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Acute motor and sensory axonal neuropathy and concomitant encephalopathy during tumor necrosis factor-alpha antagonist therapy
Journal of the Neurological Sciences 291 (2010) 103–106
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short communication
Acute motor and sensory axonal neuropathy and concomitant encephalopathy during tumor necrosis factor-alpha antagonist therapy Anthony Faivre a,b,⁎, Jérome Franques b, Andre Maues De Paula c, Mariana Gutierrez b, Sandie Bret b, Sandrine Aubert d, Shahram Attarian b, Jean Pouget b a
Hôpital d'Instruction des Armées Sainte-Anne, Service de Neurologie, Boulevard Ste-Anne, BP 20545 83041 Toulon cedex 9, France Service de Neurologie et Maladies Neuromusculaires, Centre de Référence national pour les Maladies Neuromusculaires et la SLA, Hôpital la Timone, 264 boulevard St-Pierre, 13385 Marseille cedex 05, France c Laboratoire d'anatomie pathologique et neuropathologie, Hôpital la Timone, 264 boulevard St-Pierre, 13385 Marseille cedex 05, France d Service de Neurophysiologie Clinique, Hôpital la Timone, 264 boulevard St-Pierre, 13385 Marseille cedex 05, France b
a r t i c l e
i n f o
Article history: Received 19 October 2009 Received in revised form 14 December 2009 Accepted 7 January 2010 Available online 8 February 2010 Keywords: Neuropathy Tumor necrosis factor-alpha Infliximab Acute Encephalopathy Crohn's disease
a b s t r a c t A woman with Crohn's disease developed acute neuropathy and concomitant encephalopathy while being treated with infliximab. The etiological investigations were negative. Infliximab was stopped and she was given four series of polyvalent immunoglobulin injections. Eighteen months later, the encephalitic symptoms had disappeared and the neuropathic symptoms were less severe. TNF-alpha antagonists have been previously blamed for triggering neurological disorders, but no cases of acute neuropathy concomitant with encephalopathy have been reported so far. © 2010 Elsevier B.V. All rights reserved.
1. Introduction
2. Case report
By 2009, almost one million patients had been treated with the tumor necrosis factor-alpha blocking molecules which revolutionized the management of inflammatory diseases such as rheumatoid arthritis, Crohn's disease and psoriatic arthropathy [1]. However, approximately 400 cases have been reported to date where these molecules have caused dysimmune conditions [1], including central neurological disorders (the induction or aggravation of multiple sclerosis and retrobulbar optic neuritis), myasthenia gravis [2], and various forms of demyelinating neuropathy (amounting to less than 50 cases in the literature) [3–8]. Here we describe what seems to be the first case of severe acute axonal neuropathy associated with acute encephalopathy subsequent to TNF-alpha antagonist therapy with infliximab, a drug based on a chimeric human and murine monoclonal IgG1-κ antibody [3].
A 64-year old woman patient was hospitalised with severe tetraparesis, which had gradually developed during the previous month. The antecedents included neurofibromatosis 1 (NF1), type 2 diabetes and Hashimoto thyroiditis. She was being treated with prednisolone (40 mg/day) and azathioprine (50 mg/day) for Crohn's disease. Subsequent to an episode of rectocolitis in December 2007, the patient was given 2 infliximab infusions (300 mg) 3 weeks apart. One week after the second infusion, severe but painless motor deficits developed in all four limbs, as the result of which the patient was confined to bed within 4 weeks, accompanied by partial right facial motor epileptic fits with secondary generalized seizures. The clinical examination at admission showed the presence of severe symmetrical motor deficits in all 4 limbs, mainly at proximal level and in the lower limbs, whereas the face was spared. The Overall Neuropathy Limitations Scale (ONLS) score was 10/12. There was moderate general amyotrophy and hypoesthesia to touch in the distal lower limbs, associated with apallesthesia and a loss of proprioception. The deep tendon reflexes were abolished in the lower limbs, and the plantar reflexes were flexor. Skin examination showed the presence of diffuse neurofibromes, many café-au-lait spots and axillary lentiginous macules. The patient was afebrile and the clinical examination was otherwise normal. The neuropsychological tests
⁎ Corresponding author. Tel.: + 33 4 83162476; fax: +33 4 83162662. E-mail addresses: [email protected] (A. Faivre), [email protected] (J. Franques), [email protected] (A.M. De Paula), [email protected] (M. Gutierrez), [email protected] (S. Bret), [email protected] (S. Aubert), [email protected] (S. Attarian), [email protected] (J. Pouget). 0022-510X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2010.01.004
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A. Faivre et al. / Journal of the Neurological Sciences 291 (2010) 103–106
