Journal of the Neurological Sciences 351 (2015) 214–215
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Mononeuritis multiplex associated with primary livedoid vasculopathy: Neuropathological evidence of ischemic nerve damage Keywords: Neuropathology Neuropathy Vasculitis Trombophilia
Mononeuritis multiplex (MM) is a pattern of peripheral neuropathy characterized by multifocal damage to at least two different nerves. It is associated with several distinct systemic disorders such as diabetes, connective tissue disease, vasculitis, amyloidosis, cryoglobulinemia, sarcoidosis, neoplasm and infections. Nerve biopsy is in most cases useful in demonstrating the aetiology of nerve damage and establishing a causal link with the underlying systemic disorder. Conversely, in some forms of MM the pathophysiology is controversial, especially in those cases associated with uncommon types of organ-specific diseases. Here we report the findings of comprehensive clinical, neurophysiological and neuropathological investigations carried out on a case of MM associated with livedoid vasculopathy (LV). LV is a rare dermatological disorder that affects mainly young women and is characterized by a painful cutaneous purpuric rash affecting lower limbs and specifically ankles and dorsum of the feet. Lesions have a chronic, relapsing/remitting course, evolving to ulcerations and atrophic white scars. The diagnosis relies on clinical features and skin biopsy. Pathological findings include hyalinotic thrombosis and fibrin deposition within dermal vessel walls and scattered perivascular lymphocytic infiltration without overt signs of vasculitis. Although LV was formerly considered a vasculitic disorder, recent advances have suggested that the primary cause of ischemic damage and cutaneous manifestations is more likely a primary hypercoagulation state rather than inflammation [1]. LV can be a primary disorder or a secondary manifestation of inflammatory and hypercoagulation disorders [3]. Peripheral neuropathy associated with primary LV has been previously described in only five cases [4,6–9], of which only three provided nerve pathology data [4,7,8]. 1. Case report A 45-year-old woman presented to our attention complaining of subacute weakness and paresthesias in upper and lower limbs. She had suffered since the age of 36 years of recurrent skin lesions confined to distal lower limbs. These consisted in multiple purpuric patches which evolved into painful ulcerations and finally into fibrosclerotic white scars in few weeks. Treatment with topical/systemic corticosteroids had been unsuccessful. At age 44, during a new recurrence of painful skin ulcerations, she started complaining of tingling sensation and numbness in her right foot and left hand. The remainder
http://dx.doi.org/10.1016/j.jns.2015.03.013 0022-510X/© 2015 Elsevier B.V. All rights reserved.
of her personal and family histories was unremarkable. On admission, eight months after neuropathic symptoms onset, neurological examination showed weakness in left hand ulnar-innervated muscles and sensory loss in the territories of right median and right sural nerves. Routine blood tests, comprehensive screening for infectious, autoimmune, paraneoplastic and metabolic disorders resulted normal. An extensive laboratory screening for thrombophilia also resulted normal. This included the assessment of deficiencies of natural anticoagulants (antithrombin, proteins C and S), prothrombin mutation, factor V mutation (Leiden), hyperhomocysteinemia, plasma levels of coagulation factors (VIII, IX and XI) and lipoprotein(a) levels. Neurophysiological investigation (NCS and EMG) showed axonal damage limited to motor fibers of the left distal ulnar nerve and sensory fibers of right median and right sural nerves (left ulnar nerve cMAP amplitude: 4.7 mV; wrist–elbow CV: 55 m/s; right median nerve SAP amplitude: 7.6 μV; Wrist–digit III CV: 50.2 m/s; right sural nerve SAP: absent). Chronic neurogenic findings with ongoing denervation were detected in left ulnar innervated muscles. This supported a diagnosis of MM. At this stage sural nerve biopsy was performed. Microscopic pathological examination disclosed an asymmetric loss of myelinated fibers both within and between fascicles. A high proportion of fibers at different stages of Wallerian degeneration were observed, as well as clusters of regenerating small myelinated fibers. Some pleomorphic mononuclear cell infiltrates were observed in the endoneurium, perineurium and epineurium. In