Characteristics of bortezomib‐ and thalidomide‐induced peripheral neuropathy

Abstract Dose‐limiting peripheral neuropathy (PN) is frequently reported with the use of thalidomide and bortezomib, novel proteasome inhibitors. While these two agents have significant activity in multiple myeloma (MM), the combination and the associated PN have not been fully examined in untreated patients. The objective of this study was to report the baseline prevalence and occurrence of PN in newly diagnosed MM patients treated with bortezomib and thalidomide. Twenty‐seven patients (11 men and 16 women) with previously untreated MM were prospectively monitored for PN. Total neuropathy score reduced (TNSr) was calculated at baseline and after every two cycles of bortezomib treatment. The median cumulative dose of bortezomib was 35.6 mg/m² (median 8 cycles) and of thalidomide was 16.8 g. Only three subjects showed mild PN at baseline (whole group median TNSr 0). At the end of treatment, PN developed in 26 patients (median TNSr 8). PN was of mild to moderate severity (TNSr grade 1 = 11, grade 2 = 10, grade 3 = 5, and grade 4 = 0). Nerve conduction studies showed axonal physiology in all except three subjects in whom demyelinating physiology was noted. The median TNSr was 17 in the demyelinating group and 9 in the axonal group. There was no significant correlation of TNSr with cumulative bortezomib or thalidomide dose. At follow‐up, 80% of patients had become asymptomatic after discontinuation of the chemotherapy. We conclude that bortezomib and thalidomide combination chemotherapy induces a reversible length‐dependent sensory>motor, predominantly axonal, large‐fiber>small‐fiber polyneuropathy. In a subset, a more severe demyelinating polyneuropathy may develop.     

Correspondence between neurophysiological and clinical measurements of chemotherapy‐induced peripheral neuropathy: secondary analysis of data from the CI‐PeriNomS study

Chemotherapy‐induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI‐PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28–6.07), 3.49 (95%CI: 1.61–7.55), and 4.42 (95%CI: 1.35–14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81–41.42), 2.54 (95%CI: 1.19–5.41), and 7.47 (95%CI: 2.49–22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.     

Lifestyle risk factors for ulnar neuropathy and ulnar neuropathy‐like symptoms

Introduction: We examined whether lifestyle factors differ between patients with ulnar neuropathy confirmed by electroneurography (ENG) and those with ulnar neuropathy‐like symptoms with normal ulnar nerve ENG. Methods: Among patients examined by ENG for suspected ulnar neuropathy, we identified 546 patients with ulnar neuropathy and 633 patients with ulnar neuropathy‐like symptoms. These groups were compared with 2 separate groups of matched community referents and to each other. Questionnaire information on lifestyle was obtained. The electrophysiological severity of neuropathy was also graded. We used conditional and unconditional logistic regression. Results: Responses were obtained from 59%. Ulnar neuropathy was related to smoking, adjusted odds ratio (OR) 4.31 (95% confidence interval [CI] 2.43–7.64) for >24 pack‐years. Ulnar neuropathy‐like symptoms were related to body mass index ≥30 kg/m², OR 1.99 (95% CI 1.25–3.19). Smoking was associated with increased severity of ulnar neuropathy. Conclusions: Findings suggest that smoking specifically affects the ulnar nerve. Muscle Nerve 48 : 507–515, 2013     

Lenalidomide in patients with chemotherapy‐induced polyneuropathy and relapsed or refractory multiple myeloma: results from a single‐centre prospective study

Lenalidomide, an immunomodulatory drug used in myeloma therapy, has been claimed to be less neurotoxic than thalidomide, but evidence is still weak. We prospectively assessed lenalidomide safety in myeloma patients to evaluate whether it would induce or modify a previously ensued chemotherapy‐induced peripheral neuropathy (CIPN). Thirty consecutive patients (17 men, mean age 63.7 ± 9.4) previously treated with bortezomib and/or thalidomide and starting on lenalidomide (25 mg/day for 21‐day cycles) for relapsed or refractory myeloma were assessed at baseline, 6, and 12 months from the beginning of lenalidomide with Total Neuropathy Score clinical version (TNSc), Eastern Cooperative Oncology Group (ECOG) performance status, and numeric rating scale (NRS) for pain. TNSc >2 was considered significant for CIPN. TNSc changes of at least 4 points from baseline value were considered clinically relevant. At baseline 16 of the 30 patients (53.3%) had CIPN (mean TNSc 5.8, range 3–15). After 6 months, 13 patients were unchanged, 1 improved, and 2 worsened. After 12 months the patient who had improved persisted stable, and the two who had worsened returned to TNSc baseline value. The 14 patients without CIPN at baseline did not develop neuropathy. NRS and ECOG performance status persisted unchanged. Our results demonstrate lenalidomide safety and very low neurotoxicity also in patients with pre‐existing CIPN treated for 1 year.     

