Clinical/Scientific Notes
Shyamal H. Mehta, MD, PhD* Jeffrey A. Switzer, DO, MCTS* Paul Biddinger, MD Amyn M. Rojiani, MD, PhD, CPE
Supplemental data at www.neurology.org
540
IgG4-RELATED LEPTOMENINGITIS: A REVERSIBLE CAUSE OF RAPIDLY PROGRESSIVE COGNITIVE DECLINE
Immunoglobulin G4–related diseases (IgG4-RD) are a newly recognized category of diseases. CNS involvement in IgG4-RD includes hypophysitis1 and intracranial or spinal manifestations of hypertrophic pachymeningitis.2,3 We present a unique case of rapid cognitive decline due to IgG4-related leptomeningitis. Case report. A 74-year-old woman with rheumatoid arthritis and hypothyroidism was referred to the neurology clinic. Three months prior, she was driving and active socially. She experienced gait difficulty and falls and became wheelchair-bound and dependent on her daughter’s assistance. Her neurologist, suspecting Parkinson disease, started her on carbidopa/levodopa and referred her to a movement disorder specialist. On examination, she was alert and cooperative but had decreased verbal output. She had significant apraxia for routine maneuvers. Her strength was normal; myoclonic jerks were noted in the upper extremities with action. There was no tremor or ataxia. Toes were upgoing bilaterally. She was admitted for further evaluation (see video on the Neurology® Web site at www. neurology.org). MRI showed diffuse leptomeningeal enhancement over both cerebral convexities (figure, A). MRI of the cervical spine was unremarkable. EEG showed mild background slowing but was otherwise unremarkable. Routine blood tests were normal, angiotensinconverting enzyme and antineutrophil cytoplasmic antibodies were negative, erythrocyte sedimentation rate 15, antinuclear antibodies 1:40, rheumatoid factor 375 (normal , 14), and anti–cyclic citrullinated peptide antibodies were elevated (consistent with rheumatoid arthritis). Infectious workup including rapid plasma reagin, HIV, QuantiFERON-Gold, Brucella, and histoplasmosis was negative as well. A serum IgG4 level was not obtained. CT of the chest and abdomen was unremarkable with no granulomatous disease. CSF studies revealed 14 leukocytes (55% lymphocytes, 41% monocytes, 4% segs), glucose 46, and protein 64 mg/dL; bacterial, fungal, and acid-fast bacilli cultures were negative. Flow cytometry did not reveal an aberrant cellular phenotype. Neurology 82
February 11, 2014
To rule out a treatable etiology, a biopsy was obtained. Examination revealed a lymphoplasmacytic infiltrate limited to the leptomeninges, inner surface of the dura, and around some vessels (figure, B and C). Lymphocytes and plasma cells were present in a perivascular distribution and as an intramural infiltrate in some vessels. This vasculitic involvement or phlebitis is illustrated in the figure, B. Although focal necrosis was present, no granulomas or giant cells were seen. Special stains for acid-fast bacilli, fungi, spirochetes, nocardia, and Gram stain for bacteria were negative. IgG4 immunoreactivity was readily seen in multiple foci of dense inflammatory infiltrates. The IgG4-positive cells displayed a plasma cell phenotype, and in at least 3 foci .50 IgG4-positive cells were seen per 340 high-power field (figure, D). IgG4-immunoreactive plasma cells were also seen in a perivenular distribution (figure, E). IgG-positive cells were present in almost equal numbers as IgG4immunoreactive cells with a ratio of over 80% (figure, F and G). The patient was treated with IV methylprednisolone, followed by prednisone 40 mg daily. Two months later, she showed remarkable improvement in her mentation and daily functioning (video) and significant reduction in leptomeningeal enhancement (figure, H). Six months post-biopsy, the patient developed rapid atrial fibrillation and congestive heart failure. She had aspiration pneumonia requiring mechanical ventilation, was placed on comfort care, and died shortly after. Discussion. IgG4-RD causing pachymeningitis has been the subject of a few case reports, presenting with cranial nerve dysfunction or symptoms of spinal compression.2 Here, we describe a patient with IgG4-RD with leptomeningitis. Our case broadens the phenotypic presentation for neurologic sequelae of IgG4-RD. Alternative etiologies, including rheumatoid meningitis, were considered. Rheumatoid pathology is predominantly granulomatous in appearance, with fibrinoid necrosis surrounded by lymphocytes and epithelioid histiocytes. Plasma cells are a minor component. It is also characterized by a polyarteritis nodosa type of vasculitis. Our case had no necrotizing or nonnecrotizing granulomata and displayed an obliterative phlebitis with perivascular IgG4-positive plasma cells.