showed that her ideo-motor performances were slower than normal with moderate anterograde and working memory deficits but without confusion. The Mini Mental Score (MMS) was 23/30. At brain MRI, the FLAIR (fluid-attenuated inversion recovery) sequence and T2 gave bilateral hypersignals in the amygdalohippocampal regions without enhancement after gadolinium injection (Fig. 1A). The spinal MRI was normal. Lumbar puncture yielded a clear fluid containing no cells, showing slight hyperproteinorachia (54 mg/dl) without hypoglycorachia or intrathecal immunoglobulin synthesis (IgG index = 0.49). Biological tests showed the presence of hyponatremia (127 mmol/l) but no other ionic anomalies; the muscle enzyme levels were within the normal range and no inflammatory biological syndrome was detected. Blood tests for HIV, VZV, HSV, CMV, EBV, HHV6, measles, mumps, West-Nile virus, tick-borne encephalitis virus, syphilis, Q fever, rickettsia, Mycoplasma pneumoniae, Campylobacter jejuni, Lyme disease and the mycobacterial screening tests were all negative. Auto-immune studies gave an anti-nuclear antibody (ANA) titer of 1/200 but there was no anti-DNA or anti-ENA (anti-SSA, anti-SSB, anti-Sm) antibodies. Screening tests for onconeuronal antibodies (anti-Hu, anti-Yo, anti-Ri, anti-Ma2, anti-amphiphysin), voltage-gated potassium channels (VGKC) antibodies, glutamic acid decarboxylase (GAD) antibodies and anti-ganglioside antibodies were negative. The first nerve conduction studies (NCS) clearly showed that the neuropathy was mainly of the motor type, and that it affected all 4 limbs but mainly the lower limbs, without any signs of demyelination (Table 1). The EMG study showed no signs of spontaneous activity at rest. During voluntary muscle contraction, the traces showed discrete
signs of acute neurogenic impairements. Intercritical electroencephalogram was normal. Ten days later, the second EMG study showed major signs of neurogenic impairment in the lower limbs. Left sural nerve and quadriceps biopsies were performed the day later. The histological examination of the left sural nerve showed a considerable loss of fibers, which varied very little from one bundle to another and involved both small and large fibers. The pattern observed resembled that of regenerating chronic axonal lesions (Fig. 1B). Immunofluorescence studies on a frozen nerve showed the presence of no immunoglobulin deposits or complement. Histological analysis of the left quadriceps muscle showed no evidence of a vascular focus, but severe lesions resulting from acute denervation processes, many atrophic foci and a few rare signs of necrosis followed by regenerative processes were detected (Fig. 1C). The thoraco-abdomino-pelvic scan and the 18 F-FDG PET-scan were both normal. The possibility that an auto-immune disease may have been triggered by the TNF-alpha antagonist drug was envisaged and the infliximab injections were therefore stopped. Intravenous immunoglobulin (IgIV) treatment at a dose of 2 g/kg every six weeks was prescribed and levetiracetam (1000 mg/day) treatment was also started. Eighteen months after the onset of the disease, after 4 IgIV treatments, the patient's motor strength and sensory deficits had improved considerably and she was able to perform most everyday tasks unassisted, although she was still unable to walk. She recovered normal deep tendon reflexes in the lower limbs and her ONLS score increased to 7/12. The patient no longer suffered from epileptic fits
Fig. 1. A: Initial fluid-attenuated inversion recovery (FLAIR) MRI showing increased signal in the both medial temporal lobes (yellow arrows). B: Nerve biopsy. Density reduction of myelinated fibers. Clusters of regenerated fibers (arrows). Thinly myelinated fibers are rare (arrow head). Semithin section stained with paraphenylenediamine (PPD) (400×). Scale bar corresponds to 200 μm. C: Muscle biopsy. Size irregularity, and groups of atrophic angular muscle fibers (white circle) as well as necrosis (yellow circle). Hematoxylin eosin (400×). Scale bar corresponds to 50 μm.
A. Faivre et al. / Journal of the Neurological Sciences 291 (2010) 103–106
105
Table 1 Nerve conduction findings. Motor
Median
Right Left
Ulnar
Right
Left
Peroneal Tibial
Right Left Right Left
a b c d e
Wrist Elbow Wrist Elbow Wrist Below elbow Above elbow Wrist Below elbow Above elbow Ankle Ankle Ankle Popliteal Ankle Popliteal
Sensory
Ampa, mV
Dlb, ms
5.9 (N N 5) 4.5 4.3 (N N 5) 4.1 3.4 (N N 5) 3 3.2 1.4 (N N 5) 1.3 1 NOe NOe 1.7 (N N 5) 1.6 1.6 (N N 5) 1.2
3.0 8.2 3.4 8.4 2.5 7.3 9.1 2.6 7.8 9.4
(N b 4) (N b 4) (N b 3.5)
(N b 3.5)
5.4 (N b 7) 13.5 5 (N b 7) 14.5
CVc, m/s
Fwd
Antidromic
Ampa, µV
CVc, m/s
49 (N N 45) 49.6 (N N 45) 50.1 (N N 45) 40
27 (N b 30) 25.4 (N b 30) 27 (N b 30)
Wrist-II digit
26 (N N 10) 16.6 (N N 10) 35 (N N 10)
50 (N N 45) 55 (N N 45) 46 (N N 45)
51.3 (N N 45) 56.3
28.1 (N b 30)
Wrist-V digit
26 (N N 10)
43 (N N 45)
NOe NOe 7.7 (N N 10) 8.1 (N N 10)
50 (N N 45) 50 (N N 45)
Wrist-II digit Wrist-V digit
41 (N N 45)
NOe
Superficial peroneal nerve Superficial peroneal nerve Sural ankle-foot
41 (N N 45)
NOe
Sural ankle-foot
Amp = amplitude (baseline to pic). DL = distal latency. CV = conduction velocity. Fw = F waves. NO = not obtainable.
