- Email: [email protected]
Autoimmune encephalitis following alemtuzumab treatment of multiple sclerosis
Accepted Manuscript
Autoimmune Encephalitis following Alemtuzumab treatment of Multiple Sclerosis. Blake Giarola , Jennifer Massey , Yael Barnett , Michael Rodrigues , Ian Sutton PII: DOI: Reference:
S2211-0348(18)30532-7 https://doi.org/10.1016/j.msard.2018.12.004 MSARD 1067
To appear in:
Multiple Sclerosis and Related Disorders
Please cite this article as: Blake Giarola , Jennifer Massey , Yael Barnett , Michael Rodrigues , Ian Sutton , Autoimmune Encephalitis following Alemtuzumab treatment of Multiple Sclerosis., Multiple Sclerosis and Related Disorders (2018), doi: https://doi.org/10.1016/j.msard.2018.12.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title Page:
Autoimmune Encephalitis following Alemtuzumab treatment of Multiple Sclerosis.
1
1
2
3
1
Blake Giarola , Jennifer Massey , Yael Barnett , Michael Rodrigues , Ian Sutton .
CR IP T
1) Department of Neurology, St Vincent’s Hospital, Sydney, NSW, Australia. 2) Department of Radiology, St Vincent’s Hospital, Sydney, NSW, Australia.
Corresponding Author: Jennifer Massey Department of Neurology St Vincent’s Hospital, Sydney
Acknowledgements:
PT
Josep Dalmau
ED
[email protected]
M
390 Victoria St, Darlinghurst, NSW 2010
AN US
3) Department of Pathology, St Vincent’s Hospital, Sydney, NSW, Australia.
CE
University Hospital Clinic, University of Barcelona, Spain
AC
Highlights
This case describes the first reported case of autoimmune encephalitis as a secondary autoimmune complication of Alemtuzumab therapy.
Despite the absence of an identifiable antibody the patient responded well to immunotherapy including plasma exchange.
AC
CE
PT
ED
M
AN US
CR IP T
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT Abstract Secondary autoimmune disorders are a recognised complication of alemtuzumab treatment for multiple sclerosis. We report a case of autoimmune encephalitis manifesting as a polymorphic epilepsia partialis continua / status epilepticus seven months after the second course of alemtuzumab in a patient with previous autoimmune hypothyroidism and immune thrombocytopenic purpura. An MRI revealed multifocal cortical abnormalities and neuronal loss was evident on biopsy. Although
CR IP T
testing for anti-neuronal antibodies was negative, the patient responded well to immunotherapy
including plasma exchange. This is the first reported presentation of an autoimmune encephalopathy
AC
CE
PT
ED
M
AN US
secondary to alemtuzumab therapy.
ACCEPTED MANUSCRIPT Keywords Alemtuzumab Multiple Sclerosis Encephalitis
CR IP T
MRI
AC
CE
PT
ED
M
AN US
Histopathology
ACCEPTED MANUSCRIPT Case Report 1.1 Introduction: Alemtuzumab treatment of multiple sclerosis is associated with an increasing range 1
of secondary autoimmune disorders affecting up to 50% of treated individuals . Herein we report a case of presumed autoimmune encephalitis manifesting as a polymorphic epilepsia partialis continua / status epilepticus following alemtuzumab treatment.
CR IP T
1.2 Case History: A 20 year old female was diagnosed with multiple sclerosis in February 2014 and demonstrated clinical and MRI progression despite treatment with teriflunomide, fingolimod and
dimethyl fumarate. Due to side effects with oral medications, positive JC virus serology (index 2.83) and positive thyroglobulin (47IU) and thyroid peroxidase (74IU) antibodies the patient elected to
commence glatiramer acetate treatment in February 2016. Following an episode of right optic neuritis
AN US
and an accompanying MRI demonstrating seven gadolinium enhancing lesions, the patient consented to treatment with alemtuzumab in August 2016.
The first course of alemtuzumab was administered without complication until May 2017 when the patient developed fatigue and 3kg weight gain due to autoimmune hypothyroidism: thyroid stimulating
M
hormone 150 pmol/L (0.4 – 4.2), free T4 <3 (11 – 22 pmol/L) with elevated thyroglobulin (969IU) and
ED
thyroid peroxidase (973IU) antibodies. Symptoms improved with thyroxine replacement therapy and in August 2017 the second course of alemtuzumab was administered. In November 2017 the patient developed immune thrombocytopenic purpura (ITP) manifesting as a petechial rash and menorrhagia.
