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Chronic Inflammatory Demyelinating Polyneuropathy Associated With Autoimmune Hepatitis
Accepted Manuscript Chronic inflammatory demyelinating polyneuropathy associated with autoimmune hepatitis Joana P. Domingos, MD Cristina Garrido, MD Helena Moreira Silva, MD Claúdia Monteiro, MD Ermelinda S. Silva, MD Sónia Figueiroa, MD Inês C. Carrilho, MD PII:
S0887-8994(14)00259-8
DOI:
10.1016/j.pediatrneurol.2014.04.017
Reference:
PNU 8342
To appear in:
Pediatric Neurology
Received Date: 24 January 2014 Revised Date:
13 April 2014
Accepted Date: 15 April 2014
Please cite this article as: Domingos JP, Garrido C, Moreira Silva H, Monteiro C, Silva ES, Figueiroa S, Carrilho IC, Chronic inflammatory demyelinating polyneuropathy associated with autoimmune hepatitis, Pediatric Neurology (2014), doi: 10.1016/j.pediatrneurol.2014.04.017. 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: Chronic inflammatory demyelinating polyneuropathy associated with autoimmune hepatitis Running title: CIDP associated with autoimmune hepatitis Joana P. Domingos, MD, Department of Neurology, Centro Hospitalar do Porto – Hospital de Santo
RI PT
António, Porto, Portugal Cristina Garrido, MD, Pediatric Neurology, Department of Child and Adolescent, Centro Hospitalar do Porto – Hospital de Santo António, Porto, Portugal
M AN U
Porto – Hospital de Santo António, Porto, Portugal
SC
Helena Moreira Silva, MD, Pediatrics, Department of Child and Adolescent, Centro Hospitalar do
Claúdia Monteiro, MD, Department of Pediatrics, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal
Ermelinda S. Silva, MD, Pediatric Gastroenterology, Department of Child and Adolescent, Centro
TE D
Hospitalar do Porto – Hospital de Santo António, Porto, Portugal
Sónia Figueiroa, MD, Pediatric Neurology, Department of Child and Adolescent, Centro Hospitalar do
EP
Porto – Hospital de Santo António, Porto, Portugal Inês C. Carrilho, MD, Pediatric Neurology, Department of Child and Adolescent, Centro Hospitalar do
AC C
Porto – Hospital de Santo António, Porto, Portugal Corresponding author: Joana Pisco Domingos, Department of Neurology, Centro Hospitalar do Porto – Hospital de Santo António, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal; E-mail: [email protected]; Telephone: 00351933282372, fax 00351223320318 Word count: 679
ACCEPTED MANUSCRIPT Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system 1. Autoimmune hepatitis (AIH) is a liver disorder of unknown etiology. Type 1 is characterized by the presence of antinuclear (ANA) or anti-smooth muscle antibodies (SMA) and type 2 is associated with
RI PT
anti-liver kidney microsomal type 1 antibody (anti-LKM1) 2.
AIH is frequently associated with other autoimmune disorders (20%) such as thyroiditis2, Sjogren’s
neuropathy has been rarely described3. We report one case.