despite antiepileptic drugs being completely stopped one year after the onset of symptoms. Her MMS score increased to 25/30. There were no changes in conduction nerve and EMG studies. The brain MRI findings were unchanged. The thoraco-abdomino-pelvic scan and the 18-FDG PET-scan were still normal. 3. Discussion Here we report on a patient who developed acute axonal neuropathy concomitantly with encephalopathy while being treated with TNF-alpha antagonist therapy while undergoing treatment for Crohn's disease. The fast onset of proximal motor deficits in all four limbs associated with areflexia and proprioceptive disorder led us to first suspect that a Guillain–Barré syndrome (GBS) might be involved, but neither the NCS nor the nerve biopsy brought to light any signs of demyelination [9]. On the other hand, NF1 is a phakomatosis which can be complicated by neuropathic symptoms, which are usually slowly evolving sensorimotor symptoms associated with the presence of a characteristic neurofibromatous neural infiltrate in the patients' neural biopsies [10]. The symmetry and especially the acute nature of our patient's axonal neuropathy were therefore suggestive of acute motor and sensory axonal neuropathy (AMSAN), which is an axonal form of acute polyradiculoneuritis occurring most frequently in children [11]. ASMAN, which is characterised electrophysiologically by an overall decrease in the motor and sensory potentials, is not associated with any electrical or histological signs of demyelination, since the immunological damage probably targets axonal epitopes [9,11]. None of the anti-ganglioside antibodies which can develop in patients with ASMAN were detected here [11]. This patient concomitantly developed encephalitis resulting in acute anterograde memory deficits associated with epileptic fits with no infectious, vascular, tumoral or toxic causes. The MRI yielded bilateral hippocampal hypersignals which suggested the hypothesis of limbic encephalitis, but this diagnosis could not be formally established in this case [12]. Indeed, the clinical and radiologic course of the patient is rather unusual for a limbic encephalitis because the epileptic symptoms did not recur despite the cessation of antiepileptic drugs, the mnesic deficits regressed and the radiological picture remained unchanged. Furthermore, 18 months after the onset of the symptoms, no sign of neoplasm was detected despite regular thoraco-abdomino-pelvic scans and 18-FDG PET scans. Besides, three successive screen tests
for onconeuronal antibodies were negative. However, the hypothesis of a non-paraneoplasic limbic encephalitis could not be completely ruled out especially as forms of this kind often involve hyponatremia and has been reported to respond to immunotherapy, as it occurred in this patient. Nevertheless the screen test for anti-neuronal antibodies associated with non-paraneoplasic limbic encephalitis (VGKC antibodies, GAD antibodies) was negative, but no screening for rarer antineuronal antibodies (anti-NMDA-R, anti-neuropils) was carried out [12]. Our patient's symptoms certainly seem to have been attributable to her infliximab treatment, and this possibility is supported by the fact that the following criteria previously published in the literature were met [3,6,13]: obvious chronological concordance (the signs developed 10 days after the second infusion), the lack of any other plausible explanations, the stabilisation and improvement in the symptoms observed when infliximab was stopped, the pharmacodynamic pattern, and previous reports of other cases of central dysimmune neurological disorders induced by TNF-alpha antagonist drugs [2–4]. All the existing forms of demyelinating neuropathies have been reported to occur in patients treated with TNF-alpha antagonists: GBS and Miller–Fisher syndrome, multifocal motor neuropathy with block conduction, Lewis–Sumner syndrome and chronic polyradiculoneuritis; some cases of neural vasculitis have also been reported in this context [5–7,14]. These symptoms have developed with all kinds, but especially with infliximab, which is thought to be particularly immunogenic [15]. The exact physiopathological mechanisms of the present patient's neuropathic symptoms were not established. The possible involvement of a toxic factor cannot be completely ruled out, since the nerve biopsy analysis showed the presence of axonal lesions with no immune deposits and no antigangliosidic antibodies were identified. However, the clinical picture was more reminiscent of inflammatory demyelinating polyradiculoneuropathy, dysimmune neuropathy which has been reported to be more frequent in patients with inflammatory bowel disease and particularly among women [16]. The presence of ANAs also constitutes an indirect argument in favour of a general dysimmune process. The development of these antibodies has been reported to occur in 60% of patients undergoing infliximab treatment for 2 years, but the pathogenic processes involved have not yet been elucidated [7]. The development of demyelinating neurological disorders in patients treated with anti-TNF-alpha antagonist drugs is rather
