Chronic inflammatory demyelinating polyneuropathy or hereditary motor and sensory neuropathy?

The pathological changes generally considered to distinguish chronic inflammatory demyelinating polyneuropathy (CIDP) from hereditary motor and sensory neuropathy (HMSN) are: mononuclear cell infiltrates, prominent endoneurial oedema, and marked fascicle-to-fascicle variability. We evaluated the diagnostic significance of these pathological features which are suggestive of CIDP. Nerve biopsies from 42 dominant HMSN type I cases with a normal disease course were investigated for the occurrence of inflammatory features. A small cluster of mononuclear cells was found in 12% of the cases and marked endoneurial oedema in 21%. Variability in pathology between the fascicles was not observed. The histogram configuration yielded additional information for differential diagnosis. Subsequently, we reviewed the clinical, electrophysiological and morphological features of 18 sporadic cases of chronic progressive demyelinating motor and sensory neuropathy with mainly classic onion bulbs in their nerve biopsies and a disease onset in the first decade. In all these patients DNA investigation for the 17p11.2 duplication was performed. According to the results of the DNA investigation, autosomal dominant HMSN type Ia was diagnosed in eight patients, although in six slight CIDP-positive features were present. A diagnosis was definite or most probable CIDP in eight patients. In two patients no definite diagnosis could be made. Testing for the presence of the 17p11.2 duplication is, therefore, helpful in distinguishing between CIDP and HMSN type I. The diagnosis of CIDP requires careful evaluation of the clinical, electrophysiological and morphological data to avoid false-positive diagnoses of inflammatory disorders.     

Motor and sensory demyelinating mononeuropathy multiplex (multifocal motor and sensory demyelinating neuropathy): a separate entity or a variant of chronic inflammatory demyelinating polyneuropathy?

We report 16 patients with motor and sensory demyelinating mononeuropathy multiplex (MSDMM) or multifocal motor and sensory demyelinating neuropathy (MMSDN). These patients had the clinical pattern of motor and sensory mononeuropathy multiplex, electrophysiological evidence of demyelination including conduction block, and segmental demyelination in the sural nerve biopsy. Sixty per cent of patients had high CSF protein. Eighty per cent of patients showed good responsiveness to steroid treatment. Unlike multifocal motor neuropathy (MMN), MSDMM is characterized by a shorter course, sensory deficits and sensory nerve conduction abnormalities, absence of GM1 antibody in most patients tested, and a good response to steroid therapy. We believe that MSDMM represents a variant of chronic inflammatory demyelinating polyneuropathy (CIDP) and an intermediate link between CIDP and MMN.     

A new POLG1 mutation with peo and severe axonal and demyelinating sensory–motor neuropathy

Background Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with defective enzymatic activities of oxidative phosphorylation (OXPHOS), depletion of mitochondrial DNA (mtDNA) and/or accumulation of mtDNA mutations and deletions. Recent positional cloning studies have linked the disease to four different chromosomal loci. Mutations in POLG1 are a frequent cause of this disorder. Methods We describe two first–cousins: the propositus presented with PEO,mitochondrial myopathy and neuropathy, whereas his cousin showed a Charcot– Marie–Tooth phenotype. Neurophysiological studies, peroneal muscle and sural nerve biopsies, and molecular studies of mtDNA maintenance genes (ANT1, Twinkle, POLG1, TP) and non dominant CMT–related genes (GDAP1, LMNA, GJB1) were performed. Results A severe axonal degeneration was found in both patients whereas hypomyelination was observed only in the patient with PEO whose muscle biopsy specimen also showed defective OXPHOS and multiple mtDNA deletions. While no pathogenetic mutations in GDAP1, LMNA, and GJB1 were found, we identified a novel homozygous POLG1 mutation (G763R) in the PEO patient. The mutation was heterozygous in his healthy relatives and in his affected cousin. Conclusions A homozygous POLG1 mutation might explain PEO with mitochondrial abnormalities in skeletal muscle in our propositus, and it might have aggravated his axonal and hypomyelinating sensory–motor neuropathy. Most likely, his cousin had an axonal polyneuropathy with CMT phenotype of still unknown etiology.     

