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Guillain-Barre syndrome in a patient with primary extranodal intestinal non-hodgkin's lymphoma: paraneoplastic, drug induced or coincidental?/Primer ekstranodal intestinal lenfomali bir hastada gozlenen Guillain Barre sendromu: paraneoplastik kokenli mi, ilac yan etkisi mi, rastlantisal mi?


Guillain-Barre syndrome (GBS) is an acquired acute neuropathy and covers the spectrum of acute inflammatory demyelinating polyradiculoneuropathy (AIDP), Miller Fisher syndrome, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN) and acute pandysautonomia. GBS can affect both peripheral and cranial nerves and generally has a rapid progressive course with ascending paresis of the limbs and reduction or absence of reflexes. It is assumed that activation of T cells results in antibody production against protein antigens on peripheral nerves causing their damage. Viral and bacterial agents (especially campylobacter jejuni), immunisation, surgical treatments, drugs and neoplastic diseases are considered in the aetiology (1,2). Neurological involvement is observed in 5-25% of patients with lymphoma being either the first presentation of the disease or emerging during its course (3,4).

In this short report, we present a patient with primary extranodal non-Hodgkin's lymphoma (NHL) of the colon who developed GBS during the disease course.

Case Report

A 66-year-old male patient presented with abdominal pain and loss of weight. He was examined due to similar complaints in another centre in September 2007. Computed tomography (CT) of the abdomen revealed thickening of the cecal wall and lymphadenomegaly in the peripheral mesenteries. Colonoscopy had shown a giant ulcerated mass lesion located in the distal part of the terminal ileum and cecum. The patient underwent a right hemicolectomy (Figure 1A). Histological examination of the mass showed a tumour containing high-grade atypical cells (Figure 1B) which were CD20 (+), LCA (+), CD3 (-) and cytokeratin (-). The patient was diagnosed with ileocecal large B-cell lymphoma and treated with 5 cycles of adjuvant chemotherapy including cyclophosphamide 750 mg/[m.sup.2] day 1, epirubicin 50 mg/[m.sup.2] day 1, vincristine 1.4 mg/[m.sup.2] (max 2 mg) day 1, prednisone 100 mg/[m.sup.2] day 1-5 (CEOP) every three weeks. After the 5th cycle of therapy, the patient refused treatment and had not been followed up further.



The patient was seen in our outpatient clinic in July 2008. Positron Emission Tomography/Computed Tomography (PET/CT) scanning revealed increased fluorodeoxyglucose (FDG) uptake in the area of the terminal ileum and adjacent conglomerated enlarged lymph nodes. The patient was diagnosed with a regional relapse and a new combination chemotherapy including cyclophosphamide 750 mg/[m.sup.2] day 1, doxorubicin 50 mg/[m.sup.2] day 1, vincristine 1.4 mg/[m.sup.2] (max 2 mg) day 1, prednisone 100 mg/[m.sup.2] day 1-5, rituximab 375 mg/[m.sup.2] day 0 (R-CHOP), every tree weeks, was initiated.

Seven weeks after starting chemotherapy, the patient complained of severe fatigue, weakness in both limbs and difficulty in walking. He was normothermic (36.8 [degrees]C), slightly tachycardic (heart rate: 100/min), mildly hypertensive (blood pressure: 170/100 mmHg) and had a slight orthostatic hypotension.

The neurological examination revealed unaffected cranial nerves, symmetrical severe paresis of the lower limbs (muscle strength 3/5 according to the medical research council [MRC] grading system in the proximal muscles, and 2/5 in the distal muscles) and symmetrical slight paresis of upper distal muscles (muscle strength +4/5). Deep tendon reflexes were completely absent, there was no Babinski reflex or any other pyramidal sign. Sense of touch was reduced in both lower limbs up to the level of the knee. Sense of vibration was completely lost at the distal parts of the lower limbs. Cerebrospinal fluid (CSF) examination showed slightly elevated protein level (59 mg/dl) and no cells. Anti-GQ1a, anti-GQ1b and anti-GM antibodies were negative. In addition, protein electrophoresis and serum IgG were within normal ranges. Viral serology of serum and CSF was levels also negative. Magnetic resonance imaging (MRI) of the cranium and spinal cord was normal. Nerve conduction studies and needle electromyography (EMG) showed an acquired demyelinating polyneuropathy (PNP) which was accompanied by axonal loss. A decrease in compound muscle action potentials, prolongation of distal motor latencies and a reduction in motor conduction velocities were observed. Sensory action potentials were completely absent, median, ulnar and tibial F waves could not be obtained and needle electromyography showed signs of early denervation (Table 1a and 1b).

