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Letters to the Editor
acute hyponatraemia, brain cells adapt to the altered osmolality by the loss of solutes, followed by osmotic movement of water out of the cells.2 When the sodium is corrected, this process occurs in the reverse. With rapid correction of hyponatraemia, there is further osmotic fluid shift from intracellular to extracellular, resulting in volume loss and, potentially, cell death. This process affects the oligodendrocytes, resulting in a demyelinating lesion. The clinical manifestations of ODS may include dysarthria, dysphagia, behavioural disturbances and coma.1 The diagnosis can be confirmed with MRI brain imaging. Uhthoff phenomenon is the development or worsening of neurological deficits in multiple sclerosis (MS) and other demyelinating conditions in the setting of increasing body temperature.3 Various pathophysiological mechanisms for Uhthoff phenomenon have been proposed. Humm et al. postulated reversible temperature-dependent conduction block at the nodes of demyelinated fibres.4 However, Uhthoff symptom is often accompanied by a negligible rise in temperature5 and typically exercise causes a
References 1 Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholics and malnourished patients. AMA Arch Neurol Psychiatry 1959; 81: 154–72. 2 McManus ML, Churchwell KB, Strange K. Regulation of cell volume in health
minimal effect on central temperature.6 Additional studies suggest the metabolic effect of exercise may promote ionic leakage across the demyelinated segment of the nerve fibre and cause transient failure of conduction.6 There are few cases in the literature that describe Uhthoff phenomenon in patients without a diagnosis of MS. We describe a patient who experienced Uhthoff symptom in the setting of ODS. This is plausible as the demyelinating lesions of ODS perhaps predispose to impaired nerve conduction in the setting of elevated temperature, similar to that seen in MS. Pontine neurones may be less sensitive to the Uhthoff phenomenon than optic nerve fibres, hence the rarity of Uhthoff phenomenon in ODS. We believe this is the first reported description of Uhthoff phenomenon in ODS. Received 6 March 2014; accepted 25 April 2014. doi:10.1111/imj.12573 1
M. Papandony, R. Wesselingh1 and R. Stark2 2
Neurology Department, 1Alfred Health, Melbourne, Australia
and disease. N Engl J Med 1995; 333: 1260–6. 3 Pearce JM. Early observations on optic neuritis and Uhthoff’s sign. Eur Neurol 2010; 63: 243–7. 4 Humm AM, Beer S, Kool J, Magistris MR, Kesselring J, Rösler KM. Quantification of Uhthoff’s phenomenon in multiple sclerosis: a magnetic stimulation study. Clin Neurophysiol 2004; 115: 2493–501.
Recalcitrant paraneoplastic pemphigus associated with follicular dendritic cell sarcoma: response to prolonged rituximab and ciclosporin therapy A 46-year-old woman presented with abdominal pain. Computed tomography scan showed a 16 × 9 cm hepatic mass, which on surgical removal showed follicular dendritic cell sarcoma (FDCS). The tumour recurred a year later, showing no response to six cycles of cyclophosphamide, vincristine, doxorubicin and prednisolone and two cycles of cladribine. Three weeks after the second course of cladribine, generalised blistering skin eruptions and mucosal ulcerations developed (Fig. 1a). Skin biopsy showed interface dermatitis, suprabasal acantholysis and clefting with tombstoning (Fig. 1b). Direct immunofluorescence studies showed intercellular and basement membrane © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
5 Guthrie TC, Nelson DA. Influence of temperature changes on multiple sclerosis: critical review of mechanisms and research potential. J Neurol Sci 1995; 129: 1–8. 6 Selhorst JB, Saul RF. Uhthoff and his symptom. J Neuroophthalmol 1995; 15: 63–9.
