Chiara Dalla Torre

Cobalamin Deficiency: Clinical Picture and Radiological Findings

Vitamin B12 deficiency causes a wide range of hematological, gastrointestinal, psychiatric and neurological disorders. Hematological presentation of cobalamin deficiency ranges from the incidental increase of mean corpuscular volume and neutrophil hypersegmentation to symptoms due to severe anemia, such as angor, dyspnea on exertion, fatigue or symptoms related to congestive heart failure, such as ankle edema, orthopnea and nocturia. Neuropsychiatric symptoms may precede hematologic signs and are represented by myelopathy, neuropathy, dementia and, less often, optic nerve atrophy. The spinal cord manifestation, subacute combined degeneration (SCD), is characterized by symmetric dysesthesia, disturbance of position sense and spastic paraparesis or tetraparesis. The most consistent MRI finding is a symmetrical abnormally increased T2 signal intensity confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord. Isolated peripheral neuropathy is less frequent, but likely overlooked. Vitamin B12 deficiency has been correlated negatively with cognitive functioning in healthy elderly subjects. Symptoms include slow mentation, memory impairment, attention deficits and dementia. Optic neuropathy occurs occasionally in adult patient. It is characterized by symmetric, painless and progressive visual loss. Parenteral replacement therapy should be started soon after the vitamin deficiency has been established.

Sonographic features in hereditary neuropathy with liability to pressure palsies

Introduction: Diagnostic nerve ultrasound is becoming more commonly used by both radiologists and clinicians. The features of different neuromuscular conditions must be described to broaden our understanding and ability to interpret findings. Methods: Our study examines the sonographic features of 7 subjects with hereditary neuropathy with liability to pressure palsies (HNPP) in comparison to 32 controls by measuring the nerve cross-sectional area (CSA) of the median, ulnar and tibial nerves. Results: Significant differences (P < 0.05) in nerve size were found. The HNPP group had a larger CSA for the median nerve at the wrist and ulnar nerve at the elbow (entrapment sites), but not the forearms. The tibial nerve at the ankle was also larger in the HNPP group, suggesting possible concomitant tibial neuropathy at the ankle. Conclusion: These results will help shape imaging protocols to better detect conditions with non-uniform nerve enlargements. Muscle Nerve 2011

Vascular endothelial growth factor helps differentiate neuropathies in rare plasma cell dyscrasias.

POEMS syndrome and amyloidosis are rare plasma cell diseases that share common features, including polyneuropathy. The aim of this study was to investigate serum vascular endothelial growth factor (sVEGF) in patients with amyloidosis and to evaluate changes in response to treatment. Twenty‐five patients [17 primary light‐chain amyloidosis (AL‐A), 7 transthyretin amyloidosis (TTR‐A), 1 senile wild‐type TTR‐A] were studied. sVEGF was analyzed by ELISA. Sera from 8 myeloma and 7 POEMS patients were also evaluated. The median sVEGF level was 420 pg/ml in AL‐A and 179 pg/ml in TTR‐A patients; this was significantly lower than in POEMS syndrome (median 2580 pg/ml, P = 0.0002 and 0.001, respectively). sVEGF of AL‐A patients showed no changes in response to treatment. sVEGF was not increased in amyloid patients regardless of neuropathy, and did not mirror the course of the disease. sVEGF should be tested in patients with overlapping and atypical clinical features. Muscle Nerve, 2011

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.

Reversible isolated sensory axonal neuropathy due to cobalamin deficiency

Vitamin B12 deficiency causes a wide range of hematological, gastrointestinal, and neurological manifestations. The most common neurological complication is subacute combined degeneration, sometimes associated with polyneuropathy. Isolated peripheral neuropathy due to cyanocobalamin deficiency is less frequent, and thus it may be overlooked. We describe 2 patients with isolated sensory axonal neuropathy secondary to vitamin B12 deficiency who had complete clinical and electrophysiological recovery after cyanocobalamin replacement. Testing for serum vitamin B12 and its metabolites should be done in any distal symmetric neuropathy. Muscle Nerve, 2012

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.