The patient was diagnosed with GBS, and intravenous immunoglobulin (IVIG) was administered at doses of 0.4 g/kg/ day for 5 consecutive days. On the first day of treatment, the patient developed respiratory insufficiency due to respiratory muscle weakness and, oxygen saturation dropped to 80%. He was transferred to the intensive care unit (ICU) and he recovered on day 3. The treatment was completed in the ICU. A slight improvement of motor functions in the lower limbs was observed on examination but there was no change in deep sensation. Four weeks after initiation of treatment, muscle strength in distal limbs improved slightly, and sensation of vibration was weakly detected. Unfortunately, 2 months later, the patient died due to progression and complications of lymphoma.


The pathophysiological relationship between GBS and cancer is not established yet, but a mechanism of paraneoplastic origin is blamed (5). Antibodies developing against tumour cell antigens are supposed to cause damage of the peripheral nerves due to molecular mimicry. However, this theory is losing ground if there are no antibodies found in the CSF and sera of patients, which is the case in approximately 30% (4,6). Neoplastic diseases also suppress or modulate the immune system, and thereby can lead to GBS, considering the occurrence of GBS after surgery, infections, transplantation or HIV infections all causing immune suppression to various degrees (4).

To date, approximately 25 cases of GBS occurring together with lymphoma in adults have been published. Approximately 65% of these cases are NHL, whereas 35% are Hodgkin's lymphoma. In Table 2, we summarized the characteristics of patients with GBS and lymphoma published more recently, between 2000 and 2012 (2 [index case], 7,8,9,10,11,12,13,14,15,16,17,18,19). To our knowledge, an association between GBS and primary extranodal intestinal lymphoma is not reported yet.

The underlying cause of neurological involvement during lymphoma is mostly neurotoxicity due to chemotherapeutic agents or direct invasion of peripheral nerves and nerve roots by tumour cells. The side effect of vincristine constitutes the major cause for peripheral neuropathy (9,20,21), although cytosine arabinoside and rituximab are also accused (10,11,14,15). The clinical spectrum can vary from mild paresthesia to serious quadriplegia.

In our case, there was an acute onset of symmetrical sensorimotor PNP starting in the distal parts and spreading proximally over days. Arterial hypertension, tachycardia and orthostatic hypotension were also observed and indicated involvement of the autonomic nervous system. Symptoms of the patient started approximately 7 weeks after the initial dose of chemotherapy. It could be assumed that the neurotoxic effect of vincristine was the cause. The cumulative dose of vincristine in our case was 4 mg, however, vincristine neuropathy occurs rarely at doses of 1.4 mg/[m.sup.2], unless there is an underlying disease, such as diabetic PNP Charcot-Marie-Tooth disease or HIV infection (20,21). In these cases, severe neuropathies can be observed at even much lower doses. Additionally, vincristine is known to cause a predominantly axonal PNP (22), whereas in our case demyelination was definitely prominent, which further supported the diagnosis of GBS.

In our patient, tests for HIV were negative, he did not suffer from diabetes mellitus and the family history for hereditary neuropathies was negative. In addition, the electro-diagnostic findings, the slight elevation of protein in the CSF and the moderate response to IVIG were all supporting the diagnosis of GBS. Furthermore, there were no cells in the CSF, gadolinium-enhanced cranial and spinal MRI scans were unremarkable and the cancer was in remission when symptoms of GBS first developed. In conclusion, there was no reason to assume that peripheral nerves were infiltrated by tumour cells.

One other major aspect in the differential diagnosis of GBS is chronic inflammatory demyelinating polyneuropathy (CIDP). CIDP may also accompany lymphoproliferative diseases, such as lymphomas or plasmocytomas. Some authors suggest that CIDP is the chronic form of GBS. It is generally assumed that the disease continues to progress for about 8 weeks (23). Although electrodiagnostic features and CSF findings resemble GBS, the very slow progression of symptoms, its chronic relapsing course, the finding of monoclonal gammopathy of undetermined significance (MGUS) in 40-50% of patients, and a good response to treatment with corticosteroids are making the differential diagnosis easier (24). In our case, the acute onset, rapid progression and recovery after 4 weeks was prominent. Additionally, there was no gammopathy either, thus, CDIP was excluded.

