revealed extensive intravascular occlusion in dermal vessels with mild, focal inflammatory change around blood vessels (Fig. 2): a diagnosis of livedoid vasculopathy was made. There was no definite evidence of acute vasculitis on the skin histology. Repeat blood testing revealed no abnormality of coagulation and no evidence of systemic inflammation. Aspirin was commenced, which helped improve the appearance of her skin, but associated pain remained troublesome. Oral prednisolone was prescribed at a daily dose of 30 mg; this provided symptom relief, and the dose was weaned down gradually over the course of 1 year. Unfortunately, symptoms recurred, and oral steroids were restarted at a dose Ganglionopathy in Livedoid Vasculopathy
of 10–20 mg daily. Unsuccessful attempts to wean the steroids were made over the next 2 years, during which time aspirin was increased to 150 mg (single daily dose). After 2 years, azathioprine was commenced with a view to stopping oral steroids, however, it was discontinued quickly due to poor tolerance. By this time she was beginning to struggle with increasing pain from necrotic and hemorrhagic lesions over her lower legs to such an extent that she was unable to function in a clinical capacity in her job. Mycophenolate mofetil was tried but was stopped after 18 months due to a lack of effect and side effects. A hematologic review suggested anti-coagulants or anti-fibrinolytics; however, both therapies were declined. The patient was then referred to the Neurology clinic with a 1-year history of dysesthesia, which began in the feet and progressed to the hands. She had also begun to experience migraine headaches with aura. Examination revealed difficulty with tandem walking and disturbed sensation over her feet. Reflexes were preserved, and there was no weakness. Repeat blood tests showed no evidence of systemic inflammation, autoimmunity, or gluten sensitivity. Salivary gland imaging demonstrated no evidence of Sjogren syndrome. Nerve conduction studies revealed a slightly attenuated left sural sensory nerve action potential (SNAP) and an absent right fibular nerve SNAP (Fig. 3). Upper limb sensory studies and bilateral motor nerve conduction studies from median, ulnar, fibular, and tibial nerves, including F waves, were all within normal limits (not shown). Electromyography (EMG) of right fibularis tertius and vastus MUSCLE & NERVE
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FIGURE 2. Skin histology (320) demonstrating fibrin thrombi (arrows) within the dermal blood vessels.
medialis muscles was normal. At this time possible diagnoses considered included an early sensory neuropathy or, due to the asymmetry, a ganglionopathy. Over the course of the following year, patchy sensory loss to all modalities over both arms and legs developed. Sensory ataxia worsened and caused difficulty with walking and manipulating objects such as keys. Notably, her handwriting deteriorated. Examination demonstrated pseudoathetosis, a Romberg sign, impaired joint position sense throughout, and impaired vibration sense in the legs. Mycophenolate mofetil was again prescribed, and she tolerated a dose of 1.5 g twice daily. Repeat nerve conduction testing 10 months later demonstrated worsening of SNAPs from the right arm and leg (Fig. 3a; January 2012). Of note, marked decrements in sensory potential amplitudes were observed for the right median and radial nerves. Following this, skin disease remained under control and there were no significant issues with painful cutaneous lesions. However, sensory ataxia continued to worsen; by this time she was walking with a stick and required occupational therapy to facilitate activities of daily living, such as the use of cutlery. Neuro-imaging of the brain and spine was normal with no evidence of T2 signal change in the dorsal cord, which can sometimes be the case in sensory ganglionopathies.3 Whole body positron emission tomography imaging was normal. A decision was made to introduce rituximab, in addition to 1 g twice daily of mycophenolate mofetil and 15 mg daily prednisolone, on the basis of a possible inflammatory component to the underlying livedoid vasculopathy. Nerve conduction studies were repeated and continued to show evidence of disease progression; on this occasion involving the ulnar nerve (Fig. 3a, January 2013 study), however, other studies remained stable. All motor studies remained nor298