SC
syndrome, systemic lupus erythematosus3 and myasthenia gravis1. However, the association with
M AN U
An eight year old girl, with no previous medical history, was referred to our hospital with distal muscle weakness and severe gait disturbance. Her symptoms started 6 months earlier with nausea and anorexia. Two months before admission she had lost 3 kilograms of weight (over 2 months), complained of fatigue, reported paresthesia of all four extremities and had “clumsy” writing. One
TE D
month prior to admission she started to have difficulties performing every-day tasks (playing in the park, riding the bicycle) and her left lower limb seemed to be weaker when walking. The weakness slowly progressed affecting all four limbs and by the time she was admitted she needed support to
EP
walk. She had no history of recent infections or vaccination. At admission she had a tetraparesis grade 3-4/5, with absent reflexes in the lower limbs and distally
AC C
in the upper limbs, the remainder were hyporeflexic. She had a distal, painful hypoesthesia of the lower limbs and deep sensation (postural and vibration sense) was compromised in both halluces (worse on the left). She had a wide-based gait associated with steppage. Blood analysis revealed elevated liver enzymes with AST - 1242 U/L, ALT - 1692 U/L, gamaGT - 101 U/L, high total bilirubin 2,76 mg/dL and conjugated bilirubin 1,91 mg/dL and elevated total protein levels 10,36 g/dL. Prothrombin time and partial thromboplastin time were both prolonged. IgG levels were markedly elevated (5680mg/dL). The serological study was negative (Borrelia, HIV, Epstein Barr
ACCEPTED MANUSCRIPT virus, cytomegalovirus, Parvovírus B19, hepatitis A, B and C). Serum alpha-1-antitripsyn and ceruloplasmin were normal. The immunological study was positive for ANA (1/320), SMA (1/640) and anti-neutrophil cytoplasm (1/640) and negative for anti-LKM1, anti-ganglioside and anti-myelinassociated glycoprotein. The cerebrospinal fluid examination revealed elevated protein levels but
RI PT
was otherwise unremarkable. The motor nerve conduction studies at the left median and peroneal nerves showed a slowing of
in the left median and sural nerves were not evoked.
SC
conduction and a prolonged distal latency with conduction block. Sensory nerve conduction studies
M AN U
The liver biopsy was typical of AIH, revealing a dense mononuclear and plasma cell infiltration in the portal areas expanding to the liver lobule, destruction of the hepatocytes at the periphery of the lobule resembling an interface hepatitis, and connective tissue collapse with portal fibrosis and portal-portal septa.
TE D
The diagnosis of AIH type 1 was established and she started a four week course of oral prednisolone (60mg/day). The dose was slowly tapered once azathioprine was added. The liver enzymes and total protein levels gradually returned to within the normal range and the IgG
EP
level slowly decreased. One week after starting treatment she was able to walk without support.
AC C
Two months later the deep tendon reflexes remained absent/hyporeflexic but muscle strength and proprioception had returned to normal. Vibration sense had improved and her gait was now normal. Currently, four months after starting treatment, she is on prednisolone 12,5 mg/day and azathioprine 62,5mg/day. Her sensory deficit persists. The association between CIDP and AIH type 1 is rare and has not been previously described in children.
ACCEPTED MANUSCRIPT In the literature there are a few cases of AIH associated with different types of neuropathies namely sensory neuronopathies4 and multiplex neuritis3, all in adult patients. The pathogenesis of CIDP and AIH is not completely understood but both cellular and humoral factors are implicated1,5. Both diseases have similar treatment options. In fact, our patient had a
RI PT
good clinical response to steroids and immunosuppression both from the hepatic and neurological point of view.
SC
In our case, the co-existence of AIH and CIDP may well be the expression of the same underlying
AC C
EP
TE D
M AN U
immunological disturbance.
ACCEPTED MANUSCRIPT References 1 – Riekhoff AG, Jadoul C, Mercelis R, Cras P, Ceulemans BP. Childhood chronic inflammatory demyelinating polyneuroradiculopathy--three cases and a review of the literature. Eur J Paediatr
RI PT
Neurol. 2012 Jul;16(4):315-31 2 – Mieli-Vergani G, Vergani D. Autoimmune paediatric liver disease. World J Gastroenterol. 2008 Jun 7;14(21):3360-7.
M AN U
case report. World J Gastroenterol. 2006 Sep 7;12(33):5396-8.
SC
3 – Luth S, Birklein F, Schramm C, et al. Multiplex neuritis in a patient with autoimmune hepatitis: a
4 – Martinez AR, Nunes MB, Nucci A, França MC Jr. Sensory neuronopathy and autoimmune diseases. Autoimmune Dis. 2012;2012:873587.