In conclusion, we think it is important to recognise the clinical picture as early as possible to establish the differential diagnosis and to initiate treatment rapidly. It must be kept in mind that this syndrome may have a fatal outcome or at least may lead to permanent disability.

Anahtar kelimeler: Guillain-Barre sendromu, lenfoma, paraneoplastik sendrom, norotoksisite, vinkristin

Cikar catismasi: Yazarlar bu makale ile ilgili olarak herhangi bir cikar catismasi bildirmemislerdir.

Doi: 10.4274/npa.y7059


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Asli KIYAT ATAMER [1], Kerem OKUTUR [2], Erdem TUZUN [3], Baris HASBAL [4], Ari BOYACIYAN [5], Yakup KRESPI [1], Gokhan DEMIR [2]

[1] Istanbul Bilim University Faculty of Medicine, Department of Neurology, Istanbul, Turkey

[2] Istanbul Bilim University Faculty of Medicine, Department of Medical Oncology, Istanbul, Turkey

[3] Istanbul University Istanbul Faculty of Medicine, Institute of Experimental Medicine, Istanbul, Turkey

[4] Istanbul Bilim University Faculty of Medicine, Department of Internal Medicine, Istanbul, Turkey

[5] Vehbi Koc Foundation American Hospital, Department of Neurology, Istanbul, Turkey

Correspondence Address/Yazisma Adresi

Asli Kiyat Atamer MD, Istanbul Bilim University Faculty of Medicine, Department of Neurology, Istanbul, Turkey Gsm: +90 532 317 22 57 E-mail: Received/Gelis tarihi: 06.02.2013 Accepted/Kabul tarihi: 03.04.2013
Table 1a. Electrodiagnostic findings/Motor Nerve
Conduction Studies

Nerve        Site of        Recording   Latency
             stimulation    site        (ms)

L. Median    Wrist          APB         4.95
             Elbow          APB         10.00
             Upper elbow    APB         13,15
L.Ulnar      Wrist          ADM         4.60
             Lower elbow    ADM         6.50
             Upper elbow    ADM         10.65
             Axilla         ADM         12.45
L.Common     Ankle          EDB         9.50
  Peroneal   Fibular head   EDB         18.65
             Knee           EDB         21.40
R.Common     Ankle          EDB         9.20
  Peroneal   Fibular head   EDB         17.80
             Knee           EDB         21.20
L Tibial     Ankle          AH          7.30
             Knee           AH          22.40
R. Tibial    Ankle          AH          7.20
             Knee           AH          23.50

Nerve        Site of        Amplitude   Velocity
             stimulation    (mV)        (m/s)

L. Median    Wrist          2.80
             Elbow          2.40        45.50
             Upper elbow    2,30        54.00
L.Ulnar      Wrist          3.70
             Lower elbow    3.50        57.90
             Upper elbow    2.90        38.60
             Axilla         2.60        66.70
L.Common     Ankle          0.20
  Peroneal   Fibular head   0.20        36.10
             Knee           0.20        35.50
R.Common     Ankle          0.20
  Peroneal   Fibular head   0.10        40.70
             Knee           0.00        23.50
L Tibial     Ankle          0.30
             Knee           0.20        25.80
R. Tibial    Ankle          0.40
             Knee           0.40        22.10

L.: left, R.: right, ms: millisecond, mV: millivolt,
m/s: meter/second, APB: abductor pollicis brevis,
ADM: abductor digiti minimi, EDB: extensor digitorum
brevis, AH: abductor hallucis

Table 1b. Electrodiagnostic findings/Electromyography


                        IA   Fib.   PSW    Fasc.   HF

L. Tib. Ant.            1+   None   None   None    None
L. Gastrocn. (med)      1+   None   None   None    None
R. Tib. Ant.            2+   2+     2+     None    None
L. First D. Inteross.   1+   1+     1+     None    None

                        MUAP                Recruitment

                        Amp.   Dur.   PPP   Pattern

L. Tib. Ant.            --     --     --    No activity
L. Gastrocn. (med)      --     --     --    No activity
R. Tib. Ant.            --     --     --    No activity
L. First D. Inteross.   1+     1+     1+    Discrete