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paradoxical, since hyperproduction of TNF-alpha is known to occur in GBS and MS [3,4]. Chronic inhibition of TNF-alpha may however increase the anti-myelin immune and inflammatory responses by increasing the numbers of activated T lymphocytes, which may create inflammatory neurological lesions upon crossing the blood–brain barrier [3]. It is very difficult to explain what caused the encephalopathy in the present patient. It probably resulted from a dysimmune process triggered by infliximab, although we were unable to identify the antibody responsible. The co-existence of several known auto-immune diseases in our patient may well have favoured the development of her symptoms. However, a significant drop in the TNF-alpha levels has been found to occur in the CSF of patients with limbic encephalitis, and infliximab may in fact have been directly responsible for generating the present patient's encephalopathy [17]. The evolution of the neurological complications associated with TNF-alpha antagonists has been reported to be favourable in 66% of cases, although the initial picture can be extremely severe, as in the present case [3]. Although there exist no clear-cut recommendations so far on the management of the neurological complications associated with TNF-alpha antagonist drugs, it is probably advisable to stop the treatment when these complications occur [3,7]. Several treatments based on corticotherapy or the IgIV treatment used here have been tested, but their efficacy still remains to be established [3,8]. References [1] Ramos-Casals M, Brito-Zerón P, Soto MJ, Cuadrado MJ, Khamashta MA. Autoimmune diseases induced by TNF-targeted therapies. Best Pract Res Clin Rheumatol 2008;22:847–61. [2] Fee DB, Kasarskis EJ. Myasthenia gravis associated with etanercept therapy. Muscle Nerve 2009;39:866–70.
[3] Stubgen JP. Tumor necrosis factor-antagonists and neuropathy. Muscle Nerve 2008;37:281–92. [4] Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G, Crayton H, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001;44:2862–9. [5] Shin IS, Baer AN, Kwon HJ, Papadopoulos EJ, Siegel JN. Guillain–Barre and Miller Fisher syndrome occurring with tumor necrosis factor alpha antagonist therapy. Arthritis Rheum 2006;54:1429–34. [6] Richez C, Blanco P, Lagueny A, Schaeverbeke T, Dehais J. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers. Neurology 2005;64: 1468–70. [7] Hooper DR, Tarnopolsky MA, Baker SK. Lewis–Sumner syndrome associated with infliximab therapy in rheumatoid arthritis. Muscle Nerve 2008;38:1318–25. [8] Lozeron P, Denier C, Lacroix C, Adams D. Long-term course of demyelinating neuropathies occuring during tumor necrosis factor-alpha-blocker therapy. Arch Neurol 2009;66:490–7. [9] Hughes RA, Cornblath DR. Guillain–Barré syndrome. Lancet 2005;366:1653–66. [10] Drouet A, Wolkenstein P, Lefaucheur JP, Pinson S, Combemale P, Gherardi RK, et al. Neurofibromatosis 1-associated neuropathies: a reappraisal. Brain 2004;127: 1993–2009. [11] Yuki N, Kuwabara S, Koga M, Hirata K. Acute motor axonal neuropathy and acute motor-sensory axonal neuropathy share a common immunological profile. J Neurol Sci 1999;168:121–6. [12] Anderson NE, Barber PA. Limbic encephalitis, a review. J Clin Neurosci 2008;15: 961–71. [13] Miller FW, Hess EV, Clauw DJ, Hertzman PA, Pincus T, Silver RM, et al. Approaches for identifying and defining environmentally associated rheumatic disorders. Arthritis Rheum 2000;43:243–9. [14] Richette P, Dieude P, Damiano J, Liote F, Orcel P, Bardin T. Sensory neuropathy revealing necrotizing vasculitis during infliximab therapy for rheumatoïd arthritis. J Rheumatol 2004;31:2079–81. [15] Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008;117: 244–79. [16] Gondim FAA, Brannagan TH, Sander HW, Chin RL, Latov N. Peripheral neuropathy in patients with inflammatory bowel disease. Brain 2005;128:867–79. [17] Ichiyama T, Shoji H, Takahashi Y, Matsushige T, Kajimoto M, Inuzuka T, et al. Cerebrospinal fluid levels of cytokines in non-herpetic acute limbic encephalitis: comparison with herpes simplex encephalitis. Cytokine 2008;44:149–53.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short communication
Acute motor and sensory axonal neuropathy and concomitant encephalopathy during tumor necrosis factor-alpha antagonist therapy Anthony Faivre a,b,⁎, Jérome Franques b, Andre Maues De Paula c, Mariana Gutierrez b, Sandie Bret b, Sandrine Aubert d, Shahram Attarian b, Jean Pouget b a