Late‐onset hereditary sensory and autonomic neuropathy expands the phenotypic spectrum of MFN2‐related diseases

Mutations in the Mitofusin 2 (MFN2) gene have been identified in patients with autosomal dominant axonal motor and sensory neuropathy or Charcot–Marie‐Tooth 2A (CMT2A). Here we describe clinical and pathological changes in an adult patient with sporadic hereditary sensory and autonomic neuropathy (HSAN) due to an MFN2 mutation. The patient was a 53‐year‐old man who had sensory involvement and anhidrosis in all limbs without motor features. The electrophysiological assessment documented severe axonal sensory neuropathy. The sural nerve biopsy confirmed the electrophysiological findings, revealing severe loss of myelinated and unmyelinated fibers with regeneration clusters. Genetic analysis revealed the previously identified mutation c.776 G > A in MFN2. Our report expands the phenotypic spectrum of MFN2‐related diseases. Sequencing of MFN2 should be considered in all patients presenting with late‐onset HSAN.     

Antihypoxic treatment at an early stage of diabetic neuropathy: an electrophysiological study with sabeluzole

Thirty-seven non-IDDM patients at an early stage of polyneuropathy, defined as the presence of symptoms for less than two years, as well as an abnormal perception threshold and/or abnormal thermal discrimination threshold, were treated with sabeluzole, a new antihypoxic drug, or placebo for 1 year in a double-blind, placebo-controlled study. They were examined neurophysiologically every 3 months, when motor (tibial, ulnar) nerve and sensory (sural, ulnar) nerve conduction velocities, H-reflex of the soleus muscle, SF-EMG of the anterior tibial muscle, static and dynamic pupillometry were measured. Statistical analysis did not show significant differences in nerve function between the sabeluzole group and the placebo group. There were also no significant changes within each group over the 1-year period. The results of the present study show no beneficial effect of sabeluzole on peripheral nerve function in patients at an early stage of diabetic polyneuropathy.     

Ultrasound evaluation in transthyretin‐related amyloid neuropathy

Introduction: Familial amyloid polyneuropathy is a rare condition caused by mutations of the transthyretin gene (TTR). We assessed the pattern of nerve ultrasound (US) abnormalities in patients with TTR‐related neuropathy. Methods: Seven patients with TTR‐related neuropathy (TTR‐N) and 5 asymptomatic TTR‐mutation carriers (TTR‐C) underwent neurological examination, nerve conduction studies, and US evaluation. Results: Multifocal US abnormalities were identified in 6 of 7 TTR‐N patients. A single patient with only a mild sensory polyneuropathy had normal nerves on US evaluation. In the TTR‐C, we only detected an enlarged ulnar nerve at the elbow. Interestingly, disease severity correlated with number of nerves affected on US evaluation. Conclusions: No specific pattern of US abnormalities was identified in this cohort. However, in TTR‐related amyloid neuropathy, US may be a helpful tool in monitoring disease progression, and/or clinical response to pharmacological treatment. Muscle Nerve 50 : 372–376, 2014     

The evolving natural history of neurophysiologic function in patients with well‐controlled diabetes

This study aimed to investigate prospective changes to neurophysiologic function over 3 years in patients with well‐controlled diabetes. Sixty‐two subjects had neurologic examinations, symptom scores, autonomic testing, nerve conduction studies, quantitative sensory testing, and laser‐Doppler flowmetry at 18‐month intervals for 3 years. During the study, there was a 1 µV decrease in sural amplitude (p < 0.05), an increase in monofilament detection threshold of 0.36 g (p < 0.001), and a decrease in the axon‐reflex vasodilation in the foot (p < 0.005) and forearm (p < 0.05). There was an increase in symptoms of distal hypersensitivity (p < 0.005) but no change in neuropathy frequency or severity. Our findings suggest that laser‐Doppler flowmetry, a test of small fiber function, can detect the largest neurophysiologic change over time in groups of patients with diabetes. Sural nerve amplitude and monofilament thresholds may be more effective at detecting change in individual patients. Other tests of neurophysiologic function may require longer periods of time and greater numbers of participants to detect a difference. We conclude that patients with well‐controlled diabetes and optimal medical management of comorbid risk factors have low rates of neuropathy development and progression although the clinical relevance of this finding to the general population of individuals with diabetes is unknown.     