the epineurium, lymphocytic infiltrates, consisting of small to medium-size lymphocytes, were predominantly distributed in the perivascular spaces, without signs of obvious vasculitis. Immunophenotyping showed almost all lymphocytes to be of T-cell lineage (CD3+) and few scattered B cells (CD20+). Many macrophages (CD68 +) were detected around endo-and epineurial vessels and scattered in the endoneurium (Fig. 1A, B, C, D). The findings were interpreted as the product of ischemic nerve damage, in the absence of clear signs of vasculitis. Skin biopsy showed the typical features of LV (Fig. 1E, F) as described above. Notably, also deep subcutaneous tissues showed the same typical findings, without pathological evidence of vasculitis, further excluding an underlying yet not defined subtle primary inflammatory process [2]. Finally, cerebral MRI, lower limb venous colour Doppler, PET–CT and CSF examinations, performed to exclude neurolymphomatosis, were normal. The patient was then started on antithrombotic therapy (acetylsalicylate 100 mg). After a follow-up period of two-years no new active skin lesions appeared; neurological symptoms had considerably improved and NCS were unchanged.
2. Discussion We report a rare case of MM associated with LV. The absence of any detectable systemic thrombophylic alteration and the exclusion of any underlying systemic immune-mediated or inflammatory disorder, by means of extensive clinical workup, support the classification of our case as primary LV. Both skin and nerve pathological findings were strongly suggestive of an ischemic pathogenetic mechanism, supporting
Letter to the Editor
215
Fig. 1. Sural nerve biopsy. (A) Asymmetrical involvement of nerve fascicles (transverse semithin sections, toluidine blue ×200); (B) Severe loss of myelinated fibers and some axonal degeneration (transverse semithin sections, toluidine blue ×500); (C) epineurial perivascular mononuclear cell infiltrates (paraffin section, hematoxylin–eosin staining, ×200); (D) T-lymphocytes in epineurial infiltrate (paraffin section, ICH with anti-CD3 antibody, ×500); Skin lesion biopsy. (E) epidermal necrosis, hyalinized dermal blood vessels with intravascular thrombosis and mild perivacular inflammatory infiltrate (paraffin section, hematoxylin–eosin staining, ×100). (F) fibrinoid material in the wall of blood vessels (paraffin section, Periodic acidSchiff (PAS) staining with diastase digestion, ×100).
the emerging view that this clinical condition is to be considered more appropriately as a primary vascular occlusive pathology rather than a vasculitis of nerve. Similar findings are reported in two out of three previous neuropathological descriptions of primary LV-associated MM [4,8]. One novel aspect of our report is the distribution pattern and immunophenotypization of lymphoid cells infiltrates. These findings are common in several nerve pathological conditions and are generally considered as non-specific, though immune cells have a known role in regulating coagulation processes [5]. Hence, our observations might be helpful, in future studies, to provide cues towards a possible interaction of immune cells and coagulation in triggering/maintaining the pathological process in LV-MNM. A second novel aspect of the present case is the temporal relation of the appearance of MM with respect to the associated LV. In both biopsy-documented cases of LV-associated MM described in literature, neuropathic symptoms occurred before the onset of skin lesions of primary LV [4,8]. In our case, MM occurred 8 years after the first cutaneous symptoms, and therefore should no longer be considered as an early manifestation of LV.
[5] Leclerc A, Braeken C, Marot L, Tennstedt D, Lachapelle M. La vasculite livedoide. Traitement par ciclosporine: a propos de cinq cas. Lês Nouv Dermatol 2000;19(4): 356–60. [6] Osada S, Kimura Y, Kawana S. Case of livedoid vasculopathy with peripheral neuropathy successfully treated with low-dose warfarin. J Dermatol 2010;37(1):98–101. [7] Pai BS, Pai K. Livedoid vasculopathy and mononeuritis multiplex, with a fulminant hepatic failure which was caused by herpes simplex hepatitis: a case report. J Clin Diagn Res 2013;7(5):921–3. [8] Toth C, Trotter M, Clark A, Zochodne D. Mononeuropathy multiplex in association with livedoid vasculitis. Muscle Nerve 2003;7:634–9. [9] Winkelmann RK, Schroeter AL, Kierland RR, Ryan TM. Clinical studies of livedoid vasculitis: (segmental hyalinizing vasculitis). Mayo Clin Proc 1974;49(10):746–50.