Hôpital d'Instruction des Armées Sainte-Anne, Service de Neurologie, Boulevard Ste-Anne, BP 20545 83041 Toulon cedex 9, France Service de Neurologie et Maladies Neuromusculaires, Centre de Référence national pour les Maladies Neuromusculaires et la SLA, Hôpital la Timone, 264 boulevard St-Pierre, 13385 Marseille cedex 05, France c Laboratoire d'anatomie pathologique et neuropathologie, Hôpital la Timone, 264 boulevard St-Pierre, 13385 Marseille cedex 05, France d Service de Neurophysiologie Clinique, Hôpital la Timone, 264 boulevard St-Pierre, 13385 Marseille cedex 05, France b
a r t i c l e
i n f o
Article history: Received 19 October 2009 Received in revised form 14 December 2009 Accepted 7 January 2010 Available online 8 February 2010 Keywords: Neuropathy Tumor necrosis factor-alpha Infliximab Acute Encephalopathy Crohn's disease
a b s t r a c t A woman with Crohn's disease developed acute neuropathy and concomitant encephalopathy while being treated with infliximab. The etiological investigations were negative. Infliximab was stopped and she was given four series of polyvalent immunoglobulin injections. Eighteen months later, the encephalitic symptoms had disappeared and the neuropathic symptoms were less severe. TNF-alpha antagonists have been previously blamed for triggering neurological disorders, but no cases of acute neuropathy concomitant with encephalopathy have been reported so far. © 2010 Elsevier B.V. All rights reserved.
1. Introduction
2. Case report
By 2009, almost one million patients had been treated with the tumor necrosis factor-alpha blocking molecules which revolutionized the management of inflammatory diseases such as rheumatoid arthritis, Crohn's disease and psoriatic arthropathy [1]. However, approximately 400 cases have been reported to date where these molecules have caused dysimmune conditions [1], including central neurological disorders (the induction or aggravation of multiple sclerosis and retrobulbar optic neuritis), myasthenia gravis [2], and various forms of demyelinating neuropathy (amounting to less than 50 cases in the literature) [3–8]. Here we describe what seems to be the first case of severe acute axonal neuropathy associated with acute encephalopathy subsequent to TNF-alpha antagonist therapy with infliximab, a drug based on a chimeric human and murine monoclonal IgG1-κ antibody [3].
A 64-year old woman patient was hospitalised with severe tetraparesis, which had gradually developed during the previous month. The antecedents included neurofibromatosis 1 (NF1), type 2 diabetes and Hashimoto thyroiditis. She was being treated with prednisolone (40 mg/day) and azathioprine (50 mg/day) for Crohn's disease. Subsequent to an episode of rectocolitis in December 2007, the patient was given 2 infliximab infusions (300 mg) 3 weeks apart. One week after the second infusion, severe but painless motor deficits developed in all four limbs, as the result of which the patient was confined to bed within 4 weeks, accompanied by partial right facial motor epileptic fits with secondary generalized seizures. The clinical examination at admission showed the presence of severe symmetrical motor deficits in all 4 limbs, mainly at proximal level and in the lower limbs, whereas the face was spared. The Overall Neuropathy Limitations Scale (ONLS) score was 10/12. There was moderate general amyotrophy and hypoesthesia to touch in the distal lower limbs, associated with apallesthesia and a loss of proprioception. The deep tendon reflexes were abolished in the lower limbs, and the plantar reflexes were flexor. Skin examination showed the presence of diffuse neurofibromes, many café-au-lait spots and axillary lentiginous macules. The patient was afebrile and the clinical examination was otherwise normal. The neuropsychological tests
⁎ Corresponding author. Tel.: + 33 4 83162476; fax: +33 4 83162662. E-mail addresses: [email protected] (A. Faivre), [email protected] (J. Franques), [email protected] (A.M. De Paula), [email protected] (M. Gutierrez), [email protected] (S. Bret), [email protected] (S. Aubert), [email protected] (S. Attarian), [email protected] (J. Pouget). 0022-510X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2010.01.004
104
A. Faivre et al. / Journal of the Neurological Sciences 291 (2010) 103–106