Is resistance to ischaemia of motor axons in diabetic subjects due to membrane depolarization?

The reasons for the resistance to ischaemia of peripheral nerves in diabetics are not well understood. We have now explored whether axonal depolarization underlies this phenomenon, as has previously been proposed. Resistance to ischaemia was determined by the new method of "threshold tracking". This method revealed an increase in excitability of the peroneal nerve at the popliteal fossa during ischaemia, and a decrease in excitability in the post-ischaemic period. The extent of these alterations in 28 type 1 diabetics without peripheral neuropathy showed a strong correlation with the mean blood glucose concentrations during the last 24 h before examination. To test whether the ischaemic resistance was related to membrane potential, we also measured axonal superexcitability in 11 selected diabetics, since it has been shown that post-spike changes in excitability depend on membrane potential. Changes in excitability of the peroneal nerve were measured in the period between 10 and 30 msec following a conditioning supramaximal compound action potential. Under resting conditions, no differences in the post-spike superexcitability were found between controls and diabetics, despite striking differences in their responses to a 10-min pressure cuff. These observations indicate that membrane depolarization is not involved in the resistance to ischaemia of motor axons in diabetic subjects.     

Expression of growth-associated proteins (GAPs) in injured sensory axons of frogs acclimatized to 15 °C and 25 °C

Labelled proteins conveyed by fast axonal transport into the sensory axons of frog sciatic nerve following axotomy have been studied by 2D gel electrophoresis. Previous work showed that in frogs acclimatized to 25 °C a cell body reaction occurs, along with regeneration of axons to their targets. In contrast, frogs acclimatized to 15 °C showed no cell body reaction and though regeneration began, it stalled after approximately 35 days. We found that axotomy at 25 °C was followed by an increase in transport of specific labelled proteins corresponding to growth-associated proteins (GAPs) identified in other regenerating systems. Surprisingly, axotomy at 15 °C also induced a similar increase, though with a slower onset, so that the highest levels of expression of GAPs occurred during the time when the axons had stalled. We conclude that sensory neurons in 15 °C frogs do detect that their axons have been injured, as shown by their ability to increase GAP synthesis. Slow and limited axonal growth is possible during a period when GAP synthesis is low compared to levels in rapidly regenerating nerves, but even when the ability to produce GAPs increases, this alone is not sufficient to sustain regeneration in the absence of other components of the cell body reaction to injury.     

Peripheral polyneuropathy in children and young adults with ataxia–telangiectasia

Background and purpose

Ataxia–telangiectasia (A-T) is a rare, autosomal recessive, multisystem disorder that leads to progressive neurodegeneration with cerebellar ataxia and peripheral polyneuropathy. Cerebellar neurodegeneration is well described in A-T. However, peripheral nervous system involvement is an underdiagnosed but important additional target for supportive and systemic therapies. The aim of this study was to conduct neurophysiological measurements to assess peripheral neurodegeneration and the development of age-dependent neuropathy in A-T.

Methods

In this prospective study, 42 classical A-T patients were assessed. The motor and sensory nerve conduction of the median and tibial nerves was evaluated. Data were compared to published standard values and a healthy age- and gender-matched control group of 23 participants. Ataxia scores (Klockgether, Scale for the Assessment and Rating of Ataxia) were also assessed.

Results

In A-T, neurophysiological assessment revealed neuropathic changes as early as the first year of life. Subjective symptomatology of neuropathy is rarely described. In the upper extremities, motor neuropathy was predominantly that of a demyelinating type and sensory neuropathy was predominantly that of a mixed type. In the lower extremities, motor and sensory neuropathy was predominantly that of a mixed type. We found significant correlations between age and the development of motor and sensory polyneuropathy in A-T compared with healthy controls (p < 0.001).

Conclusions

In A-T, polyneuropathy occurs mostly subclinically as early as the first year of life. The current study of a large national A-T cohort demonstrates that development of neuropathy in A-T differs in the upper and lower extremities.     

Is total duration of distal compound muscle action potential better than negative peak duration in the diagnosis of chronic inflammatory demyelinating polyneuropathy?