Figure
Brain MRI and pathologic findings of the biopsy
(A) Postgadolinium T1-weighted images show diffuse leptomeningeal enhancement over the bilateral frontoparietal convexities and interhemispheric sulci. (B) Multifocal, lymphoplasmacytic infiltrate is seen within the leptomeningeal tissue. (C) Perivenular infiltrate/phlebitis. (D) Focally greater than 50/high-power field, immunoglobulin G (IgG)–4 immunoreactive plasma cells. (E) IgG4-immunoreactive plasma cells in a perivenular distribution. (F) Many IgG-immunoreactive cells are present. (G) Most of these are IgG4-immunoreactive plasma cells. (H) Significant interval improvement in pathologic leptomeningeal enhancement pattern after 2 months of oral prednisone.
Neurology 82
February 11, 2014
541
This histopathologic picture of dense lymphoplasmacytic infiltration with prominent IgG4-expressing plasma cells and vasculitic involvement/phlebitis with a high IgG/IgG4 ratio is characteristic of IgG4-RD. The one histologic criterion that could not be confirmed is fibrosis. Recognizing the constraints of this limited biopsy, its site, and in concordance with the consensus statement on the pathology of IgG4-RD, the histopathology is suggestive of IgG4-RD.4 We acknowledge the limitations of our diagnosis, including the lack of evidence of other organ involvement and a serum IgG4 level. However, IgG4-RD may initially present with single-organ disease or subclinical involvement of other organ systems.5 The recognition of this leptomeningeal manifestation of IgG4-RD is important as it presents as a rapidly progressive dementia. In a series of 5 patients with meningeal sequelae of IgG4-RD, it was noted that one of the 5 had presented with cognitive decline and gait instability and was found to have leptomeningeal enhancement.2 Our patient had a similar rapid decline in gait and cognitive function. Hence, IgG4-RD leptomeningitis should be considered in the differential of rapidly progressive dementia, particularly because the dementia is potentially reversible with steroid treatment. Our patient had evidence of other autoimmune diseases as well. This may suggest that in patients presenting with leptomeningitis, history of autoimmune diseases may be a clue to IgG4-RD. However, it is not clear how IgG4 is responsible for the pathogenesis of IgG4-RD, as IgG4 primarily functions by inhibiting immune-mediated inflammation. In fact, some suggest that elevated levels of IgG4 may actually be a consequence of the disease rather than a cause.6 It is important to consider IgG4-RD leptomeningitis in a patient with rapid cognitive decline, as
appropriate treatment with steroids can potentially reverse the symptoms. *These authors contributed equally to this work. From the Medical College of Georgia, Georgia Regents University, Augusta. Author contributions: S.H.M.: drafting/revising the manuscript for content, analysis/interpretation of data. J.A.S.: drafting/revising the manuscript for content, analysis/interpretation of data. P.B.: drafting/revising the manuscript for content, analysis/interpretation of data. A.M.R.: drafting/revising the manuscript for content, analysis/interpretation of data. Acknowledgment: The authors thank movement disorders fellows Drs. Daniel Dees and Jill Trumble for assisting with the production of the video of the patient. Study funding: No targeted funding reported. Disclosure: S. Mehta reports no disclosures. J. Switzer has consulted for Genentech and REACH Health, Inc., and receives research support from Genentech and the American Heart Association. P. Biddinger and A. Rojiani report no disclosures. Go to Neurology.org for full disclosures. Received May 29, 2013. Accepted in final form October 1, 2013. Correspondence to Dr. Switzer: [email protected] © 2014 American Academy of Neurology 1.