showed that her ideo-motor performances were slower than normal with moderate anterograde and working memory deficits but without confusion. The Mini Mental Score (MMS) was 23/30. At brain MRI, the FLAIR (fluid-attenuated inversion recovery) sequence and T2 gave bilateral hypersignals in the amygdalohippocampal regions without enhancement after gadolinium injection (Fig. 1A). The spinal MRI was normal. Lumbar puncture yielded a clear fluid containing no cells, showing slight hyperproteinorachia (54 mg/dl) without hypoglycorachia or intrathecal immunoglobulin synthesis (IgG index = 0.49). Biological tests showed the presence of hyponatremia (127 mmol/l) but no other ionic anomalies; the muscle enzyme levels were within the normal range and no inflammatory biological syndrome was detected. Blood tests for HIV, VZV, HSV, CMV, EBV, HHV6, measles, mumps, West-Nile virus, tick-borne encephalitis virus, syphilis, Q fever, rickettsia, Mycoplasma pneumoniae, Campylobacter jejuni, Lyme disease and the mycobacterial screening tests were all negative. Auto-immune studies gave an anti-nuclear antibody (ANA) titer of 1/200 but there was no anti-DNA or anti-ENA (anti-SSA, anti-SSB, anti-Sm) antibodies. Screening tests for onconeuronal antibodies (anti-Hu, anti-Yo, anti-Ri, anti-Ma2, anti-amphiphysin), voltage-gated potassium channels (VGKC) antibodies, glutamic acid decarboxylase (GAD) antibodies and anti-ganglioside antibodies were negative. The first nerve conduction studies (NCS) clearly showed that the neuropathy was mainly of the motor type, and that it affected all 4 limbs but mainly the lower limbs, without any signs of demyelination (Table 1). The EMG study showed no signs of spontaneous activity at rest. During voluntary muscle contraction, the traces showed discrete
signs of acute neurogenic impairements. Intercritical electroencephalogram was normal. Ten days later, the second EMG study showed major signs of neurogenic impairment in the lower limbs. Left sural nerve and quadriceps biopsies were performed the day later. The histological examination of the left sural nerve showed a considerable loss of fibers, which varied very little from one bundle to another and involved both small and large fibers. The pattern observed resembled that of regenerating chronic axonal lesions (Fig. 1B). Immunofluorescence studies on a frozen nerve showed the presence of no immunoglobulin deposits or complement. Histological analysis of the left quadriceps muscle showed no evidence of a vascular focus, but severe lesions resulting from acute denervation processes, many atrophic foci and a few rare signs of necrosis followed by regenerative processes were detected (Fig. 1C). The thoraco-abdomino-pelvic scan and the 18 F-FDG PET-scan were both normal. The possibility that an auto-immune disease may have been triggered by the TNF-alpha antagonist drug was envisaged and the infliximab injections were therefore stopped. Intravenous immunoglobulin (IgIV) treatment at a dose of 2 g/kg every six weeks was prescribed and levetiracetam (1000 mg/day) treatment was also started. Eighteen months after the onset of the disease, after 4 IgIV treatments, the patient's motor strength and sensory deficits had improved considerably and she was able to perform most everyday tasks unassisted, although she was still unable to walk. She recovered normal deep tendon reflexes in the lower limbs and her ONLS score increased to 7/12. The patient no longer suffered from epileptic fits
Fig. 1. A: Initial fluid-attenuated inversion recovery (FLAIR) MRI showing increased signal in the both medial temporal lobes (yellow arrows). B: Nerve biopsy. Density reduction of myelinated fibers. Clusters of regenerated fibers (arrows). Thinly myelinated fibers are rare (arrow head). Semithin section stained with paraphenylenediamine (PPD) (400×). Scale bar corresponds to 200 μm. C: Muscle biopsy. Size irregularity, and groups of atrophic angular muscle fibers (white circle) as well as necrosis (yellow circle). Hematoxylin eosin (400×). Scale bar corresponds to 50 μm.
A. Faivre et al. / Journal of the Neurological Sciences 291 (2010) 103–106
105
Table 1 Nerve conduction findings. Motor
Median
Right Left
Ulnar
Right
Left
Peroneal Tibial
Right Left Right Left
a b c d e
Wrist Elbow Wrist Elbow Wrist Below elbow Above elbow Wrist Below elbow Above elbow Ankle Ankle Ankle Popliteal Ankle Popliteal
Sensory
Ampa, mV
Dlb, ms
5.9 (N N 5) 4.5 4.3 (N N 5) 4.1 3.4 (N N 5) 3 3.2 1.4 (N N 5) 1.3 1 NOe NOe 1.7 (N N 5) 1.6 1.6 (N N 5) 1.2
3.0 8.2 3.4 8.4 2.5 7.3 9.1 2.6 7.8 9.4
(N b 4) (N b 4) (N b 3.5)
(N b 3.5)
5.4 (N b 7) 13.5 5 (N b 7) 14.5
CVc, m/s
Fwd
Antidromic
Ampa, µV
CVc, m/s
49 (N N 45) 49.6 (N N 45) 50.1 (N N 45) 40
27 (N b 30) 25.4 (N b 30) 27 (N b 30)
Wrist-II digit
26 (N N 10) 16.6 (N N 10) 35 (N N 10)
50 (N N 45) 55 (N N 45) 46 (N N 45)
51.3 (N N 45) 56.3
28.1 (N b 30)
Wrist-V digit
26 (N N 10)
43 (N N 45)
NOe NOe 7.7 (N N 10) 8.1 (N N 10)
50 (N N 45) 50 (N N 45)
Wrist-II digit Wrist-V digit
41 (N N 45)
NOe
Superficial peroneal nerve Superficial peroneal nerve Sural ankle-foot
41 (N N 45)
NOe
Sural ankle-foot
Amp = amplitude (baseline to pic). DL = distal latency. CV = conduction velocity. Fw = F waves. NO = not obtainable.