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mal with no significant change relative to previous examinations. Blink reflex studies were also normal (not shown). No issues with infection were encountered at this stage. Combination immunotherapy was continued, and symptom progression appeared to halt. Further nerve conduction testing 15 months after starting rituximab demonstrated no evidence of further deterioration of sensory responses; in fact, improvements in SNAP amplitudes were observed (Fig. 3; November 2013). Neurological examination remained stable. Unfortunately she developed diarrhea due to cytomegalovirus (CMV) colitis, most probably secondary to long term immunosuppression. A good response to anti-viral treatment with intravenous gangcyclovir, followed by oral valgangcyclovir was achieved, leading to cessation of gastrointestinal symptoms and a negative CMV polymerase chain reaction (PCR) result. A decision was made to stop mycophenolate but to continue with low dose prednisolone and rituximab, and PCR for CMV was performed before administration of subsequent rituximab infusions. A repeat colonoscopy excluded an underlying inflammatory bowel disorder. Despite stopping mycophenolate, clinical symptoms and sensory nerve conduction abnormalities remained stable. The patient continues to be followed on this treatment. DISCUSSION
Livedoid vasculopathy is a rare skin disorder characterized by painful, recurrent ulceration, and livedo reticularis. Controversy exits as to whether the condition is inflammatory in nature or is an occlusive vasculopathy.2 The primary features on histological examination are fibrin deposition and thrombosis in dermal blood vessels, and the condition has been reported in association with hypercoagulable states such as hyperhomocysteinemia, protein C and S deficiency, and anti-phospholipid syndrome. As a result therapies such as aspirin, warfarin, and pentoxifylline, which reduce blood viscosity, have been used with some success.4–6 Other authors argue that there is also an autoimmune component to the condition. For example, the disorder may be seen in association with systemic connective tissue disorders,1,2 and immune staining has revealed the presence of IgM and complement in vessel walls.7 In the field of occlusive vasculopathies, the best described neurological complication is most probably stroke in the context of systemic lupus erythematosus and the anti-phospholipid syndrome (independent of cerebral vasculitis), Moyamoya disease, and sickle cell anemia.8–10 Sickle cell anemia can also be associated with peripheral nerve injury, typically the mental and mandibular nerves MUSCLE & NERVE
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FIGURE 3. a: Table detailing the neurophysiological findings at various time points. The first examination was undertaken 6 years after the histological diagnosis of livedo reticularis. Note the persistent asymmetry and non–length-dependent pattern of the abnormalities. b,c: Percentage change in median (b) and sural (c) SNAPs. Following addition of rituximab to mycophenolate and prednisolone, improvement and stabilization were observed.
due to occlusion of the vasa nervorum.11 Reports of neurological manifestations in livedoid vasculopathy are few, but a large case series of 70 patients found 9% had evidence of peripheral neuropathy on clinical examination and nerve conduction studies, although detailed data were not provided.4 In all previous reports of livedoid vasculopathy where neurological symptoms have been detailed, the symptoms reported have been entirely sensory.4,5,12,13 Despite this, Toth et al. described occasional positive sharp waves and enlarged motor unit potentials in extensor digitorum brevis and first dorsal interosseous muscles, together with long duration, high amplitude motor unit potentials in abductor pollicis brevis.12 Motor nerve conduction studies were normal, while SNAPs were reduced asymmetrically. The authors concluded that the underlying neurological disorder was mononeuritis multiplex and suggested that occlusion of the vasa nervorum and subsequent nerve infarction were the cause. Of interest, their serial sensory studies demonstrated either outright abnormality or a significant, progressive attenuation of SNAP amplitudes in 6 of 10 nerves tested12; similar results were obtained in our patient before disease control. Lim et al., also described a patient with purely senGanglionopathy in Livedoid Vasculopathy
sory symptoms in the right ulnar distribution and both feet.13 Matching abnormal sensory nerve conduction abnormalities were accompanied by reduced compound muscle action potentials of the fibular and tibial nerves. EMG findings were not reported. Abnormalities similar to those detailed by both Toth et al. and Kim et al. have also been reported in sensory ganglionopathies associated with other conditions, such as Sjogren syndrome and paraneoplastic disease, and can cause diagnostic confusion.14,15 In recognition of this, the thoughtful criteria of Camdessanche et al. score the presence of motor conduction abnormalities in less than 2 lower limb nerves in favor of a ganglionopathy diagnosis.16 In our experience, extensive serial nerve conduction studies are often required to secure the diagnosis. In our patient, the asymmetrical, non–lengthdependent abnormalities in sensory nerves only, together with the clinical findings of patchy sensory loss and sensory ataxia would favor primary sensory ganglionopathy.16 Furthermore, all motor nerve and EMG studies were normal over 3 years of serial testing, and it would seem unlikely that neurovascular thrombosis would affect sensory fibers in isolation. Lastly, nerve infarction and the axonal degeneration that follows would not show MUSCLE & NERVE