Maria C. Malaguti Neurology Department, Santa Chiara Hospital, Trento, Italy Corresponding author at: Neurology Department, Santa Chiara Hospital, Largo Medaglie d'oro n.1. 38122 Trento, Italy. Tel.: +39 461 903281; fax: +39 461 903922. E-mail address: [email protected]. Tiziana Cavallaro Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Neuropathology, University of Verona, Italy
Conflict of interest statement We have no conflict of interest to declare. References [1] Criado PR, Rivitti EA, Sotto MN, de Carvalho JF. Livedoid vasculopathy as a coagulation disorder. Autoimmun Rev 2011;10:353–60. [2] Ishibashi M, Miyamoto J, Nagasaka T, Chen KR. Livedoid vasculopathy with underlying subcutaneous necrotizing venulitis in an asymptomatic Hepatitis B virus carrier: is livedoid vasculopathy a true nonvasculitic disorder? Am J Dermatopathol 2009;31(3):293–6. [3] Khenifer S, Thomas L, Balme B, Dalle S. Livedoid vasculopathy: thrombotic or inflammatory disease? Clin Exp Dermatol 2009;35:693–8. [4] 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(4):233–6.
Luigi Speziali Dermatology Department, Santa Maria del Carmine Hospital, Rovereto, Italy Maria G. Zorzi Pathology Department, Santa Maria del Carmine Hospital, Rovereto, Italy Sabrina Marangoni Alberto Morini Neurology Department, Santa Chiara Hospital, Trento, Italy 12 December 2014
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Mononeuritis multiplex associated with primary livedoid vasculopathy: Neuropathological evidence of ischemic nerve damage Keywords: Neuropathology Neuropathy Vasculitis Trombophilia
Mononeuritis multiplex (MM) is a pattern of peripheral neuropathy characterized by multifocal damage to at least two different nerves. It is associated with several distinct systemic disorders such as diabetes, connective tissue disease, vasculitis, amyloidosis, cryoglobulinemia, sarcoidosis, neoplasm and infections. Nerve biopsy is in most cases useful in demonstrating the aetiology of nerve damage and establishing a causal link with the underlying systemic disorder. Conversely, in some forms of MM the pathophysiology is controversial, especially in those cases associated with uncommon types of organ-specific diseases. Here we report the findings of comprehensive clinical, neurophysiological and neuropathological investigations carried out on a case of MM associated with livedoid vasculopathy (LV). LV is a rare dermatological disorder that affects mainly young women and is characterized by a painful cutaneous purpuric rash affecting lower limbs and specifically ankles and dorsum of the feet. Lesions have a chronic, relapsing/remitting course, evolving to ulcerations and atrophic white scars. The diagnosis relies on clinical features and skin biopsy. Pathological findings include hyalinotic thrombosis and fibrin deposition within dermal vessel walls and scattered perivascular lymphocytic infiltration without overt signs of vasculitis. Although LV was formerly considered a vasculitic disorder, recent advances have suggested that the primary cause of ischemic damage and cutaneous manifestations is more likely a primary hypercoagulation state rather than inflammation [1]. LV can be a primary disorder or a secondary manifestation of inflammatory and hypercoagulation disorders [3]. Peripheral neuropathy associated with primary LV has been previously described in only five cases [4,6–9], of which only three provided nerve pathology data [4,7,8]. 1. Case report A 45-year-old woman presented to our attention complaining of subacute weakness and paresthesias in upper and lower limbs. She had suffered since the age of 36 years of recurrent skin lesions confined to distal lower limbs. These consisted in multiple purpuric patches which evolved into painful ulcerations and finally into fibrosclerotic white scars in few weeks. Treatment with topical/systemic corticosteroids had been unsuccessful. At age 44, during a new recurrence of painful skin ulcerations, she started complaining of tingling sensation and numbness in her right foot and left hand. The remainder
http://dx.doi.org/10.1016/j.jns.2015.03.013 0022-510X/© 2015 Elsevier B.V. All rights reserved.