PT
9
9
The platelet count of 7x10 /L recovered to 337x10 /L in mid-December following treatment with
CE
dexamethasone and intravenous immunoglobulin, but a relapse of ITP in March 2018 required further treatment with dexamethasone and intravenous immunoglobulin.
AC
In April 2018 the patient developed a march of parasthesiae in the right arm which resolved spontaneously in two hours. The following day she developed left hemifacial myoclonus and epilepsy partialis continua (EPC) of the right genioglossus. An MRI study disclosed a new small cortical/subcortical focus of T2/FLAIR and DWI hyperintensity in the posterior left parietal lobe without true diffusion restriction or contrast enhancement (Figure 1a). A CSF study demonstrated normal constituents apart from CSF-specific oligoclonal bands. Despite initiation of carbamazepine treatment the patient developed EPC of the right trapezius two days later and an EEG disclosed left hemisphere generalised theta activity with temporal lobe sharp waves. The patient then had three generalised
ACCEPTED MANUSCRIPT tonic-clonic seizures terminated with intravenous diazepam. Despite treatment with phenytoin, carbamazepine and levetiracetam the patient continued to have frequent focal motor seizures. A further CSF study 6 days after the initial presentation disclosed an elevated lymphocyte count 6
(21x10 /L). PCR studies on both CSF specimens were negative for HSV, CMV, EBV, VZV, HHV6, JCV/BKV, Enteroviruses and TB. India ink, cryptococcal antigen and bacterial and fungal cultures were negative.
CR IP T
Eight days after presentation the patient developed complex partial seizures and episodes of frontal lobe seizure activity with conjugate gaze deviation to the left. Repeat MRI study showed enlargement of the left parietal lesion and development of numerous new cortical/subcortical foci of T2/FLAIR hyperintensity throughout both hemispheres (Figure 1b-d).
AN US
A biopsy of a lesion in the left superior temporal gyrus on day 9 demonstrated a patchy
leptomeningeal mixed inflammatory infiltrate containing lymphocytes, macrophages, scattered eosinophils and rare plasma cells (Figure 1e). In the cortex multiple foci of neuronal loss and necrosis were accompanied by prominent microglial activation and diffuse gliosis with many reactive astrocytes
M
expressing MHC class II antigens (Figure 1f/g). Numerous cortical vessels were lined by swollen reactive endothelial cells, in the absence of vasculitis, with small numbers of perivascular CD68+
ED
macrophages, sparse CD3+ T cells, isolated CD20+ B cells and occasional eosinophils (Figure 1h). Rare interstitial T cells were noted. No viral inclusions or cytopathic effects were appreciated and JC
AC
CE
PT
virus PCR was negative. No cortical or white matter demyelination was identified.
AN US
CR IP T
ACCEPTED MANUSCRIPT
Figure 1: Initial MRI: (a) Axial volumetric FLAIR demonstrating small cortical/subcortical hyperintense lesion in the posterior left parietal lobe. (b) Repeat MRI demonstrating interval development of multiple new cortical lesions (broken arrows), and (c) evolution of original
M
lesion (solid arrow) with (d) corresponding DWI hyperintensity (solid arrow) without reduction in ADC (not shown). Brain biopsy: (e) Leptomeninges with chronic inflammation including
ED
CD3 + T cells (insert). (f) Cerebral cortex with perivascular inflammation, scattered necrotic neurons (white arrows) and reactive endothelial nuclei (black arrows), (g) cerebral cortex with
PT
activated microglia and reactive astrocytes (MHC Class II), (h) cerebral cortex with sparse
CE
perivascular (black arrow) and rare interstitial CD3+T cells. Post-operatively the patient was maintained on a midazolam/propofol infusion to suppress seizure
AC
activity and generalised polyspike and wave activity on the EEG. The patient received intravenous immunoglobulin (0.4g/kg/day) and 1g methylprednisolone daily for five days but attempts to withdraw midazolam resulted in emergent seizure activity despite addition of valproate and gabapentin. On day 19 the patient received a further dose of 1gm methylprednisolone and commenced the first of five alternate day plasma exchanges. Withdrawal of midazolam/propofol and extubation was possible on day 21, at which time the only abnormality on clinical examination was a continuous rhythmic contraction of the glabella region that occurred in the absence of an EEG correlate. Further plasma
ACCEPTED MANUSCRIPT exchange and methylprednisolone was administered on day 27 and 34. An MRI on day 34 disclosed a new lesion in the left temporal operculum, but subsequent MRI studies on day 41 and 62 demonstrated resolution / stabilisation of the cortical change. The patient received a reducing course of oral prednisolone and a monthly dose of intravenous immunoglobulin for three months. Antiepileptic medication was gradually withdrawn over this period and the patient remained asymptomatic with a normal EEG.