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evidence of potential recovery in the time frame of our nerve conduction studies, and immunomodulatory treatments would be ineffective. It would, therefore, seem most likely that, in this instance, the sensory ganglionopathy was driven by an immune mediated/inflammatory pathogenesis. Sensory ganglionopathies are rare in comparison to typical large fiber peripheral neuropathies and are often difficult to diagnose; as a result the disorder is likely to be under-recognized. The etiologies of acquired sensory ganglionopathies are varied and include immune-mediated conditions such as Sjogren syndrome and gluten sensitivity, infective causes such as human immunodeficiency virus, paraneoplastic disease, and some rare hereditary neurological disorders such as Friedreich ataxia.17,18 In many patients no cause is identified. Treatment often has limited success, but reports of improvement following treatment with infliximab or intravenous immunoglobulin (IVIg) have been documented in patients with Sjogren syndrome.19,20 We have also reported improvement of symptoms in patients with gluten-related sensory ganglionopathy following institution of a glutenfree diet.17 In paraneoplastic cases, early treatment of the underlying neoplasm tends to improve neurological outcome,21 although a good response to a combination of immunoglobulins, cyclophosphamide, and methylprednisolone has been described.22 Use of rituximab for sensory ganglionopathy has been reported with good effect in anti-Hu associated paraneoplastic disease23 but this remains an otherwise unexplored area. In the context of neuropathy, rituximab has been used in IgM antimyelin associated glycoprotein neuropathies,24–26 multi-focal motor neuropathy,27,28 and chronic inflammatory demyelinating polyneuropathy (CIDP).29 Reports differ as to the degree of improvement, and it is interesting to note recent work that suggests this may be due, at least in part, to leukocyte IgG receptor polymorphisms.30 Systematic analyses of immunomodulatory treatments for CIDP indicate the need for adequately powered randomized controlled studies to fully assess the efficacy of such therapeutics.31,32 In the combined context of skin disease and neuropathy, rituximab has been used successfully in cryoglobulinemic vasculitis.33–35 It is also noteworthy that a recent multi-center analysis of the effect of rituximab on peripheral nervous system involvement in primary Sj€ ogren syndrome included a patient with a purely sensory polyneuropathy and ataxia who responded to treatment.36 The proponents of an autoimmune etiology for livedoid vasculopathy point to the success of immunomodulatry therapies such as IVIg, steroids, aza300
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thioprine, and cyclophosphamide as evidence of an underlying autoimmune process.4,37 Here, the mild electrophysiological improvement and clinical stabilization followed addition of rituximab to mycophenolate mofetil and prednisolone. Skin disease was under control by this time, but rituximab has been used successfully for classical cutaneous livedoid vasculopathy in which high dose steroids, azathioprine, and methotrexate have all failed.38,39 The success of rituximab in these cases and our patient suggest that inflammatory pathways may play a role in livedoid vasculopathy, at least in some individuals. While such strong immunomodulatory treatments have inherent risks in patients with aggressive and disabling disease, the risk:benefit ratio may be tipped toward intervention. The mild improvement in some nerve conduction parameters observed in our patient is beyond that which might be expected due to technical variability (Fig. 3). These observations are of interest and raise several questions about the nature of the electrophysiological changes observed in ganglionopathy. Given the permanent deficits experienced by our patient and others reported in the literature, it is possible that the inflammatory milieu to which the dorsal root ganglia are exposed causes significant cell death, as has been reported in pathological studies of ganglionopathies.40–42 Improvement could rely theoretically on rescue of a subpopulation of “sick” dorsal root ganglia that are unable to support the distal axon. In such circumstances, axonal transport and energy production would be impaired leading to conduction failure in the segments tested with routine nerve