MUAP: motor unit action potential, IA: insertion activity, Fib.:
fibrillation potential, PSW: positive sharp wave, Fasc.:
fasciculation, HF: high frequency, Amp.: amplitude, Dur:
duration, PPP: polyphasic MUAP L.: left, R.: right, Tib.
Ant.: tibialis anterior, Gastrocn.: gastrocnemicus, First
D. Inteross.: first dorsal interosseous. N: Normal

Table 2. Cases of GBS developed during the course of various
lymphomas reported in the last 12 years

Author,           n   Gender/   Type of              Type     CT
Year                  Age       Lymphoma             of GBS   Regimen

Machida, 2012     1   F/83      B Cell NHL           NR       R-CHOP
Seffo, 2010       1   F /70     T cell NHL           NR       CHOP
Bahl, 2010        1   M/8       B cell NHL           AMSAN    CHOP
Terenghi, 2007    1   M/51      B cell NHL           NR       R-CHOP
Carmona, 2006     1   M/57      B cell NHL           AMSAN    R-CHOP
Wanschitz, 2006   1   F/36      Burkitt's Lymphoma   AMAN     CHOP
Kivity, 2006      1   F/78      B cell NHL           AMSAN    none
Magne, 2005       1   M/74      Burkitt's Lymphoma   NR       R-CHOP
Powers, 2005      1   F/53      B cell NHL           AIDP     R-CHOP
Vigliani, 2004    1   M/16      Hodgkin Lymphoma     NR       ABVD
Naidech, 2002     1   F/42      T cell NHL           NR       CHOP
Rodriguez, 2002   1   M/17      T cell NHL           NR       ARA-C
Zuk, 2001         1   F/59      Burkitt's Lymphoma   NR       CHOP
Re, 2000          1   F/21      T cell NHL           AIDP     GMALL

Author,           Neurologic          Protein     EMG   Treatment
Year              involvement         CSF

Machida, 2012     Motor + Sensorial   177 mg/dl   -     IVIG + CS's
Seffo, 2010       Motor + Sensorial   81 mg/dl    +     NR
Bahl, 2010        Motor + Autonomic   20 mg/dl    +     IVIG
Terenghi, 2007    Motor               72 mg/dl    +     IVIG+CS's
Carmona, 2006     Motor + Sensorial   63 mg/dl    +     IVIG
Wanschitz, 2006   Motor               232 mg/dl   +     IVIG+PPh
Kivity, 2006      Motor + Sensorial   62 mg/dl    +     IVIG
Magne, 2005       Motor + Sensorial   72 mg/dl    +     IVIG+PPh +CS's
Powers, 2005      Motor + Sensorial   NR          +     IVIG + PPh
Vigliani, 2004    Motor + Sensorial   110 mg/dl   -     none
Naidech, 2002     Motor               227 mg/dl   +     PPh
Rodriguez, 2002   Motor + Sensorial   162 mg/dl   +     IVIG
Zuk, 2001         Motor + Sensorial   24 mg/dl    +     none
Re, 2000          Motor + Sensorial   53 mg/dl    +     IVIG+PPh

n: number of patients, M: male, F: female, NHL: non-Hodgkin lymphoma,
IVIG: intravenous immunoglobulin, PPh: plasmapheresis, CS:
corticosteroid, AMAN: acute motor axonal neuropathy, AMSAN:
acute motor and sensorial axonal neuropathy, AIDP: acute inflammatory
demyelinating polyneuropathy, CHOP: cyclophosphamide, doxorubicin,
vincristine and prednisone, R-CHOP: rituximab, cyclophosphamide,
doxorubicin, vincristine and prednisone, ARA-C: cytosine arabinoside,
GMALL: daunorubicin, vincristine, L-Asparaginase and prednisolone,
ABVD: doxorubicin, bleomycin, vinblastine, and dacarbazine,
NR: not reported
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Article Details
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Title Annotation:Case Report/Olgu Sunumu
Author:Atamer, Asli Kiyat; Okutur, Kerem; Tuzun, Erdem; Hasbal, Baris; Boyaciyan, Ari; Krespi, Yakup; Demir
Publication:Archives of Neuropsychiatry
Article Type:Case study
Geographic Code:7TURK
Date:Sep 1, 2014
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