2.
3.
4.
5. 6.
Shimatsu A, Oki Y, Fujisawa I, Sano T. Pituitary and stalk lesions (infundibulo-hypophysitis) associated with immunoglobulin G4-related systemic disease: an emerging clinical entity. Endocr J 2009;56:1033–1041. Lindstrom KM, Cousar JB, Lopes MB. IgG4-related meningeal disease: clinico-pathological features and proposal for diagnostic criteria. Acta Neuropathol 2010;120:765–776. Kosakai A, Ito D, Yamada S, Ideta S, Ota Y, Suzuki N. A case of definite IgG4-related pachymeningitis. Neurology 2010;75:1390–1392. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012; 25:1181–1192. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539–551. Aalberse RC, Stapel SO, Schuurman J, Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy 2009;39:469–477.
Save These Dates for AAN CME Opportunities! Mark these dates on your calendar for exciting continuing education opportunities, where you can catch up on the latest neurology information. AAN Annual Meeting
• April 26-May 3, 2014, Philadelphia, Pennsylvania, Pennsylvania Convention Center
542
Neurology 82
February 11, 2014
IgG4-related leptomeningitis: A reversible cause of rapidly progressive cognitive decline Shyamal H. Mehta, Jeffrey A. Switzer, Paul Biddinger, et al. Neurology 2014;82;540-542 Published Online before print January 2, 2014 DOI 10.1212/WNL.0000000000000100 This information is current as of January 2, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/6/540.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/01/02/WNL.0000000000 000100.DC1.html
References
This article cites 6 articles, 1 of which you can access for free at: http://www.neurology.org/content/82/6/540.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Clinical Neurology http://www.neurology.org//cgi/collection/all_clinical_neurology All Cognitive Disorders/Dementia http://www.neurology.org//cgi/collection/all_cognitive_disorders_deme ntia
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Shyamal H. Mehta, MD, PhD* Jeffrey A. Switzer, DO, MCTS* Paul Biddinger, MD Amyn M. Rojiani, MD, PhD, CPE
Supplemental data at www.neurology.org
540
IgG4-RELATED LEPTOMENINGITIS: A REVERSIBLE CAUSE OF RAPIDLY PROGRESSIVE COGNITIVE DECLINE
Immunoglobulin G4–related diseases (IgG4-RD) are a newly recognized category of diseases. CNS involvement in IgG4-RD includes hypophysitis1 and intracranial or spinal manifestations of hypertrophic pachymeningitis.2,3 We present a unique case of rapid cognitive decline due to IgG4-related leptomeningitis. Case report. A 74-year-old woman with rheumatoid arthritis and hypothyroidism was referred to the neurology clinic. Three months prior, she was driving and active socially. She experienced gait difficulty and falls and became wheelchair-bound and dependent on her daughter’s assistance. Her neurologist, suspecting Parkinson disease, started her on carbidopa/levodopa and referred her to a movement disorder specialist. On examination, she was alert and cooperative but had decreased verbal output. She had significant apraxia for routine maneuvers. Her strength was normal; myoclonic jerks were noted in the upper extremities with action. There was no tremor or ataxia. Toes were upgoing bilaterally. She was admitted for further evaluation (see video on the Neurology® Web site at www. neurology.org). MRI showed diffuse leptomeningeal enhancement over both cerebral convexities (figure, A). MRI of the cervical spine was unremarkable. EEG showed mild background slowing but was otherwise unremarkable. Routine blood tests were normal, angiotensinconverting enzyme and antineutrophil cytoplasmic antibodies were negative, erythrocyte sedimentation rate 15, antinuclear antibodies 