conduction studies. Metabolic derangements in axons secondary to inflammation have also been reported and can result in conduction block.43,44 Theoretically, a multi-focal, immune mediated, reversible conduction block could have occurred in the distal axon, as is proposed to occur in acute ataxic sensory neuropathies and can show rapid resolution of neurophysiological abnormalities.45 Local changes in skin tissues might also influence results, however, in our patient, nerve conduction results continued to worsen after the skin disease had been brought under control. In summary, we report a patient with profound sensory ganglionopathy in the context of livedoid vasculopathy. Although no evidence of systemic autoimmunity was found, the patient’s skin disease and neurological symptoms were stabilized by combination immunotherapy. While reports of successful treatment for sensory ganglionopathies are limited, we propose that, at least for those associated with autoimmune and inflammatory conditions, aggressive intervention might save a subpopulation of “sick” ganglia, or relieve MUSCLE & NERVE
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inflammation-driven conduction block. This may in turn lead to symptom stabilization and perhaps even improvement. We would, therefore, advocate early consideration of such treatments in suitable patients. REFERENCES 1. Hairston BR, Davis MD, Pittelkow MR, Ahmed I. Livedoid vasculopathy: further evidence for procoagulant pathogenesis. Arch Dermatol 2006;142:1413–1418. 2. Khenifer S, Thomas L, Balme B, Dalle S. Livedoid vasculopathy: thrombotic or inflammatory disease? Clin Exp Dermatol 2010;35: 693–698. 3. Lauria G, Pareyson D, Grisoli M, Sghirlanzoni A. Clinical and magnetic resonance imaging findings in chronic sensory ganglionopathies. Ann Neurol 2000;47:104–109. 4. Gan EY, Tang MB, Tan SH, Chua SH, Tan AW. A ten-year retrospective study on livedo vasculopathy in Asian patients. Ann Acad Med Singapore 2012;41:400–406. 5. Osada S, Kimura Y, Kawana S. Case of livedoid vasculopathy with peripheral neuropathy successfully treated with low-dose warfarin. J Dermatol 2010;37:98–101. 6. Alavi A, Hafner J, Dutz JP, Mayer D, Sibbald RG, Criado PR, et al. Livedoid vasculopathy: an in-depth analysis using a modified Delphi approach. J Am Acad Dermatol 2013;69:1033–1042.e1031. 7. Schroeter AL, Diaz-Perez JL, Winkelmann RK, Jordan RE. Livedo vasculitis (the vasculitis of atrophie blanche). Immunohistopathologic study. Arch Dermatol 1975;111:188–193. 8. Webb J, Kwiatkowski JL. Stroke in patients with sickle cell disease. Expert Rev Hematol 2013;6:301–316. 9. Kassim AA, DeBaun MR. Sickle cell disease, vasculopathy, and therapeutics. Annu Rev Med 2013;64:451–466. 10. Shah NM, Khamashta MA, Atsumi T, Hughes GR. Outcome of patients with anticardiolipin antibodies: a 10 year follow-up of 52 patients. Lupus 1998;7:3–6. 11. Ballas SK, Darbari DS. Neuropathy, neuropathic pain, and sickle cell disease. Am J Hematol 2013;88:927–929. 12. Toth C, Trotter M, Clark A, Zochodne D. Mononeuropathy multiplex in association with livedoid vasculitis. Muscle Nerve 2003;28: 634–639. 13. Kim JE, Park SY, Sinn DI, Kim SM, Hong YH, Park KS, et al. Ischemic neuropathy associated with livedoid vasculitis. J Clin Neurol 2011;7:233–236. 14. Griffin JW, Cornblath DR, Alexander E, Campbell J, Low PA, Bird S, et al. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sj€ ogren’s syndrome. Ann Neurol 1990;27:304–315. 15. Lauria G, Pareyson D, Sghirlanzoni A. Neurophysiological diagnosis of acquired sensory ganglionopathies. Eur Neurol 2003;50:146–152. 16. Camdessanche JP, Jousserand G, Ferraud K, Vial C, Petiot P, Honnorat J, et al. The pattern and diagnostic criteria of sensory neuronopathy: a case-control study. Brain 2009;132(Pt 7):1723–1733. 17. Hadjivassiliou M, Rao DG, Wharton SB, Sanders DS, Gr€ unewald RA, Davies-Jones AG. Sensory ganglionopathy due to gluten sensitivity. Neurology 2010;75:1003–1008. 18. Sghirlanzoni A, Pareyson D, Lauria G. Sensory neuron diseases. Lancet Neurol 2005;4:349–361. 19. Takahashi Y, Takata T, Hoshino M, Sakurai M, Kanazawa I. Benefit of IVIG for long-standing ataxic sensory neuronopathy with Sj€ ogren’s syndrome. IV immunoglobulin. Neurology 2003;60:503–505. 20. Caroyer JM, Manto MU, Steinfeld SD. Severe sensory neuronopathy responsive to infliximab in primary Sj€ ogren’s syndrome. Neurology 2002;59:1113–1114. 21. Graus F, Keime-Guibert F, Re~ ne R, Benyahia B, Ribalta T, Ascaso C, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124(Pt 6):1138–1148. 22. Keime-Guibert F, Graus F, Fleury A, Ren e R, Honnorat J, Broet P, et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 2000;68:479–482. 23. Coret F, Bosca I, Fratalia L, Perez-Griera J, Pascual A, Casanova B. Long-lasting remission after rituximab treatment in a case of anti-Hu-
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