5 – Vergani D, Mieli-Vergani G. Aetiopathogenesis of autoimmune hepatitis. World J Gastroenterol.
AC C
EP
TE D
2008 Jun 7;14(21):3306-12.
S0887-8994(14)00259-8
DOI:
10.1016/j.pediatrneurol.2014.04.017
Reference:
PNU 8342
To appear in:
Pediatric Neurology
Received Date: 24 January 2014 Revised Date:
13 April 2014
Accepted Date: 15 April 2014
Please cite this article as: Domingos JP, Garrido C, Moreira Silva H, Monteiro C, Silva ES, Figueiroa S, Carrilho IC, Chronic inflammatory demyelinating polyneuropathy associated with autoimmune hepatitis, Pediatric Neurology (2014), doi: 10.1016/j.pediatrneurol.2014.04.017. 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: Chronic inflammatory demyelinating polyneuropathy associated with autoimmune hepatitis Running title: CIDP associated with autoimmune hepatitis Joana P. Domingos, MD, Department of Neurology, Centro Hospitalar do Porto – Hospital de Santo
RI PT
António, Porto, Portugal Cristina Garrido, MD, Pediatric Neurology, Department of Child and Adolescent, Centro Hospitalar do Porto – Hospital de Santo António, Porto, Portugal
M AN U
Porto – Hospital de Santo António, Porto, Portugal
SC
Helena Moreira Silva, MD, Pediatrics, Department of Child and Adolescent, Centro Hospitalar do
Claúdia Monteiro, MD, Department of Pediatrics, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal
Ermelinda S. Silva, MD, Pediatric Gastroenterology, Department of Child and Adolescent, Centro
TE D
Hospitalar do Porto – Hospital de Santo António, Porto, Portugal
Sónia Figueiroa, MD, Pediatric Neurology, Department of Child and Adolescent, Centro Hospitalar do
EP
Porto – Hospital de Santo António, Porto, Portugal Inês C. Carrilho, MD, Pediatric Neurology, Department of Child and Adolescent, Centro Hospitalar do
AC C
Porto – Hospital de Santo António, Porto, Portugal Corresponding author: Joana Pisco Domingos, Department of Neurology, Centro Hospitalar do Porto – Hospital de Santo António, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal; E-mail: [email protected]; Telephone: 00351933282372, fax 00351223320318 Word count: 679
ACCEPTED MANUSCRIPT Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system 1. Autoimmune hepatitis (AIH) is a liver disorder of unknown etiology. Type 1 is characterized by the presence of antinuclear (ANA) or anti-smooth muscle antibodies (SMA) and type 2 is associated with
RI PT
anti-liver kidney microsomal type 1 antibody (anti-LKM1) 2.
AIH is frequently associated with other autoimmune disorders (20%) such as thyroiditis2, Sjogren’s
neuropathy has been rarely described3. We report one case.