despite antiepileptic drugs being completely stopped one year after the onset of symptoms. Her MMS score increased to 25/30. There were no changes in conduction nerve and EMG studies. The brain MRI findings were unchanged. The thoraco-abdomino-pelvic scan and the 18-FDG PET-scan were still normal. 3. Discussion Here we report on a patient who developed acute axonal neuropathy concomitantly with encephalopathy while being treated with TNF-alpha antagonist therapy while undergoing treatment for Crohn's disease. The fast onset of proximal motor deficits in all four limbs associated with areflexia and proprioceptive disorder led us to first suspect that a Guillain–Barré syndrome (GBS) might be involved, but neither the NCS nor the nerve biopsy brought to light any signs of demyelination [9]. On the other hand, NF1 is a phakomatosis which can be complicated by neuropathic symptoms, which are usually slowly evolving sensorimotor symptoms associated with the presence of a characteristic neurofibromatous neural infiltrate in the patients' neural biopsies [10]. The symmetry and especially the acute nature of our patient's axonal neuropathy were therefore suggestive of acute motor and sensory axonal neuropathy (AMSAN), which is an axonal form of acute polyradiculoneuritis occurring most frequently in children [11]. ASMAN, which is characterised electrophysiologically by an overall decrease in the motor and sensory potentials, is not associated with any electrical or histological signs of demyelination, since the immunological damage probably targets axonal epitopes [9,11]. None of the anti-ganglioside antibodies which can develop in patients with ASMAN were detected here [11]. This patient concomitantly developed encephalitis resulting in acute anterograde memory deficits associated with epileptic fits with no infectious, vascular, tumoral or toxic causes. The MRI yielded bilateral hippocampal hypersignals which suggested the hypothesis of limbic encephalitis, but this diagnosis could not be formally established in this case [12]. Indeed, the clinical and radiologic course of the patient is rather unusual for a limbic encephalitis because the epileptic symptoms did not recur despite the cessation of antiepileptic drugs, the mnesic deficits regressed and the radiological picture remained unchanged. Furthermore, 18 months after the onset of the symptoms, no sign of neoplasm was detected despite regular thoraco-abdomino-pelvic scans and 18-FDG PET scans. Besides, three successive screen tests
for onconeuronal antibodies were negative. However, the hypothesis of a non-paraneoplasic limbic encephalitis could not be completely ruled out especially as forms of this kind often involve hyponatremia and has been reported to respond to immunotherapy, as it occurred in this patient. Nevertheless the screen test for anti-neuronal antibodies associated with non-paraneoplasic limbic encephalitis (VGKC antibodies, GAD antibodies) was negative, but no screening for rarer antineuronal antibodies (anti-NMDA-R, anti-neuropils) was carried out [12]. Our patient's symptoms certainly seem to have been attributable to her infliximab treatment, and this possibility is supported by the fact that the following criteria previously published in the literature were met [3,6,13]: obvious chronological concordance (the signs developed 10 days after the second infusion), the lack of any other plausible explanations, the stabilisation and improvement in the symptoms observed when infliximab was stopped, the pharmacodynamic pattern, and previous reports of other cases of central dysimmune neurological disorders induced by TNF-alpha antagonist drugs [2–4]. All the existing forms of demyelinating neuropathies have been reported to occur in patients treated with TNF-alpha antagonists: GBS and Miller–Fisher syndrome, multifocal motor neuropathy with block conduction, Lewis–Sumner syndrome and chronic polyradiculoneuritis; some cases of neural vasculitis have also been reported in this context [5–7,14]. These symptoms have developed with all kinds, but especially with infliximab, which is thought to be particularly immunogenic [15]. The exact physiopathological mechanisms of the present patient's neuropathic symptoms were not established. The possible involvement of a toxic factor cannot be completely ruled out, since the nerve biopsy analysis showed the presence of axonal lesions with no immune deposits and no antigangliosidic antibodies were identified. However, the clinical picture was more reminiscent of inflammatory demyelinating polyradiculoneuropathy, dysimmune neuropathy which has been reported to be more frequent in patients with inflammatory bowel disease and particularly among women [16]. The presence of ANAs also constitutes an indirect argument in favour of a general dysimmune process. The development of these antibodies has been reported to occur in 60% of patients undergoing infliximab treatment for 2 years, but the pathogenic processes involved have not yet been elucidated [7]. The development of demyelinating neurological disorders in patients treated with anti-TNF-alpha antagonist drugs is rather