Introduction: The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) is difficult, and the role of electrophysiology is crucial. Distal compound muscle action potential (CMAP) duration is a useful tool that is assessed by measuring negative peak duration (NP). The value of total distal CMAP duration (T), which seems more precise from a physiological standpoint, has not been studied. Methods: We reviewed retrospectively the records of 50 patients with CIDP and 50 controls with chronic axonal neuropathy. We constructed ROC curves for NP and T. Results: Comparison of AUC for T vs. NP showed an advantage for the former (P = 0.026 for the fibular nerve). Our derived cut‐offs offered a sensitivity of 42.3% for T vs. 35.3% for NP. Conclusion: This study suggests a slight advantage for T over NP duration of the distal CMAP in the diagnosis of CIDP. However, the clinical relevance of this result must be weighed against the feasibility of this measurement. Muscle Nerve 49 : 895–899, 2014     

Does order and timing in performance of imagined and actual movements affect the motor imagery process? The duration of walking and writing task

The purpose of the present study was to investigate the effects on the duration of imagined movements of changes in timing and order of performance of actual and imagined movement. Two groups of subjects had to actually execute and imagine a walking and a writing task. The first group first executed 10 trials of the actual movements (block A) and then imagined the same movements at different intervals: immediately after actual movements (block I-1) and after 25 min (I-2), 50 min (I-3) and 75 min (I-4) interval. The second group first imagined and then actually executed the tasks. The duration of actual and imagined movements, recorded by means of an electronic stopwatch operated by the subjects, was analysed. The duration of imagined movements was very similar to those of actual movements, for both tasks, regardless of either the interval elapsed from the actual movements (first group) or the order of performance (second group). However, the variability of imagined movement duration was significantly increased compared to variability of the actual movements, for both motor tasks and groups. The findings give evidence of similar cognitive processes underlying both imagination and actual performance of movement.     

Chronic axonal sensory and autonomic polyneuropathy without motor involvement: a new ‘chronic inflammatory neuropathy?’

We report the case of a woman with axonal sensory and autonomic neuropathy lasting several months who improved in association with steroid administration. During the course of her disease and in the follow-up, the patient underwent repeated cerebrospinal fluid (CSF) examinations, neurophysiological somatic, autonomic nervous system studies and sural nerve biopsy. Clinical and laboratory assessments demonstrated the occurrence of a monophasic, chronic sensory and autonomic neuropathy. A sural nerve biopsy suggested an axonopathy. After a progressive worsening of symptoms lasting about 6 months, steroid treatment was started and within 6 months a complete recovery, with normalization of the CSF findings, was observed. Although the 'chronic inflammatory neuropathies' are still debated entities, the features of this chronic, exclusively sensory and autonomic neuropathy are new, and the occurrence of a high protein level in the CSF, together with the favorable outcome associated with steroid treatment, suggests that our case might be another variant in this debated area.     

Detection of early motor involvement in diabetic polyneuropathy using a novel MUNE method – MScanFit MUNE

ObjectiveDetection of motor involvement in diabetic polyneuropathy (DPN) by nerve conduction studies (NCS) does not occur until there is substantial loss of motor units, because collateral reinnervation maintains compound muscle action potential (CMAP) amplitude. Motor unit number estimation (MUNE) methods may therefore be more sensitive. This study was undertaken to test whether the novel method, MScanFit MUNE (MScan) can detect motor involvement in DPN despite normal NCS.MethodsFifty-two type-2 diabetic patients and 38 healthy controls were included. The median nerve was examined in all participants using standard NCS and a detailed CMAP scan, used for MScan. Additional lower extremity NCS in patients were used for DPN diagnosis.ResultsOf 52 diabetic patients, 21 had NCS-defined DPN while lower extremity NCS were normal in 31 patients. MScan motor unit number and size showed higher sensitivity and incidence of abnormality than motor NCS parameters, and a similar sensitivity to sensory NCS.ConclusionsMScan is able to detect motor axonal damage at times when collateral reinnervation limits NCS changes.SignificanceMScan is a sensitive method to detect motor involvement in DPN, which our data suggests is present as early as sensory.     

Vecuronium-associated axonal motor neuropathy: a variant of critical illness polyneuropathy?

