Stefano Jann

Multi‐center assessment of the Total Neuropathy Score for chemotherapy‐induced peripheral neurotoxicity

Abstract  The aim of this multi‐center study was to assess with reduced versions of the Total Neuropathy Score (TNS), the severity of chemotherapy‐induced peripheral neurotoxicity (CIPN), and to compare the results with those obtained with common toxicity scales. An unselected population of 428 cancer patients was evaluated at 11 different centers using a composite (clinical + neurophysiological, TNSr) or clinical (TNSc) examination and with the National Cancer Institute – Common Toxicity Criteria (NCI‐CTC) 2.0 and Eastern Cooperative Oncology Group (ECOG) scores. A highly significant correlation was demonstrated between the TNSr and the NCI‐CTC 2.0 and ECOG scores; but the TNSr evaluation was more accurate in view of the more extended score range. Also, the simpler and faster TNSc (based only on the clinical neurological examination) allowed to grade accurately CIPN and correlated with the common toxicity scores. The correlation tended to be closer when the sensory items were considered, but also the TNSr motor items, which were not specifically investigated in any other previous study, significantly correlated with the results of the common toxicity scales. In conclusion, this study suggests that the TNSr is a reliable tool for accurately grading and reporting CIPN, with the additional and so far unique support of a formal comparison with known and widely used common toxicity scales. The TNSc is a valid alternative if neurophysiological examination is not feasible. The longer time needed to calculate the TNSr and TNSc in comparison to the ECOG or the NCI‐CTC 2.0 scales is offset by the more detailed knowledge of the CIPN characteristics.

β-enolase deficiency, a new metabolic myopathy of distal glycolysis

A severe muscle enolase deficiency, with 5% of residual activity, was detected in a 47‐year‐old man affected with exercise intolerance and myalgias. No rise of serum lactate was observed with the ischemic forearm exercise. Ultrastructural analysis showed focal sarcoplasmic accumulation of glycogen β particles. The enzyme enolase catalyzes the interconversion of 2‐phosphoglycerate and phosphoenolpyruvate. In adult human muscle, over 90% of enolase activity is accounted for by the β‐enolase subunit, the protein product of the ENO3 gene. The β‐enolase protein was dramatically reduced in the muscle of our patient, by both immunohistochemistry and immunoblotting, while α‐enolase was normally represented. The ENO3 gene of our patient carries two heterozygous missense mutations affecting highly conserved amino acid residues: a G467A transition changing a glycine residue at position 156 to aspartate, in close proximity to the catalytic site, and a G1121A transition changing a glycine to glutamate at position 374. These mutations were probably inherited as autosomal recessive traits since the mother was heterozygous for the G467A and a sister was heterozygous for the G1121A transition. Our data suggest that ENO3 mutations result in decreased stability of mutant β‐enolase. Muscle β‐enolase deficiency should be considered in the differential diagnosis of metabolic myopathies due to inherited defects of distal glycolysis.

Diagnosis, treatment and follow-up of the carpal tunnel syndrome: a review.

The carpal tunnel syndrome is a compressive neuropathy with high incidence rates, and its correct diagnosis, treatment and follow-up may lead to significant benefits in healthcare, social and economic terms. In this review, based on systematic review databases and guidelines, we summarise the appropriate indications for the diagnosis, treatment and follow-up, accompanied, whenever possible, by the levels of evidence and strength of recommendations.

A nationwide retrospective analysis on the effect of immune therapies in patients with chronic inflammatory demyelinating polyradiculoneuropathy

Background and purpose:  The guidelines for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) therapy suggest to use immunoglobulins (IVIg) and steroid as first‐line therapies. Patients who do not respond to one of the two drugs should be switched to the other drug. We collected therapeutic outcome data in patients followed at 11 centres in order to document the clinical practice in Italy.

Role of a pre-existing neuropathy on the course of bortezomib-induced peripheral neurotoxicity.

Abstract  We investigated a series of bortezomib‐treated patients and correlated the course of bortezomib‐induced peripheral neurotoxicity with the presence or absence of peripheral neuropathy at baseline. Forty‐eight patients were examined with the total neuropathy score reduced version (TNSr), visual analogue score (VAS) for pain, and nerve conduction studies at baseline and after two and four cycles of chemotherapy. Twenty‐three patients had a baseline TNSr = 0–2, and 25 patients had a baseline TNSr >2 (median = 6, range 3–13). The course of bortezomib‐induced peripheral neurotoxicity was generally more severe in those patients with the highest baseline TNSr. However, among those subjects with a normal baseline TNSr, two patients developed a clinically relevant peripheral neuropathy with a marked increase in TNSr as early as after two cycles of bortezomib treatment (TNSr = 10 and 15, respectively), while after four cycles, three other patients with normal baseline TNSr had a TNSr of 11, 12, and 13. VAS reporting confirmed that painful neuropathy is frequent after bortezomib administration. Our results indicate that the course of bortezomib‐induced peripheral neurotoxicity can be severe in subjects with normal neurological examination at baseline, and therefore, careful monitoring during treatment is suggested in these patients.