deposits of complement and immunoglobulin G. Antibodies against epidermal intercellular substance (desmoglein-1, desmoglein-3 and desmoplakin-1) were positive at 1/640. Overall features were consistent with paraneoplastic pemphigus (PNP).1 Treatment with intravenous immunoglobulin (1 g/kg/day × 3) and prednisolone (1 mg/kg/day) was not efficacious. Multiple salvage chemotherapies for the FDCS were ineffective. PNP was unabated. Rituximab (375 mg/m2/week) and oral ciclosporin (80 mg twice daily) were administered. In the initial 4 weeks, there was no response. However, from the fifth week, skin and oral lesions progressively improved, and by the seventh week had practically healed (Fig. 1c). On completion of 8 weeks of rituximab, remission of the PNP was achieved. Rituximab was stopped and ciclosporin continued. Four weeks afterwards, PNP relapsed catastrophically 1145
Letters to the Editor
Figure 1 Paraneoplastic pemphigus complicating follicular dendritic cell sarcoma. (A) Generalised bullous eruption over the body. The dressing was the site of biopsy. Mucosal involvement necessitated the insertion of a urinary catheter. Insert showed mucosal ulcerations in the mouth and tongue. (B) Skin biopsy showing a florid lichenoid interface dermatitis with basal vacuolation and Civatte bodies (white arrow) merging with the edge of an intraepithelial blister (asterisk) in which there is acantholysis and tombstoning (black arrows) of the basal keratinocytes, appearances characteristic of paraneoplastic pemphigus (haematoxylin eosin, original magnification ×100). (C) Complete healing of skin lesions after 8 weeks of rituximab and ciclosporin, with residual pigmentation and desquamation.
PNP is characterised by severe and often therapyrefractory oral mucosal ulcerations and extensive skin lesions. The pathogenesis is thought to be due to production of antibodies against tumour-derived antigens, which mimic the epithelial antigens plakin and desmoglein.1 FDCS-associated PNP was reported to have a dismal outcome, with virtually no responses to highdose corticosteroids, plasmapheresis and intravenous immunoglobulin.2 Rituximab had also been reported ineffective.2,3 For the first time, we controlled FDCS-associated PNP with rituximab, although others had so far failed.2,3 Two factors might be involved. First, our patient showed very little response to four courses of rituximab (cumulative dose: 1.5 g/m2), a conventional dosage adopted for PNP and pemphigus vulgaris. Had we stopped, we might not have seen a therapeutic benefit. On persevering to eight courses (cumulative dose: 3 g/m2), a complete response was obtained. This dosage was also higher than that of 2 g recently advocated for pemphigus vulgaris.4 Second, T-cell and natural killer cell (NK) lymphomas have been reported to be associated with PNP,5,6 suggesting that T-cells and NK-cells might also be involved pathogenetically. The use of ciclosporin, which targets T-cells, might have acted synergistically. Our observations suggest that for recalcitrant PNP, combined B-cell and T-cell targeting might be efficacious. The relapse on rituximab cessation and response on re-institution implies that even more prolonged rituximab may be required. Received 12 February 2014; accepted 6 April 2014. doi:10.1111/imj.12576
with widespread skin denudation. Rituximab was re-instituted. Skin lesions responded rapidly and had almost completely healed after two courses. However, because of heavy immunosuppression, the patient developed multilobar pneumonia and died.
References 1 Meijs M, Mekkes J, van Noesel C, Nijhuis E, Leeksma O, Jonkman M et al. Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma without Castleman’s disease: treatment with rituximab. Int J Dermatol 2008; 47: 632–4. 2 Rice BL, Bedocs LA, Sahi H. A 41-year-old woman with severe dyspnea and painful oral mucosal ulcerations. Chest 2010; 137: 1236–9.
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Y.-Y. Hwang, J. C. Y. Chan, N. J. Trendell-Smith2 and Y.-L. Kwong1 Departments of 1Medicine and 2Pathology, Queen Mary Hospital, Hong Kong, China
3 Behzad M, Möbs C, Kneisel A, Möller M, Hoyer J, Hertl M et al. Combined treatment with immunoadsorption and rituximab leads to fast and prolonged clinical remission in difficult-to-treat pemphigus vulgaris. Br J Dermatol 2012; 166: 844–52. 4 Cianchini G, Lupi F, Masini C, Corona R, Puddu P, De Pità O. Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study on 42 cases with long-term
follow-up. J Am Acad Dermatol 2012; 67: 617–22. 5 Gill H, Trendell-Smith NJ, Loong F, Yeung CK, Kwong YL. Paraneoplastic pemphigus due to CD8-positive cytotoxic T-cell lymphoma. Br J Haematol 2010; 149: 464. 6 Gill H, Trendell-Smith NJ, Loong F, Chan JC, Kwong YL. Paraneoplastic pemphigus due to natural-killer/T-cell lymphoma. Br J Haematol 2011; 154: 160.
© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
Copyright of Internal Medicine Journal is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Letters to the Editor
acute hyponatraemia, brain cells adapt to the altered osmolality by the loss of solutes, followed by osmotic movement of water out of the cells.2 When the sodium is corrected, this process occurs in the reverse. With rapid correction of hyponatraemia, there is further osmotic fluid shift from intracellular to extracellular, resulting in volume loss and, potentially, cell death. This process affects the oligodendrocytes, resulting in a demyelinating lesion. The clinical manifestations of ODS may include dysarthria, dysphagia, behavioural disturbances and coma.1 The diagnosis can be confirmed with MRI brain imaging. Uhthoff phenomenon is the development or worsening of neurological deficits in multiple sclerosis (MS) and other demyelinating conditions in the setting of increasing body temperature.3 Various pathophysiological mechanisms for Uhthoff phenomenon have been proposed. Humm et al. postulated reversible temperature-dependent conduction block at the nodes of demyelinated fibres.4 However, Uhthoff symptom is often accompanied by a negligible rise in temperature5 and typically exercise causes a
References 1 Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholics and malnourished patients. AMA Arch Neurol Psychiatry 1959; 81: 154–72. 2 McManus ML, Churchwell KB, Strange K. Regulation of cell volume in health
minimal effect on central temperature.6 Additional studies suggest the metabolic effect of exercise may promote ionic leakage across the demyelinated segment of the nerve fibre and cause transient failure of conduction.6 There are few cases in the literature that describe Uhthoff phenomenon in patients without a diagnosis of MS. We describe a patient who experienced Uhthoff symptom in the setting of ODS. This is plausible as the demyelinating lesions of ODS perhaps predispose to impaired nerve conduction in the setting of elevated temperature, similar to that seen in MS. Pontine neurones may be less sensitive to the Uhthoff phenomenon than optic nerve fibres, hence the rarity of Uhthoff phenomenon in ODS. We believe this is the first reported description of Uhthoff phenomenon in ODS. Received 6 March 2014; accepted 25 April 2014. doi:10.1111/imj.12573 1
M. Papandony, R. Wesselingh1 and R. Stark2 2
Neurology Department, 1Alfred Health, Melbourne, Australia
and disease. N Engl J Med 1995; 333: 1260–6. 3 Pearce JM. Early observations on optic neuritis and Uhthoff’s sign. Eur Neurol 2010; 63: 243–7. 4 Humm AM, Beer S, Kool J, Magistris MR, Kesselring J, Rösler KM. Quantification of Uhthoff’s phenomenon in multiple sclerosis: a magnetic stimulation study. Clin Neurophysiol 2004; 115: 2493–501.
Recalcitrant paraneoplastic pemphigus associated with follicular dendritic cell sarcoma: response to prolonged rituximab and ciclosporin therapy A 46-year-old woman presented with abdominal pain. Computed tomography scan showed a 16 × 9 cm hepatic mass, which on surgical removal showed follicular dendritic cell sarcoma (FDCS). The tumour recurred a year later, showing no response to six cycles of cyclophosphamide, vincristine, doxorubicin and prednisolone and two cycles of cladribine. Three weeks after the second course of cladribine, generalised blistering skin eruptions and mucosal ulcerations developed (Fig. 1a). Skin biopsy showed interface dermatitis, suprabasal acantholysis and clefting with tombstoning (Fig. 1b). Direct immunofluorescence studies showed intercellular and basement membrane © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
5 Guthrie TC, Nelson DA. Influence of temperature changes on multiple sclerosis: critical review of mechanisms and research potential. J Neurol Sci 1995; 129: 1–8. 6 Selhorst JB, Saul RF. Uhthoff and his symptom. J Neuroophthalmol 1995; 15: 63–9.
