Perché IgEV nella Neuropatia Diabetica?

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Ann Madeleine Greer
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1 Immunoglobuline, Neuropatia Diabetica e a Piccole Fibre Il Ruolo delle Immunoglobuline nella Patologia Neurologica,Milano Jann Stefano, MD Department of Neuroscience A.O. Ospedale Niguarda Ca Granda Milan, Italy

2 Perché IgEV nella Neuropatia Diabetica? Radicolo Plessopatia Lombosacrale in corso di Diabete Mellito Polineuropatia Cronica Demielinizzante Infiammatoria (CIDP) in corso di Diabete Mellito Neuropatia Diabetica Dolorosa con Dolore Neuropatico Resistente al Trattamento?

Polineuropatia Cronica Demielinizzante Infiammatoria (CIDP) in

11 CIDP in corso di Diabete Mellito

13 A 19-year-old girl was referred to endocrinology department because of progressive numbness and proximal lower limb weakness for 4 years, and persistent hyperglycemia for 2 years. Since Jan 2006, she began complained of numbness, weakness, paresthesia and pain in bilateral lower extremities, which progressively spread to bilateral upper extremities. Since May 2007, she had also suffered from polydipsia and polyuria, until August 2010 she began to search for medical care in local hospital. Laboratory examination showed persistent hyperglycemia (preprandial mmol/l, postprandial mmol/l, respectively). Intensive insulin therapy got good response in blood glucose control.. At that time the diagnosis of DPN were presumed. However, routine combination therapy on DPN included alprostadil, mecobalamine and a-lipoic acid intravenous did not get any effect... All these clinical data confirmed the diagnosis of CIPD mimicking DPN in this patient. Subsequently, immunoglobulin (400 mg/kg/d, 5 days) in combination with high dose methylprednisolone pulse therapy (HDMPT) was administered intravenously. The HDMPT proposal was methylprednisolone 200 mg/d 3 d iv, 100 mg/d 3 d iv, then changed to oral prednisone 15 mg/d and tapered by 5 mg every 2 weeks to withdrawal. In the following weeks, her muscle power recovered to normal, and the symptoms of weakness and all the sensory discomforts were relieved completely. Currently the patient remains in remission. d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 9 6 ( ) e 1 5 e 1 7

Since May 2007, she had also suffered from polydipsia and polyuria, until August 2010 she began to search for medical care in local hospital.

15 Conclusions: The clinical phenotype and electrophysiological profile of CIDP + DM patients is marked by more severe neuropathy and better glycemic control than in patients with D-DSP. These findings indicate that these two conditions despite similarities in their electrophysiological pattern of demyelination likely differ in etiology. Many authors underlie the difficulty of distinguishing CIDP from severe DP which frequently is progressive, associated with radiculopathy and may feature a degree of demyelination on neurophysiological studies that meets accepted criteria for CIDP. Moreover the spinal fluid protein level is often elevated in diabetic patients, and the nerve biopsy shows varying degrees of axonal and demyelinating changes and inflammatory infiltrates in both conditions.

Many authors underlie the difficulty of distinguishing CIDP from severe DP which frequently is progressive, associated with radiculopathy and may feature a degree of demyelination on

17 In immunocytochemical studies of sural nerve biopsies, CD68+ macrophage clusters were present significantly more frequently in CIDP than in CMT1, and immunoreactive deposits of MMP-9 in endoneurial blood vessels were present in CIDP and diabetes significantly more frequently than in diabetic neuropathy or CMT1 (Table 3) (Jann et al., 2003; Sommer et al., 2005). Differential gene expression studies have also identified specific mrna transcripts whose expression is upregulated in skin from CIDP in comparison to diabetic neuropathy or CMT1 (Lee et al., 2010a). If confirmed, these could serve as diagnostic markers for CIDP. N. Latov, Biomarkers of CIDP in patients with diabetes or CMT1, Journal of the Peripheral Nervous System 16(Supplement):14 17 (2011)

Differential gene expression studies have also identified specific mrna transcripts whose expression is upregulated in skin from CIDP in comparison to diabetic neuropathy or CMT1 (Lee et al.

19 MMP-9 expressionin CIDP-DM

21 Jann S et al JNNP 2009, 80, 70-73

22 NIS 0 NIS 40 Jann S et al JNNP 2009, 80, 70-73

23 Neuropatia Diabetica Dolorosa con Dolore Neuropatico Resistente al Trattamento?

24 Randomized, double-blind placebo controlled trial to evaluate the efficacy and safety of high dose intravenous immunoglobulins in diabetic painful polyneuropathy (DPNP) resistant to conventional therapies Recentemente concluso (dicembre 2014) ed in attesa della analisi statistica

26 How pro-inflammatory cytokines can result in pain? TNF-alpha contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury. He XH, Zang Y, Chen X, Pang RP, Xu JT, Zhou X, Wei XH, Li YY, Xin WJ, Qin ZH, Liu X. (Pain 2010) Indeed, we found that peri-sciatic administration of Indeed, we found that peri-sciatic administration of recombinant rat TNF-alpha (rrtnf) without any nerve injury, which produced lasting mechanical allodynia, also up-regulated Nav1.3 and Nav1.8 in DRG neurons in vivo and that rrtnf enhanced the expression of Nav1.3 and Nav1.8 in cultured adult rat DRG neurons in a dosedependent manner. Furthermore, inhibition of TNF-alpha synthesis, which prevented neuropathic pain, strongly inhibited the up-regulation of Nav1.3 and Nav1.8.

30 Stefano Jann, MD,* Ada Francia, MD, Maria E. Fruguglietti, MD,* Luisa De Toni Franceschini, MD,* and Roberto Sterzi, MD* *Department of Neurology, Niguarda Hospital, Milan; Neurological Clinic, University La Sapienza, Rome, Italy

35 Thank you for your attention

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