Immunosuppressive treatment in refractory chronic inflammatory demyelinating polyradiculoneuropathy. A nationwide retrospective analysis

Background and purpose:  There are other options open to patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are non‐responders to conventional treatment, including immunosuppressive and immunomodulatory agents (IA). The aim of this study was to assess whether the use of IA is able to increase the number of responders.

Diagnostic value of sural nerve matrix metalloproteinase-9 in diabetic patients with CIDP

Patients with diabetes mellitus (DM) may develop chronic inflammatory demyelinating polyneuropathy (CIDP), which may be difficult to distinguish from diabetic neuropathy (DNP). Here the authors show that immunoreactivity for matrix metalloproteinase-9 on sural nerve biopsies may help to identify CIDP-DM. In a pilot study on 10 CIDP-DM patients with IV immunoglobulins and tight glycemic control, the CIDP-DM patients had a better outcome than DNP patients treated with tight glycemic control only.

High-dose intravenous human immunoglobulin in polymyositis resistant to treatment

Two patients were treated with treatment-resistant polymyositis with intravenous immunoglobulin over four days at a dose of 0.4 g/kg/day. Clinical recovery followed within two months. Serum creatine kinase (CK) activity decreased to normal, and a clear improvement in muscle strength was observed. One patient showed neither clinical relapses nor increase in serum CK activity after 20 months. The other showed a mild increase in serum CK activity after 24 months and was successfully retreated with intravenous immunoglobulin. There were no significant adverse side effects.

Intravenous immunoglobulin is effective in patients with diabetes and with chronic inflammatory demyelinating polyneuropathy: long term follow-up

Background and aim: Chronic inflammatory demyelinating polyneuropathy (CIDP) seems to be more common in patients with diabetes than in the general population. The long term outcome of these patients after receiving intravenous immunoglobulin is unclear and the precise optimal regimen needed has yet to be ascertained. Moreover, the influence of chronic hyperglycaemia on this neuropathy is not clear. Methods: This prospective follow-up study included all consecutive patients with diabetes with a CIDP referred to our department during the 18 months of the study. Results: 198 consecutive patients were referred to our neuromuscular unit and exhaustively screened. 16 patients with diabetes (8%) had a demyelinating polyneuropathy fulfilling the most restrictive diagnostic criteria for CIDP. They were treated with at least one course of intravenous immunoglobulin and, if responders, retreated in case of relapse. All patients were followed for at least 40 months. Patients with diabetes with CIDP significantly improved after immunotherapy and during follow-up. The Neuropathy Impairment Score changed from 38 at presentation to 16 at the end of the follow-up. Eight patients developed distal sensory disturbances during follow-up and four of these patients complained of distal paresthesias but no neuropathic pain. Sensory disturbances were detected after 30 months (mean time) from baseline. Conclusion: CIDP is not an unusual neuropathy in patients with diabetes. Our study underlines the importance of extensively investigating patients with diabetes with polyneuropathy to identify those with a treatment responsive demyelinating polyneuropathy.

Frequency and time to relapse after discontinuing 6-month therapy with IVIg or pulsed methylprednisolone in CIDP

Background We reported that 6-month therapy with intravenous immunoglobulin (IVIg) was more frequently effective or tolerated than intravenous methylprednisolone (IVMP) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We now retrospectively compared the proportion of patients who eventually worsened after discontinuing therapy and the median time to clinical worsening. Methods By March 2013, data were available from 41 of the 45 patients completing the trial with a median follow-up after therapy discontinuation of 42 months (range 1–60). Three patients withdrew during the original study and one failed to respond to either of the therapies. No patient received a diagnosis alternative to CIDP during the follow-up. Results Twenty-eight of the 32 patients treated with IVIg (as primary or secondary therapy after failing to respond to IVMP) improved after therapy (87.5%) as compared with 13 of the 24 patients treated with IVMP as primary or secondary therapy (54.2%). After a median follow-up of 42 months (range 1–57), 24 out of 28 patients responsive to IVIg (85.7%) worsened after therapy discontinuation. The same occurred in 10 out of 13 patients (76.9%) responsive to IVMP (p=0.659) after a median follow-up of 43 months (range 7–60). Worsening occurred 1–24 months (median 4.5) after IVIg discontinuation and 1–31 months (median 14) after IVMP discontinuation (p=0.0126). Conclusions A similarly high proportion of patients treated with IVIg or IVMP eventually relapse after therapy discontinuation but the median time to relapse was significantly longer after IVMP than IVIg. This difference may help to balance the more frequent response to IVIg than to IVMP in patients with CIDP.