deposits of complement and immunoglobulin G. Antibodies against epidermal intercellular substance (desmoglein-1, desmoglein-3 and desmoplakin-1) were positive at 1/640. Overall features were consistent with paraneoplastic pemphigus (PNP).1 Treatment with intravenous immunoglobulin (1 g/kg/day × 3) and prednisolone (1 mg/kg/day) was not efficacious. Multiple salvage chemotherapies for the FDCS were ineffective. PNP was unabated. Rituximab (375 mg/m2/week) and oral ciclosporin (80 mg twice daily) were administered. In the initial 4 weeks, there was no response. However, from the fifth week, skin and oral lesions progressively improved, and by the seventh week had practically healed (Fig. 1c). On completion of 8 weeks of rituximab, remission of the PNP was achieved. Rituximab was stopped and ciclosporin continued. Four weeks afterwards, PNP relapsed catastrophically 1145
Letters to the Editor
Figure 1 Paraneoplastic pemphigus complicating follicular dendritic cell sarcoma. (A) Generalised bullous eruption over the body. The dressing was the site of biopsy. Mucosal involvement necessitated the insertion of a urinary catheter. Insert showed mucosal ulcerations in the mouth and tongue. (B) Skin biopsy showing a florid lichenoid interface dermatitis with basal vacuolation and Civatte bodies (white arrow) merging with the edge of an intraepithelial blister (asterisk) in which there is acantholysis and tombstoning (black arrows) of the basal keratinocytes, appearances characteristic of paraneoplastic pemphigus (haematoxylin eosin, original magnification ×100). (C) Complete healing of skin lesions after 8 weeks of rituximab and ciclosporin, with residual pigmentation and desquamation.
PNP is characterised by severe and often therapyrefractory oral mucosal ulcerations and extensive skin lesions. The pathogenesis is thought to be due to production of antibodies against tumour-derived antigens, which mimic the epithelial antigens plakin and desmoglein.1 FDCS-associated PNP was reported to have a dismal outcome, with virtually no responses to highdose corticosteroids, plasmapheresis and intravenous immunoglobulin.2 Rituximab had also been reported ineffective.2,3 For the first time, we controlled FDCS-associated PNP with rituximab, although others had so far failed.2,3 Two factors might be involved. First, our patient showed very little response to four courses of rituximab (cumulative dose: 1.5 g/m2), a conventional dosage adopted for PNP and pemphigus vulgaris. Had we stopped, we might not have seen a therapeutic benefit. On persevering to eight courses (cumulative dose: 3 g/m2), a complete response was obtained. This dosage was also higher than that of 2 g recently advocated for pemphigus vulgaris.4 Second, T-cell and natural killer cell (NK) lymphomas have been reported to be associated with PNP,5,6 suggesting that T-cells and NK-cells might also be involved pathogenetically. The use of ciclosporin, which targets T-cells, might have acted synergistically. Our observations suggest that for recalcitrant PNP, combined B-cell and T-cell targeting might be efficacious. The relapse on rituximab cessation and response on re-institution implies that even more prolonged rituximab may be required. Received 12 February 2014; accepted 6 April 2014. doi:10.1111/imj.12576
with widespread skin denudation. Rituximab was re-instituted. Skin lesions responded rapidly and had almost completely healed after two courses. However, because of heavy immunosuppression, the patient developed multilobar pneumonia and died.
References 1 Meijs M, Mekkes J, van Noesel C, Nijhuis E, Leeksma O, Jonkman M et al. Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma without Castleman’s disease: treatment with rituximab. Int J Dermatol 2008; 47: 632–4. 2 Rice BL, Bedocs LA, Sahi H. A 41-year-old woman with severe dyspnea and painful oral mucosal ulcerations. Chest 2010; 137: 1236–9.
1146
1
1
Y.-Y. Hwang, J. C. Y. Chan, N. J. Trendell-Smith2 and Y.-L. Kwong1 Departments of 1Medicine and 2Pathology, Queen Mary Hospital, Hong Kong, China
3 Behzad M, Möbs C, Kneisel A, Möller M, Hoyer J, Hertl M et al. Combined treatment with immunoadsorption and rituximab leads to fast and prolonged clinical remission in difficult-to-treat pemphigus vulgaris. Br J Dermatol 2012; 166: 844–52. 4 Cianchini G, Lupi F, Masini C, Corona R, Puddu P, De Pità O. Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study on 42 cases with long-term
follow-up. J Am Acad Dermatol 2012; 67: 617–22. 5 Gill H, Trendell-Smith NJ, Loong F, Yeung CK, Kwong YL. Paraneoplastic pemphigus due to CD8-positive cytotoxic T-cell lymphoma. Br J Haematol 2010; 149: 464. 6 Gill H, Trendell-Smith NJ, Loong F, Chan JC, Kwong YL. Paraneoplastic pemphigus due to natural-killer/T-cell lymphoma. Br J Haematol 2011; 154: 160.
© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
Copyright of Internal Medicine Journal is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