1:40, rheumatoid factor 375 (normal , 14), and anti–cyclic citrullinated peptide antibodies were elevated (consistent with rheumatoid arthritis). Infectious workup including rapid plasma reagin, HIV, QuantiFERON-Gold, Brucella, and histoplasmosis was negative as well. A serum IgG4 level was not obtained. CT of the chest and abdomen was unremarkable with no granulomatous disease. CSF studies revealed 14 leukocytes (55% lymphocytes, 41% monocytes, 4% segs), glucose 46, and protein 64 mg/dL; bacterial, fungal, and acid-fast bacilli cultures were negative. Flow cytometry did not reveal an aberrant cellular phenotype. Neurology 82
February 11, 2014
To rule out a treatable etiology, a biopsy was obtained. Examination revealed a lymphoplasmacytic infiltrate limited to the leptomeninges, inner surface of the dura, and around some vessels (figure, B and C). Lymphocytes and plasma cells were present in a perivascular distribution and as an intramural infiltrate in some vessels. This vasculitic involvement or phlebitis is illustrated in the figure, B. Although focal necrosis was present, no granulomas or giant cells were seen. Special stains for acid-fast bacilli, fungi, spirochetes, nocardia, and Gram stain for bacteria were negative. IgG4 immunoreactivity was readily seen in multiple foci of dense inflammatory infiltrates. The IgG4-positive cells displayed a plasma cell phenotype, and in at least 3 foci .50 IgG4-positive cells were seen per 340 high-power field (figure, D). IgG4-immunoreactive plasma cells were also seen in a perivenular distribution (figure, E). IgG-positive cells were present in almost equal numbers as IgG4immunoreactive cells with a ratio of over 80% (figure, F and G). The patient was treated with IV methylprednisolone, followed by prednisone 40 mg daily. Two months later, she showed remarkable improvement in her mentation and daily functioning (video) and significant reduction in leptomeningeal enhancement (figure, H). Six months post-biopsy, the patient developed rapid atrial fibrillation and congestive heart failure. She had aspiration pneumonia requiring mechanical ventilation, was placed on comfort care, and died shortly after. Discussion. IgG4-RD causing pachymeningitis has been the subject of a few case reports, presenting with cranial nerve dysfunction or symptoms of spinal compression.2 Here, we describe a patient with IgG4-RD with leptomeningitis. Our case broadens the phenotypic presentation for neurologic sequelae of IgG4-RD. Alternative etiologies, including rheumatoid meningitis, were considered. Rheumatoid pathology is predominantly granulomatous in appearance, with fibrinoid necrosis surrounded by lymphocytes and epithelioid histiocytes. Plasma cells are a minor component. It is also characterized by a polyarteritis nodosa type of vasculitis. Our case had no necrotizing or nonnecrotizing granulomata and displayed an obliterative phlebitis with perivascular IgG4-positive plasma cells.
Figure
Brain MRI and pathologic findings of the biopsy
(A) Postgadolinium T1-weighted images show diffuse leptomeningeal enhancement over the bilateral frontoparietal convexities and interhemispheric sulci. (B) Multifocal, lymphoplasmacytic infiltrate is seen within the leptomeningeal tissue. (C) Perivenular infiltrate/phlebitis. (D) Focally greater than 50/high-power field, immunoglobulin G (IgG)–4 immunoreactive plasma cells. (E) IgG4-immunoreactive plasma cells in a perivenular distribution. (F) Many IgG-immunoreactive cells are present. (G) Most of these are IgG4-immunoreactive plasma cells. (H) Significant interval improvement in pathologic leptomeningeal enhancement pattern after 2 months of oral prednisone.