of her personal and family histories was unremarkable. On admission, eight months after neuropathic symptoms onset, neurological examination showed weakness in left hand ulnar-innervated muscles and sensory loss in the territories of right median and right sural nerves. Routine blood tests, comprehensive screening for infectious, autoimmune, paraneoplastic and metabolic disorders resulted normal. An extensive laboratory screening for thrombophilia also resulted normal. This included the assessment of deficiencies of natural anticoagulants (antithrombin, proteins C and S), prothrombin mutation, factor V mutation (Leiden), hyperhomocysteinemia, plasma levels of coagulation factors (VIII, IX and XI) and lipoprotein(a) levels. Neurophysiological investigation (NCS and EMG) showed axonal damage limited to motor fibers of the left distal ulnar nerve and sensory fibers of right median and right sural nerves (left ulnar nerve cMAP amplitude: 4.7 mV; wrist–elbow CV: 55 m/s; right median nerve SAP amplitude: 7.6 μV; Wrist–digit III CV: 50.2 m/s; right sural nerve SAP: absent). Chronic neurogenic findings with ongoing denervation were detected in left ulnar innervated muscles. This supported a diagnosis of MM. At this stage sural nerve biopsy was performed. Microscopic pathological examination disclosed an asymmetric loss of myelinated fibers both within and between fascicles. A high proportion of fibers at different stages of Wallerian degeneration were observed, as well as clusters of regenerating small myelinated fibers. Some pleomorphic mononuclear cell infiltrates were observed in the endoneurium, perineurium and epineurium. In the epineurium, lymphocytic infiltrates, consisting of small to medium-size lymphocytes, were predominantly distributed in the perivascular spaces, without signs of obvious vasculitis. Immunophenotyping showed almost all lymphocytes to be of T-cell lineage (CD3+) and few scattered B cells (CD20+). Many macrophages (CD68 +) were detected around endo-and epineurial vessels and scattered in the endoneurium (Fig. 1A, B, C, D). The findings were interpreted as the product of ischemic nerve damage, in the absence of clear signs of vasculitis. Skin biopsy showed the typical features of LV (Fig. 1E, F) as described above. Notably, also deep subcutaneous tissues showed the same typical findings, without pathological evidence of vasculitis, further excluding an underlying yet not defined subtle primary inflammatory process [2]. Finally, cerebral MRI, lower limb venous colour Doppler, PET–CT and CSF examinations, performed to exclude neurolymphomatosis, were normal. The patient was then started on antithrombotic therapy (acetylsalicylate 100 mg). After a follow-up period of two-years no new active skin lesions appeared; neurological symptoms had considerably improved and NCS were unchanged.
2. Discussion We report a rare case of MM associated with LV. The absence of any detectable systemic thrombophylic alteration and the exclusion of any underlying systemic immune-mediated or inflammatory disorder, by means of extensive clinical workup, support the classification of our case as primary LV. Both skin and nerve pathological findings were strongly suggestive of an ischemic pathogenetic mechanism, supporting
Letter to the Editor
215
Fig. 1. Sural nerve biopsy. (A) Asymmetrical involvement of nerve fascicles (transverse semithin sections, toluidine blue ×200); (B) Severe loss of myelinated fibers and some axonal degeneration (transverse semithin sections, toluidine blue ×500); (C) epineurial perivascular mononuclear cell infiltrates (paraffin section, hematoxylin–eosin staining, ×200); (D) T-lymphocytes in epineurial infiltrate (paraffin section, ICH with anti-CD3 antibody, ×500); Skin lesion biopsy. (E) epidermal necrosis, hyalinized dermal blood vessels with intravascular thrombosis and mild perivacular inflammatory infiltrate (paraffin section, hematoxylin–eosin staining, ×100). (F) fibrinoid material in the wall of blood vessels (paraffin section, Periodic acidSchiff (PAS) staining with diastase digestion, ×100).