Neuromuscular blocking agents are routinely used as an adjunct therapy for critically ill patients. Unlike many neuromuscular blocking agents, vecuronium does not cause significant histamine release, which may lead to bronchoconstriction. Due to a short duration of action and limited accumulation, vecuronium has been widely used. Prolonged ventilatory dependence due to persistent neuromuscular blockade has been reported in patients treated with vecuronium. We report a case of an 8-year-old girl who had a primarily motor axonopathy presenting with weakness after extended vecuronium administration with prolonged course of recovery. This primarily motor neuropathy with axonal features may be a variant of critical illness polyneuropathy, a rarely reported condition in pediatric patients.     

Choice and stimulus–response compatibility affect duration of response selection

In general, for movements to visual targets, response times increase with the number of possible response choices. However, this rule only seems to hold when an incompatibility exists between the stimulus and response, and is absent when stimulus and response are highly compatible (e.g., when reaching toward the location of the stimulus). Stimulus–response (S–R) compatibility can be manipulated either at the level of stimulus and response characteristics, or at the level of the mapping between elements of the stimulus and response sets. The current study was undertaken to determine the extent of the interaction between choice and each of these two levels of S–R compatibility. Subjects used a joystick to move a cursor in response to two, four or eight possible cues, with S–R compatibility manipulated along two dimensions (type of stimulus, and mapping between stimulus and response sets) in separate blocks of trials. Choice effects were absent when S–R relationships were highly compatible, moderate when incompatible in either of the two dimensions, and greatest when incompatible in both dimensions. These results indicate that choice affects response selection at each stage in the decoding of S–R relationships. Similar but smaller effects were seen for trials in which the stimulus was the same as that presented in the immediately preceding trial, suggesting that repeated stimulus–response transformations are faster and more efficient due to the priming effects of previous trials.     

A clinical and neurophysiological motor signature of Unverricht–Lundborg disease

Objectives

Unverricht–Lundborg disease (ULD) is the most common form of progressive myoclonus epilepsy. Cerebellar dysfunction may appear over time, contributing along with myoclonus to motor disability. The purpose of the present work was to clarify the motor and neurophysiological characteristics of ULD patients.

Pathology and pathogenesis of sensory neuropathy in Friedreich’s ataxia

Friedreich’s ataxia (FRDA) causes a complex neuropathological phenotype with characteristic lesions of dorsal root ganglia (DRG); dorsal spinal roots; dorsal nuclei of Clarke; spinocerebellar and corticospinal tracts; dentate nuclei; and sensory nerves. This report presents a systematic morphological analysis of sural nerves obtained by autopsy of six patients with genetically confirmed FRDA. The outstanding lesion consisted of lack of myelinated fibers whereas axons were present in normal numbers. On cross-sections, only 11% of all class III-β-tubulin-positive axons were myelinated in FRDA, contrasting with 36% in normal control nerves. Despite their paucity, thin myelinated fibers assembled compact sheaths containing the peripheral myelin proteins PMP-22, P₀, and myelin basic protein. The nerves displayed major modifications in Schwann cells that were apparent by laminin 2 and S100α immunocytochemistry. Few S100α-immunoreactive cells remained detectable whereas laminin 2 reaction product was abundant. The normal honeycomb-like distribution of laminin 2 around myelinated fibers was replaced by confluent regions of reaction product that enveloped clusters of closely apposed thin axons. Electron microscopy not only confirmed the lack of myelin but also showed abnormal Schwann cells and axons. Ferritin localized to normal Schwann cell cytoplasm. In the sensory nerves of patients with FRDA, the distribution of this protein strongly resembled laminin 2, but there was no net increase of the total ferritin-reactive area. Ferroportin reaction product occurred in all axons of sural nerves in FRDA, which was at variance with dorsal spinal roots. In the pathogenesis of sensory neuropathy in FRDA, two mechanisms are likely: hypomyelination due to faulty interaction between axons and Schwann cells; and slow axonal degeneration. Neurons of DRG, satellite cells, Schwann cells, and axons of sensory nerves and dorsal spinal roots derive from the neural crest, and hypomyelination in FRDA may be attributed to defects of regulation or migration of shared precursor cells. Sural nerves in FRDA showed no convincing change in ferritin and ferroportin, militating against local iron dysmetabolism. The result stands out in contrast to the previously reported changes in dorsal spinal roots of patients with FRDA.     