CR IP T
Although an autoimmune aetiology was suspected, serum and CSF testing with rat brain tissue
immunohistochemistry and cell-based assays in Hospital Clinic, University of Barcelona was negative for antibodies to cell surface neuronal antigens (NMDA, AMPA, GABA(A), GABA(B), mGluR1, and mGluR5 receptors, LGI1 and Caspr2, DPPX, Neurexin3 and Iglon5).
AN US
1.3 Discussion: Alemtuzumab treatment in multiple sclerosis results in a rapid and profound depletion of circulating lymphocytes and is followed by an immune reconstitution that is characterised by early B 2
cell hyperproliferation . Whilst an increasing number of antibody-associated autoimmune diseases are 1
a recognised complication of therapy , CNS complications are rare with only a single case of 3
M
disseminated necrotizing leukoencephalopathy reported to date . Herein we report a presentation of EPC / status epilepticus characterised by cortical MRI changes and neuronal loss on biopsy occurring
ED
seven months after the second course of alemtuzumab in a patient with autoimmune hypothyroidism
PT
and ITP.
A number of neurological syndromes, including EPC, associate with thyroid autoimmunity and are 4
CE
collectively termed ‘Hashimoto’s Encephalopathy’ (HE) . Both GABA(A) and AMPA antibodies have been reported in HE and up to 25% of cases of HE associate with an antibody response to alpha5
AC
enolase, which hasn’t been tested for in this case . Although anti-neuronal antibodies were not identified, the absence of an infective cause and response to immunotherapy leads us to conclude this presentation arose as an autoimmune encephalopathy secondary to alemtuzumab therapy.
ACCEPTED MANUSCRIPT The patient has given informed consent for publication of this case. A signed consent form can be provided if required.
Declaration of interests - Statement Dr. Massey reports honoraria from Biogen, Merck, Genzyme and Teva, outside the submitted work.
CR IP T
Dr. Massey has received a postgraduate research scholarship from MS Research Australia. Dr. Sutton reports honoraria from Biogen, Merck, Genzyme and Teva, outside the submitted work.
AC
CE
PT
ED
M
AN US
There are no other funding sources to disclose.
ACCEPTED MANUSCRIPT References:
Tuohy O, Costelloe L, Hill-Cawthorne G, Bjornson I, Harding K, Robertson N et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry 2015; 86(2): 208-215. e-pub ahead of print 2014/05/23; doi: 10.1136/jnnp-2014-307721
2.
Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol 2017. epub ahead of print 2017/06/13; doi: 10.1001/jamaneurol.2017.0676
3.
Metz I, Rieckmann P, Kallmann BA, Bruck W. Disseminated necrotizing leukoencephalopathy eight months after alemtuzumab treatment for multiple sclerosis. Acta neuropathologica communications 2016; 4(1): 81. e-pub ahead of print 2016/08/10; doi: 10.1186/s40478-0160352-1
4.
Masuda H, Mori M, Ito S, Yagishita T, Kuwabara S. Steroid-Responsive Epilepsia Partialis Continua with Anti-Thyroid Antibodies: A Spectrum of Hashimoto's Encephalopathy? Case Rep Neurol 2014; 6(2): 166-170. e-pub ahead of print 2014/06/17; doi: 10.1159/000363178
5.
Kishitani T, Matsunaga A, Ikawa M, Hayashi K, Yamamura O, Hamano T et al. Limbic encephalitis associated with anti-NH2-terminal of alpha-enolase antibodies: A clinical subtype of Hashimoto encephalopathy. Medicine (Baltimore) 2017; 96(10): e6181. e-pub ahead of print 2017/03/09; doi: 10.1097/MD.0000000000006181
AC
CE
PT
ED
M
AN US
CR IP T
1.