Pachymeningeal involvement in POEMS syndrome: MRI and histopathological study

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome is a rare plasma cell disease. Vascular endothelial growth factor (VEGF) seems to play a pathogenic role. Peripheral neuropathy is the main neurological feature. Cranial pachymeningitis has occasionally been reported, but no histopathological studies have been performed. The authors extensively evaluated the central nervous system MRI in 11 patients (seven men, four women; mean age at diagnosis 54.45 years) with POEMS syndrome. In two patients, meningeal histopathology with staining for VEGF and VEGF receptor was performed, and pachymeningeal involvement characterised at histopathological, immunohistochemical and confocal microscopy levels. Nine patients presented with cranial pachymeningitis. One patient suffered from migraine, and none complained of cranial nerve palsies or visual loss. None showed any MRI signs of spinal pachymeningitis. No correlation was found with disease duration and VEGF serum level. Histopathology showed hyperplasia of meningothelial cells, neovascularisation and obstructive vessel remodelling, without inflammation. VEGF and VEGF receptor were strongly coexpressed on endothelium, smooth-muscle cells of arterioles and meningothelial cells. In conclusion, POEMS patients present a high prevalence of meningeal involvement. The histological changes, different from those present in chronic pachymeningitis of other aetiology, suggest a possible VEGF role in the pathogenesis of the meningeal remodelling.

Polyneuropathy with anti-sulfatide and anti-MAG antibodies: Clinical, neurophysiological, pathological features and response to treatment

IgM paraproteins often present reactivity to myelin-associated glycoprotein (MAG) and sulfatide. We describe the clinical and neurophysiological findings, and therapy response in 21 patients with IgM paraproteinemic neuropathy (15 with anti-MAG antibodies, 1 with anti-sulfatide antibodies, and 5 with both reactivity), and in 2 with anti-sulfatide positivity and no hematological disease. All patients complained of sensory symptoms, the majority had demyelinating neuropathy. Indirect immunofluorescence on human normal sural nerves disclosed different staining patterns. Eight of 13 patients (6 anti-MAG, 1 anti-sulfatide, 1 both anti-sulfatide and anti-MAG antibodies) improved after Rituximab. IVIg, steroids and plasma-exchange were also administered with different responses.

Lenalidomide long-term neurotoxicity Clinical and neurophysiologic prospective study

Objective: To evaluate long-term lenalidomide neurotoxicity and correlation with cumulative dose and hematologic response. Methods: Nineteen myeloma patients (7 men, mean age 63.2 years) underwent clinical and neurophysiologic assessment at baseline and at 2 (8 patients, group A) or 5 years (11 patients, group B) after starting lenalidomide therapy for relapsed/refractory multiple myeloma. Neuropathy was scored with Total Neuropathy Score clinical version (TNSc). Lenalidomide cumulative dose was correlated with severity of neuropathy and hematologic response. Results: At enrollment, 7/19 patients (3 in group A, 4 in group B) had neurophysiologic signs of neuropathy secondary to previous chemotherapy, in 2 of them subclinical. Neurophysiologic evidence of sensory axonal neuropathy occurred in 4/8 patients at 2 years follow-up (group A) and in 3/11 patients at 5 years follow-up (group B). Dorsal sural nerve sensory action potential amplitude was the earliest neurophysiologic abnormality. No relevant (≥4) clinical changes were found in TNSc score. Hematologic overall response was 62% in group A and 100% in group B. No correlation was found between lenalidomide cumulative dose and neuropathy or between neuropathy and hematologic response. Conclusions: In our study, up to 50% of myeloma patients on long-term lenalidomide therapy developed sensory axonal neuropathy. Reduced dorsal sural nerve sensory action potential amplitude was the first neurophysiologic alteration. Neuropathy was usually subclinical or mild, however. Neurotoxicity was independent of lenalidomide cumulative dose and hematologic response.

Novel mutation of the mitofusin 2 gene in a family with Charcot-Marie-Tooth disease type 2.

tion and the patient’s father displayed the exon 6 mutation in heterozygous states, respectively. The patient had worsening proximal weakness of upper and lower limbs at 9 years, starting to restrict activities such as climbing stairs. There were no signs of deteriorating cardiac function, and cardiac treatment has not been necessary. Data on the consequences of sarcoglycan-deficiency on expression, assembly, and trafficking of dystrophin are rather scarce, in particular for c-sarcoglycan. Deletion of 525-T causes a frameshift mutation within the extracellular region of c-sarcoglycan. This causes loss of immunostaining plus reduced immunoreactivity for dystrophin, and on immunoblots. However, this feature has not been described in other mutations of c-sarcoglycan, raising the question whether this specific mutation, and not disruption of csarcoglycan in general, is responsible for the reduction in dystrophin expression. We can only speculate about the impact of the intron 3-mutation c.298-1G>A described here. However, this mutation affects a highly conserved splice region and obviously leads to a major disruption of c-sarcoglycan; it may, in fact also influence dystrophin expression.