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paradoxical, since hyperproduction of TNF-alpha is known to occur in GBS and MS [3,4]. Chronic inhibition of TNF-alpha may however increase the anti-myelin immune and inflammatory responses by increasing the numbers of activated T lymphocytes, which may create inflammatory neurological lesions upon crossing the blood–brain barrier [3]. It is very difficult to explain what caused the encephalopathy in the present patient. It probably resulted from a dysimmune process triggered by infliximab, although we were unable to identify the antibody responsible. The co-existence of several known auto-immune diseases in our patient may well have favoured the development of her symptoms. However, a significant drop in the TNF-alpha levels has been found to occur in the CSF of patients with limbic encephalitis, and infliximab may in fact have been directly responsible for generating the present patient's encephalopathy [17]. The evolution of the neurological complications associated with TNF-alpha antagonists has been reported to be favourable in 66% of cases, although the initial picture can be extremely severe, as in the present case [3]. Although there exist no clear-cut recommendations so far on the management of the neurological complications associated with TNF-alpha antagonist drugs, it is probably advisable to stop the treatment when these complications occur [3,7]. Several treatments based on corticotherapy or the IgIV treatment used here have been tested, but their efficacy still remains to be established [3,8]. References [1] Ramos-Casals M, Brito-Zerón P, Soto MJ, Cuadrado MJ, Khamashta MA. Autoimmune diseases induced by TNF-targeted therapies. Best Pract Res Clin Rheumatol 2008;22:847–61. [2] Fee DB, Kasarskis EJ. Myasthenia gravis associated with etanercept therapy. Muscle Nerve 2009;39:866–70.
[3] Stubgen JP. Tumor necrosis factor-antagonists and neuropathy. Muscle Nerve 2008;37:281–92. [4] Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G, Crayton H, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001;44:2862–9. [5] Shin IS, Baer AN, Kwon HJ, Papadopoulos EJ, Siegel JN. Guillain–Barre and Miller Fisher syndrome occurring with tumor necrosis factor alpha antagonist therapy. Arthritis Rheum 2006;54:1429–34. [6] Richez C, Blanco P, Lagueny A, Schaeverbeke T, Dehais J. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers. Neurology 2005;64: 1468–70. [7] Hooper DR, Tarnopolsky MA, Baker SK. Lewis–Sumner syndrome associated with infliximab therapy in rheumatoid arthritis. Muscle Nerve 2008;38:1318–25. [8] Lozeron P, Denier C, Lacroix C, Adams D. Long-term course of demyelinating neuropathies occuring during tumor necrosis factor-alpha-blocker therapy. Arch Neurol 2009;66:490–7. [9] Hughes RA, Cornblath DR. Guillain–Barré syndrome. Lancet 2005;366:1653–66. [10] Drouet A, Wolkenstein P, Lefaucheur JP, Pinson S, Combemale P, Gherardi RK, et al. Neurofibromatosis 1-associated neuropathies: a reappraisal. Brain 2004;127: 1993–2009. [11] Yuki N, Kuwabara S, Koga M, Hirata K. Acute motor axonal neuropathy and acute motor-sensory axonal neuropathy share a common immunological profile. J Neurol Sci 1999;168:121–6. [12] Anderson NE, Barber PA. Limbic encephalitis, a review. J Clin Neurosci 2008;15: 961–71. [13] Miller FW, Hess EV, Clauw DJ, Hertzman PA, Pincus T, Silver RM, et al. Approaches for identifying and defining environmentally associated rheumatic disorders. Arthritis Rheum 2000;43:243–9. [14] Richette P, Dieude P, Damiano J, Liote F, Orcel P, Bardin T. Sensory neuropathy revealing necrotizing vasculitis during infliximab therapy for rheumatoïd arthritis. J Rheumatol 2004;31:2079–81. [15] Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008;117: 244–79. [16] Gondim FAA, Brannagan TH, Sander HW, Chin RL, Latov N. Peripheral neuropathy in patients with inflammatory bowel disease. Brain 2005;128:867–79. [17] Ichiyama T, Shoji H, Takahashi Y, Matsushige T, Kajimoto M, Inuzuka T, et al. Cerebrospinal fluid levels of cytokines in non-herpetic acute limbic encephalitis: comparison with herpes simplex encephalitis. Cytokine 2008;44:149–53.