Autoimmune Encephalitis following Alemtuzumab treatment of Multiple Sclerosis. Blake Giarola , Jennifer Massey , Yael Barnett , Michael Rodrigues , Ian Sutton PII: DOI: Reference:
S2211-0348(18)30532-7 https://doi.org/10.1016/j.msard.2018.12.004 MSARD 1067
To appear in:
Multiple Sclerosis and Related Disorders
Please cite this article as: Blake Giarola , Jennifer Massey , Yael Barnett , Michael Rodrigues , Ian Sutton , Autoimmune Encephalitis following Alemtuzumab treatment of Multiple Sclerosis., Multiple Sclerosis and Related Disorders (2018), doi: https://doi.org/10.1016/j.msard.2018.12.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title Page:
Autoimmune Encephalitis following Alemtuzumab treatment of Multiple Sclerosis.
1
1
2
3
1
Blake Giarola , Jennifer Massey , Yael Barnett , Michael Rodrigues , Ian Sutton .
CR IP T
1) Department of Neurology, St Vincent’s Hospital, Sydney, NSW, Australia. 2) Department of Radiology, St Vincent’s Hospital, Sydney, NSW, Australia.
Corresponding Author: Jennifer Massey Department of Neurology St Vincent’s Hospital, Sydney
Acknowledgements:
PT
Josep Dalmau
ED
[email protected]
M
390 Victoria St, Darlinghurst, NSW 2010
AN US
3) Department of Pathology, St Vincent’s Hospital, Sydney, NSW, Australia.
CE
University Hospital Clinic, University of Barcelona, Spain
AC
Highlights
This case describes the first reported case of autoimmune encephalitis as a secondary autoimmune complication of Alemtuzumab therapy.
Despite the absence of an identifiable antibody the patient responded well to immunotherapy including plasma exchange.
AC
CE
PT
ED
M
AN US
CR IP T
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT Abstract Secondary autoimmune disorders are a recognised complication of alemtuzumab treatment for multiple sclerosis. We report a case of autoimmune encephalitis manifesting as a polymorphic epilepsia partialis continua / status epilepticus seven months after the second course of alemtuzumab in a patient with previous autoimmune hypothyroidism and immune thrombocytopenic purpura. An MRI revealed multifocal cortical abnormalities and neuronal loss was evident on biopsy. Although
CR IP T
testing for anti-neuronal antibodies was negative, the patient responded well to immunotherapy
including plasma exchange. This is the first reported presentation of an autoimmune encephalopathy
AC
CE
PT
ED
M
AN US
secondary to alemtuzumab therapy.
ACCEPTED MANUSCRIPT Keywords Alemtuzumab Multiple Sclerosis Encephalitis
CR IP T
MRI
AC
CE
PT
ED
M
AN US
Histopathology
ACCEPTED MANUSCRIPT Case Report 1.1 Introduction: Alemtuzumab treatment of multiple sclerosis is associated with an increasing range 1
of secondary autoimmune disorders affecting up to 50% of treated individuals . Herein we report a case of presumed autoimmune encephalitis manifesting as a polymorphic epilepsia partialis continua / status epilepticus following alemtuzumab treatment.
CR IP T
1.2 Case History: A 20 year old female was diagnosed with multiple sclerosis in February 2014 and demonstrated clinical and MRI progression despite treatment with teriflunomide, fingolimod and
dimethyl fumarate. Due to side effects with oral medications, positive JC virus serology (index 2.83) and positive thyroglobulin (47IU) and thyroid peroxidase (74IU) antibodies the patient elected to
commence glatiramer acetate treatment in February 2016. Following an episode of right optic neuritis
AN US
and an accompanying MRI demonstrating seven gadolinium enhancing lesions, the patient consented to treatment with alemtuzumab in August 2016.
The first course of alemtuzumab was administered without complication until May 2017 when the patient developed fatigue and 3kg weight gain due to autoimmune hypothyroidism: thyroid stimulating
M
hormone 150 pmol/L (0.4 – 4.2), free T4 <3 (11 – 22 pmol/L) with elevated thyroglobulin (969IU) and
ED
thyroid peroxidase (973IU) antibodies. Symptoms improved with thyroxine replacement therapy and in August 2017 the second course of alemtuzumab was administered. In November 2017 the patient developed immune thrombocytopenic purpura (ITP) manifesting as a petechial rash and menorrhagia.