Neurology 82
February 11, 2014
541
This histopathologic picture of dense lymphoplasmacytic infiltration with prominent IgG4-expressing plasma cells and vasculitic involvement/phlebitis with a high IgG/IgG4 ratio is characteristic of IgG4-RD. The one histologic criterion that could not be confirmed is fibrosis. Recognizing the constraints of this limited biopsy, its site, and in concordance with the consensus statement on the pathology of IgG4-RD, the histopathology is suggestive of IgG4-RD.4 We acknowledge the limitations of our diagnosis, including the lack of evidence of other organ involvement and a serum IgG4 level. However, IgG4-RD may initially present with single-organ disease or subclinical involvement of other organ systems.5 The recognition of this leptomeningeal manifestation of IgG4-RD is important as it presents as a rapidly progressive dementia. In a series of 5 patients with meningeal sequelae of IgG4-RD, it was noted that one of the 5 had presented with cognitive decline and gait instability and was found to have leptomeningeal enhancement.2 Our patient had a similar rapid decline in gait and cognitive function. Hence, IgG4-RD leptomeningitis should be considered in the differential of rapidly progressive dementia, particularly because the dementia is potentially reversible with steroid treatment. Our patient had evidence of other autoimmune diseases as well. This may suggest that in patients presenting with leptomeningitis, history of autoimmune diseases may be a clue to IgG4-RD. However, it is not clear how IgG4 is responsible for the pathogenesis of IgG4-RD, as IgG4 primarily functions by inhibiting immune-mediated inflammation. In fact, some suggest that elevated levels of IgG4 may actually be a consequence of the disease rather than a cause.6 It is important to consider IgG4-RD leptomeningitis in a patient with rapid cognitive decline, as
appropriate treatment with steroids can potentially reverse the symptoms. *These authors contributed equally to this work. From the Medical College of Georgia, Georgia Regents University, Augusta. Author contributions: S.H.M.: drafting/revising the manuscript for content, analysis/interpretation of data. J.A.S.: drafting/revising the manuscript for content, analysis/interpretation of data. P.B.: drafting/revising the manuscript for content, analysis/interpretation of data. A.M.R.: drafting/revising the manuscript for content, analysis/interpretation of data. Acknowledgment: The authors thank movement disorders fellows Drs. Daniel Dees and Jill Trumble for assisting with the production of the video of the patient. Study funding: No targeted funding reported. Disclosure: S. Mehta reports no disclosures. J. Switzer has consulted for Genentech and REACH Health, Inc., and receives research support from Genentech and the American Heart Association. P. Biddinger and A. Rojiani report no disclosures. Go to Neurology.org for full disclosures. Received May 29, 2013. Accepted in final form October 1, 2013. Correspondence to Dr. Switzer: [email protected] © 2014 American Academy of Neurology 1.
2.
3.
4.
5. 6.
Shimatsu A, Oki Y, Fujisawa I, Sano T. Pituitary and stalk lesions (infundibulo-hypophysitis) associated with immunoglobulin G4-related systemic disease: an emerging clinical entity. Endocr J 2009;56:1033–1041. Lindstrom KM, Cousar JB, Lopes MB. IgG4-related meningeal disease: clinico-pathological features and proposal for diagnostic criteria. Acta Neuropathol 2010;120:765–776. Kosakai A, Ito D, Yamada S, Ideta S, Ota Y, Suzuki N. A case of definite IgG4-related pachymeningitis. Neurology 2010;75:1390–1392. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012; 25:1181–1192. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539–551. Aalberse RC, Stapel SO, Schuurman J, Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy 2009;39:469–477.
Save These Dates for AAN CME Opportunities! Mark these dates on your calendar for exciting continuing education opportunities, where you can catch up on the latest neurology information. AAN Annual Meeting
• April 26-May 3, 2014, Philadelphia, Pennsylvania, Pennsylvania Convention Center
542
Neurology 82
February 11, 2014
IgG4-related leptomeningitis: A reversible cause of rapidly progressive cognitive decline Shyamal H. Mehta, Jeffrey A. Switzer, Paul Biddinger, et al. Neurology 2014;82;540-542 Published Online before print January 2, 2014 DOI 10.1212/WNL.0000000000000100 This information is current as of January 2, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/6/540.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/01/02/WNL.0000000000 000100.DC1.html
References
This article cites 6 articles, 1 of which you can access for free at: http://www.neurology.org/content/82/6/540.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Clinical Neurology http://www.neurology.org//cgi/collection/all_clinical_neurology All Cognitive Disorders/Dementia http://www.neurology.org//cgi/collection/all_cognitive_disorders_deme ntia
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