the emerging view that this clinical condition is to be considered more appropriately as a primary vascular occlusive pathology rather than a vasculitis of nerve. Similar findings are reported in two out of three previous neuropathological descriptions of primary LV-associated MM [4,8]. One novel aspect of our report is the distribution pattern and immunophenotypization of lymphoid cells infiltrates. These findings are common in several nerve pathological conditions and are generally considered as non-specific, though immune cells have a known role in regulating coagulation processes [5]. Hence, our observations might be helpful, in future studies, to provide cues towards a possible interaction of immune cells and coagulation in triggering/maintaining the pathological process in LV-MNM. A second novel aspect of the present case is the temporal relation of the appearance of MM with respect to the associated LV. In both biopsy-documented cases of LV-associated MM described in literature, neuropathic symptoms occurred before the onset of skin lesions of primary LV [4,8]. In our case, MM occurred 8 years after the first cutaneous symptoms, and therefore should no longer be considered as an early manifestation of LV.
[5] Leclerc A, Braeken C, Marot L, Tennstedt D, Lachapelle M. La vasculite livedoide. Traitement par ciclosporine: a propos de cinq cas. Lês Nouv Dermatol 2000;19(4): 356–60. [6] Osada S, Kimura Y, Kawana S. Case of livedoid vasculopathy with peripheral neuropathy successfully treated with low-dose warfarin. J Dermatol 2010;37(1):98–101. [7] Pai BS, Pai K. Livedoid vasculopathy and mononeuritis multiplex, with a fulminant hepatic failure which was caused by herpes simplex hepatitis: a case report. J Clin Diagn Res 2013;7(5):921–3. [8] Toth C, Trotter M, Clark A, Zochodne D. Mononeuropathy multiplex in association with livedoid vasculitis. Muscle Nerve 2003;7:634–9. [9] Winkelmann RK, Schroeter AL, Kierland RR, Ryan TM. Clinical studies of livedoid vasculitis: (segmental hyalinizing vasculitis). Mayo Clin Proc 1974;49(10):746–50.
Maria C. Malaguti Neurology Department, Santa Chiara Hospital, Trento, Italy Corresponding author at: Neurology Department, Santa Chiara Hospital, Largo Medaglie d'oro n.1. 38122 Trento, Italy. Tel.: +39 461 903281; fax: +39 461 903922. E-mail address: [email protected]. Tiziana Cavallaro Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Neuropathology, University of Verona, Italy
Conflict of interest statement We have no conflict of interest to declare. References [1] Criado PR, Rivitti EA, Sotto MN, de Carvalho JF. Livedoid vasculopathy as a coagulation disorder. Autoimmun Rev 2011;10:353–60. [2] Ishibashi M, Miyamoto J, Nagasaka T, Chen KR. Livedoid vasculopathy with underlying subcutaneous necrotizing venulitis in an asymptomatic Hepatitis B virus carrier: is livedoid vasculopathy a true nonvasculitic disorder? Am J Dermatopathol 2009;31(3):293–6. [3] Khenifer S, Thomas L, Balme B, Dalle S. Livedoid vasculopathy: thrombotic or inflammatory disease? Clin Exp Dermatol 2009;35:693–8. [4] 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(4):233–6.
Luigi Speziali Dermatology Department, Santa Maria del Carmine Hospital, Rovereto, Italy Maria G. Zorzi Pathology Department, Santa Maria del Carmine Hospital, Rovereto, Italy Sabrina Marangoni Alberto Morini Neurology Department, Santa Chiara Hospital, Trento, Italy 12 December 2014