PT
9
9
The platelet count of 7x10 /L recovered to 337x10 /L in mid-December following treatment with
CE
dexamethasone and intravenous immunoglobulin, but a relapse of ITP in March 2018 required further treatment with dexamethasone and intravenous immunoglobulin.
AC
In April 2018 the patient developed a march of parasthesiae in the right arm which resolved spontaneously in two hours. The following day she developed left hemifacial myoclonus and epilepsy partialis continua (EPC) of the right genioglossus. An MRI study disclosed a new small cortical/subcortical focus of T2/FLAIR and DWI hyperintensity in the posterior left parietal lobe without true diffusion restriction or contrast enhancement (Figure 1a). A CSF study demonstrated normal constituents apart from CSF-specific oligoclonal bands. Despite initiation of carbamazepine treatment the patient developed EPC of the right trapezius two days later and an EEG disclosed left hemisphere generalised theta activity with temporal lobe sharp waves. The patient then had three generalised
ACCEPTED MANUSCRIPT tonic-clonic seizures terminated with intravenous diazepam. Despite treatment with phenytoin, carbamazepine and levetiracetam the patient continued to have frequent focal motor seizures. A further CSF study 6 days after the initial presentation disclosed an elevated lymphocyte count 6
(21x10 /L). PCR studies on both CSF specimens were negative for HSV, CMV, EBV, VZV, HHV6, JCV/BKV, Enteroviruses and TB. India ink, cryptococcal antigen and bacterial and fungal cultures were negative.
CR IP T
Eight days after presentation the patient developed complex partial seizures and episodes of frontal lobe seizure activity with conjugate gaze deviation to the left. Repeat MRI study showed enlargement of the left parietal lesion and development of numerous new cortical/subcortical foci of T2/FLAIR hyperintensity throughout both hemispheres (Figure 1b-d).
AN US
A biopsy of a lesion in the left superior temporal gyrus on day 9 demonstrated a patchy
leptomeningeal mixed inflammatory infiltrate containing lymphocytes, macrophages, scattered eosinophils and rare plasma cells (Figure 1e). In the cortex multiple foci of neuronal loss and necrosis were accompanied by prominent microglial activation and diffuse gliosis with many reactive astrocytes
M
expressing MHC class II antigens (Figure 1f/g). Numerous cortical vessels were lined by swollen reactive endothelial cells, in the absence of vasculitis, with small numbers of perivascular CD68+
ED
macrophages, sparse CD3+ T cells, isolated CD20+ B cells and occasional eosinophils (Figure 1h). Rare interstitial T cells were noted. No viral inclusions or cytopathic effects were appreciated and JC
AC
CE
PT
virus PCR was negative. No cortical or white matter demyelination was identified.
AN US
CR IP T
ACCEPTED MANUSCRIPT
Figure 1: Initial MRI: (a) Axial volumetric FLAIR demonstrating small cortical/subcortical hyperintense lesion in the posterior left parietal lobe. (b) Repeat MRI demonstrating interval development of multiple new cortical lesions (broken arrows), and (c) evolution of original
M
lesion (solid arrow) with (d) corresponding DWI hyperintensity (solid arrow) without reduction in ADC (not shown). Brain biopsy: (e) Leptomeninges with chronic inflammation including
ED
CD3 + T cells (insert). (f) Cerebral cortex with perivascular inflammation, scattered necrotic neurons (white arrows) and reactive endothelial nuclei (black arrows), (g) cerebral cortex with
PT
activated microglia and reactive astrocytes (MHC Class II), (h) cerebral cortex with sparse
CE
perivascular (black arrow) and rare interstitial CD3+T cells. Post-operatively the patient was maintained on a midazolam/propofol infusion to suppress seizure
AC
activity and generalised polyspike and wave activity on the EEG. The patient received intravenous immunoglobulin (0.4g/kg/day) and 1g methylprednisolone daily for five days but attempts to withdraw midazolam resulted in emergent seizure activity despite addition of valproate and gabapentin. On day 19 the patient received a further dose of 1gm methylprednisolone and commenced the first of five alternate day plasma exchanges. Withdrawal of midazolam/propofol and extubation was possible on day 21, at which time the only abnormality on clinical examination was a continuous rhythmic contraction of the glabella region that occurred in the absence of an EEG correlate. Further plasma
ACCEPTED MANUSCRIPT exchange and methylprednisolone was administered on day 27 and 34. An MRI on day 34 disclosed a new lesion in the left temporal operculum, but subsequent MRI studies on day 41 and 62 demonstrated resolution / stabilisation of the cortical change. The patient received a reducing course of oral prednisolone and a monthly dose of intravenous immunoglobulin for three months. Antiepileptic medication was gradually withdrawn over this period and the patient remained asymptomatic with a normal EEG.
