Immunoglobuline, Neuropatia Diabetica ea Piccole Fibre Il Ruolo

Immunoglobuline, Neuropatia
Diabetica e a Piccole Fibre
Il Ruolo delle Immunoglobuline nella Patologia
Neurologica,Milano 6.3.2015
Jann Stefano, MD
Department of Neuroscience
A.O.
A.O. Ospedale Niguarda Ca’ Granda
Milan, Italy
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?
CIDP in corso di Diabete Mellito
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 18.35 mmol/L, postprandial 23.00 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.
diabetesresearchandclinicalpractice96(2012)e15–e17
“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.”
“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)
MMP-9 expression in CIDP-DM
Jann S et al JNNP 2009, 80, 70-73
50
45
40
35
30
25
20
15
10
5
0
NIS 0
NIS 40
Jann S et al JNNP 2009, 80, 70-73
Neuropatia Diabetica Dolorosa
con Dolore Neuropatico
Resistente al Trattamento?
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
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
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”.
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
Thank you for your attention