SC
syndrome, systemic lupus erythematosus3 and myasthenia gravis1. However, the association with
M AN U
An eight year old girl, with no previous medical history, was referred to our hospital with distal muscle weakness and severe gait disturbance. Her symptoms started 6 months earlier with nausea and anorexia. Two months before admission she had lost 3 kilograms of weight (over 2 months), complained of fatigue, reported paresthesia of all four extremities and had “clumsy” writing. One
TE D
month prior to admission she started to have difficulties performing every-day tasks (playing in the park, riding the bicycle) and her left lower limb seemed to be weaker when walking. The weakness slowly progressed affecting all four limbs and by the time she was admitted she needed support to
EP
walk. She had no history of recent infections or vaccination. At admission she had a tetraparesis grade 3-4/5, with absent reflexes in the lower limbs and distally
AC C
in the upper limbs, the remainder were hyporeflexic. She had a distal, painful hypoesthesia of the lower limbs and deep sensation (postural and vibration sense) was compromised in both halluces (worse on the left). She had a wide-based gait associated with steppage. Blood analysis revealed elevated liver enzymes with AST - 1242 U/L, ALT - 1692 U/L, gamaGT - 101 U/L, high total bilirubin 2,76 mg/dL and conjugated bilirubin 1,91 mg/dL and elevated total protein levels 10,36 g/dL. Prothrombin time and partial thromboplastin time were both prolonged. IgG levels were markedly elevated (5680mg/dL). The serological study was negative (Borrelia, HIV, Epstein Barr
ACCEPTED MANUSCRIPT virus, cytomegalovirus, Parvovírus B19, hepatitis A, B and C). Serum alpha-1-antitripsyn and ceruloplasmin were normal. The immunological study was positive for ANA (1/320), SMA (1/640) and anti-neutrophil cytoplasm (1/640) and negative for anti-LKM1, anti-ganglioside and anti-myelinassociated glycoprotein. The cerebrospinal fluid examination revealed elevated protein levels but
RI PT
was otherwise unremarkable. The motor nerve conduction studies at the left median and peroneal nerves showed a slowing of
in the left median and sural nerves were not evoked.
SC
conduction and a prolonged distal latency with conduction block. Sensory nerve conduction studies
M AN U
The liver biopsy was typical of AIH, revealing a dense mononuclear and plasma cell infiltration in the portal areas expanding to the liver lobule, destruction of the hepatocytes at the periphery of the lobule resembling an interface hepatitis, and connective tissue collapse with portal fibrosis and portal-portal septa.
TE D
The diagnosis of AIH type 1 was established and she started a four week course of oral prednisolone (60mg/day). The dose was slowly tapered once azathioprine was added. The liver enzymes and total protein levels gradually returned to within the normal range and the IgG
EP
level slowly decreased. One week after starting treatment she was able to walk without support.
AC C
Two months later the deep tendon reflexes remained absent/hyporeflexic but muscle strength and proprioception had returned to normal. Vibration sense had improved and her gait was now normal. Currently, four months after starting treatment, she is on prednisolone 12,5 mg/day and azathioprine 62,5mg/day. Her sensory deficit persists. The association between CIDP and AIH type 1 is rare and has not been previously described in children.
ACCEPTED MANUSCRIPT In the literature there are a few cases of AIH associated with different types of neuropathies namely sensory neuronopathies4 and multiplex neuritis3, all in adult patients. The pathogenesis of CIDP and AIH is not completely understood but both cellular and humoral factors are implicated1,5. Both diseases have similar treatment options. In fact, our patient had a
RI PT
good clinical response to steroids and immunosuppression both from the hepatic and neurological point of view.
SC
In our case, the co-existence of AIH and CIDP may well be the expression of the same underlying
AC C
EP
TE D
M AN U
immunological disturbance.
ACCEPTED MANUSCRIPT References 1 – Riekhoff AG, Jadoul C, Mercelis R, Cras P, Ceulemans BP. Childhood chronic inflammatory demyelinating polyneuroradiculopathy--three cases and a review of the literature. Eur J Paediatr
RI PT
Neurol. 2012 Jul;16(4):315-31 2 – Mieli-Vergani G, Vergani D. Autoimmune paediatric liver disease. World J Gastroenterol. 2008 Jun 7;14(21):3360-7.
M AN U
case report. World J Gastroenterol. 2006 Sep 7;12(33):5396-8.
SC
3 – Luth S, Birklein F, Schramm C, et al. Multiplex neuritis in a patient with autoimmune hepatitis: a
4 – Martinez AR, Nunes MB, Nucci A, França MC Jr. Sensory neuronopathy and autoimmune diseases. Autoimmune Dis. 2012;2012:873587.
5 – Vergani D, Mieli-Vergani G. Aetiopathogenesis of autoimmune hepatitis. World J Gastroenterol.
AC C
EP
TE D
2008 Jun 7;14(21):3306-12.