Clinical study of FK506 in patients with myasthenia gravis

Focal demyelinating lesions typically occur within a 1-cm segment of a nerve. In electrodiagnostic studies, measurements over longer distances decrease the chance of detecting such lesions, but measurements over shorter distances result in greater experimental error. Our objective was therefore to determine the optimal screening distance for ulnar neuropathy at the elbow (UNE) incorporating previously derived experimental errors for calculating nerve conduction velocity (NCV). Using a lesion model wherein prolongation of 0.4 ms was added to the expected latency of a 1-cm nerve segment, new NCVs were derived for distances between 1 and 10 cm for nerves normally conducting between 40 and 65 m/s. Lesion detection, or sensitivity, was defined as the likelihood of calculating a decrease of 10 m/s from the normal NCV while including the experimental error. Specificity was related to the likelihood of an inadvertent calculation of such a decrease in NCV in a segment without a lesion. Sensitivity and specificity were derived at multiple distances with varying NCVs. The total percentage error was the sum of the false-negative and false-positive percentages. The least total percentage error occurred at 3-4 cm, 4-6 cm, and 6-8 cm for nerves normally conducting at 40-50 m/s, 50-60 m/s, and 60-65 m/s, respectively. We conclude that the optimal distance for screening UNE, considering both sensitivity and specificity, is significantly less than 10 cm, perhaps as low as 4-6 cm; considering in addition the likely locations of focal lesions, the best distance is 6-8 cm.     

Late‐onset Becker muscular dystrophy: Refining the clinical features and electrophysiological findings

Introduction: The aim of this study was to characterize a unique distribution of muscle involvement in sporadic Becker muscle dystrophy (BMD). Methods: Retrospective chart review, clinical examination, electrophysiological studies, cardiac testing, and genetic testing were performed in 5 patients. Results: Predominant weakness and atrophy of biceps brachii, hip adduction, and quadriceps muscles was noted along with calf and extensor forearm hypertrophy. Finger flexor muscles were severely weak in 3 of 5 patients, a feature that could lead to a misdiagnosis of inclusion body myositis. Creatinine kinase was only mildly elevated in most patients. Electromyography was abnormal in all patients. Muscle biopsy in 1 patient demonstrated normal immunostaining for dystrophin. Conclusions: We found a unique and uniform distribution of muscle involvement in 5 sporadic cases of BMD. Recognizing these features is important for differentiating it from other myopathies that may have similar features and avoids unnecessary invasive procedures such as muscle biopsy. Muscle Nerve 52 : 885–887, 2015     

Late‐onset myasthenia gravis: A review when incidence in older adults keeps increasing

We define late‐onset myasthenia gravis (LOMG) when symptoms appear at ≥65 years of age. There has been a continuous increase in the incidence of LOMG with a clear male predominance. Commonly, patients present with focal (ocular or bulbar) weakness. A high index of suspicion required to achieve early diagnosis and to improve prognosis. Management options include acetylcholinesterase inhibitors, steroids, and immunosuppressants. The most controversial issue in treatment is thymectomy, because not enough data are available. Successful treatment is associated with improved survival, and death is often secondary to comorbidities. Muscle Nerve 48:705–710, 2013     

Accidental choke cherry poisoning: early symptoms and neurological sequelae of an unusual case of cyanide intoxication

We report the case of a 56-year-old woman who was accidentally poisoned when she ingested choke cherries whose pulp contained cyanide, and describe the acute clinical picture, the neurological sequelae and the neuroradiological findings. After recovery from coma, the patient showed signs of a parkinsonian syndrome, retrobulbar neuritis and sensory-motor neuropathy. MRI showed abnormal signal intensities involving the basal ganglia. Since no memory deficits were observed, we argue that the parkinsonian syndrome was caused by cyanide intoxication rather than by subcortical damage due to hypoxia.

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Sommario Viene descritto un caso di una donna di 56 anni che ha manifestato un avvelenamento accidentale da cianuro dopo ingestione di bacche di laurino che contenevano cianuro nella polpa. Ne riportiamo il quadro clinico acuto, le sequele neurologiche e i reperti neuroradiologici. Dopo essersi ripresa dal coma, la paziente manifestò una sindrome parkinsoniana, neurite retrobulbare e neuropatia sensitivo-motoria. La RMN evidenziò aree di alterato segnale a livello dei gangli della base. La paziente non aveva disturbi di memoria per cui è possibile ipotizzare che la sindrome parkinsoniana sia stata causata dall'intossicazione da cianuro piuttosto che da un danno sottocorticale dovuto a ipossia.