CR IP T
Although an autoimmune aetiology was suspected, serum and CSF testing with rat brain tissue
immunohistochemistry and cell-based assays in Hospital Clinic, University of Barcelona was negative for antibodies to cell surface neuronal antigens (NMDA, AMPA, GABA(A), GABA(B), mGluR1, and mGluR5 receptors, LGI1 and Caspr2, DPPX, Neurexin3 and Iglon5).
AN US
1.3 Discussion: Alemtuzumab treatment in multiple sclerosis results in a rapid and profound depletion of circulating lymphocytes and is followed by an immune reconstitution that is characterised by early B 2
cell hyperproliferation . Whilst an increasing number of antibody-associated autoimmune diseases are 1
a recognised complication of therapy , CNS complications are rare with only a single case of 3
M
disseminated necrotizing leukoencephalopathy reported to date . Herein we report a presentation of EPC / status epilepticus characterised by cortical MRI changes and neuronal loss on biopsy occurring
ED
seven months after the second course of alemtuzumab in a patient with autoimmune hypothyroidism
PT
and ITP.
A number of neurological syndromes, including EPC, associate with thyroid autoimmunity and are 4
CE
collectively termed ‘Hashimoto’s Encephalopathy’ (HE) . Both GABA(A) and AMPA antibodies have been reported in HE and up to 25% of cases of HE associate with an antibody response to alpha5
AC
enolase, which hasn’t been tested for in this case . Although anti-neuronal antibodies were not identified, the absence of an infective cause and response to immunotherapy leads us to conclude this presentation arose as an autoimmune encephalopathy secondary to alemtuzumab therapy.
ACCEPTED MANUSCRIPT The patient has given informed consent for publication of this case. A signed consent form can be provided if required.
Declaration of interests - Statement Dr. Massey reports honoraria from Biogen, Merck, Genzyme and Teva, outside the submitted work.
CR IP T
Dr. Massey has received a postgraduate research scholarship from MS Research Australia. Dr. Sutton reports honoraria from Biogen, Merck, Genzyme and Teva, outside the submitted work.
AC
CE
PT
ED
M
AN US
There are no other funding sources to disclose.
ACCEPTED MANUSCRIPT References:
Tuohy O, Costelloe L, Hill-Cawthorne G, Bjornson I, Harding K, Robertson N et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry 2015; 86(2): 208-215. e-pub ahead of print 2014/05/23; doi: 10.1136/jnnp-2014-307721
2.
Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol 2017. epub ahead of print 2017/06/13; doi: 10.1001/jamaneurol.2017.0676
3.
Metz I, Rieckmann P, Kallmann BA, Bruck W. Disseminated necrotizing leukoencephalopathy eight months after alemtuzumab treatment for multiple sclerosis. Acta neuropathologica communications 2016; 4(1): 81. e-pub ahead of print 2016/08/10; doi: 10.1186/s40478-0160352-1
4.
Masuda H, Mori M, Ito S, Yagishita T, Kuwabara S. Steroid-Responsive Epilepsia Partialis Continua with Anti-Thyroid Antibodies: A Spectrum of Hashimoto's Encephalopathy? Case Rep Neurol 2014; 6(2): 166-170. e-pub ahead of print 2014/06/17; doi: 10.1159/000363178
5.
Kishitani T, Matsunaga A, Ikawa M, Hayashi K, Yamamura O, Hamano T et al. Limbic encephalitis associated with anti-NH2-terminal of alpha-enolase antibodies: A clinical subtype of Hashimoto encephalopathy. Medicine (Baltimore) 2017; 96(10): e6181. e-pub ahead of print 2017/03/09; doi: 10.1097/MD.0000000000006181
AC
CE
PT
ED
M
AN US
CR IP T
1.