Medial plantar-to-radial amplitude ratio: does it have electrodiagnostic utility in distal sensory polyneuropathy?

Purpose of the study: We proposed a new electrophysiological parameter medial plantar (MP)-to-radial amplitude ratio (MPRAR), similar to sural-to-radial amplitude ratio (SRAR), in the diagnosis of distal sensory polyneuropathy (DSP), based on the concept that distal nerves are affected more and earlier than proximal nerves in axonal neuropathies. We aimed to investigate the diagnostic sensitivity of this parameter in diabetic DSP, together with sensitivities of SRAR and MP nerve action potential (NAP) amplitude. Materials and Methods: In 124 healthy controls and 87 diabetic patients with clinically defined DSP and normal sural responses, we prospectively performed sensory nerve conduction studies (NCS), and evaluated the MP NAP amplitude, MPRAR and SRAR values. We determined the lower limits of normal (LLN) of these parameters in the healthy controls and calculated their sensitivities and specificities in detecting DSP in diabetic patients. Results: MP nerve amplitude and MPRAR values were significantly lower in the patient group, compared to controls. However, SRAR values did not differ significantly between the two groups. The LLN of MP NAP amplitude was found to be 4.1?μV. The cutoff values for SRAR and MPRAR were determined as 0.24 and 0.16, respectively. MPRAR was abnormal in 21.8% of patients. However, the most sensitive parameter in detection of DSP was MP NAP amplitude, which showed a sensitivity of 31% and a specificity of 100%. Conclusions: Although MPRAR is more sensitive than SRAR in detecting DSP, it does not provide additional diagnostic yield to the assessment of MP NCS alone in diabetic DSP patients with normal sural responses.     

Altered hippocampal-dependent memory and motor function in neuropilin 2–deficient mice

Semaphorins have an important role in synapse refinement in the mammalian nervous system. The class 3 semaphorin-3F (Sema3F) acting through neuropilin 2/plexin-A3 (Nrp2/PlexA3) holoreceptor complex signals in vivo to restrain apical dendritic spine morphogenesis of cortical pyramidal neurons and hippocampal neurons during postnatal development and mediates excitatory synaptic transmission. Semaphorin signaling has been implicated in the etiology of a number of neurodevelopmental disorders; however, the effects on behavior and mental function of dysregulated Sema3F-Nrp2 signaling have not been fully addressed. The present study is the first behavioral investigation of mice harboring a mutation of the nrp2 gene. Given that loss of Nrp2 signaling alters cortical and hippocampal synaptic organization, we investigated performance of nrp2-deficient mice on learning and sensorimotor function that are known to depend on cortical and hippocampal circuitry. When compared with age-matched controls, nrp2 null mice showed striking impairments in object recognition memory and preference for social novelty. In addition, nrp2^−/− mice displayed impaired motor function in the rotarod test and in observations of grooming behavior. Exploration of novel olfactory sensory stimuli and nociception were unaffected by the loss of Nrp2. Overall, loss of Nrp2 may induce aberrant processing within hippocampal and corticostriatal networks that may contribute to neurodevelopmental disease mechanisms.     

Immunopathology and treatments of Guillain-Barré syndrome and of chronic inflammatory demyelinating polyneuropathy

The concepts of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) have changed over the last decade. The spectrum of GBS ranges from acute inflammatory demyelinating polyneuropathy to pure motor, sensory-motor or bulbar variants and the Miller Fisher syndrome. Also CIDP includes different variants in addition to the typical clinical picture with symmetrical proximal and distal weakness, such as a form with predominant distal weakness, a pure sensory form, an asymmetric form and a form with predominant cranial nerve involvement. Detailed immunopathologic features have been described in GBS and CIDP: most current investigations are centered on the hypothesis of molecular mimicry in GBS and together with the pathogenic role of cell-mediated immunity different antibodies have been discovered in GBS which interfere with nerve impulse conduction on neuromuscular transmission. The immunopathogenesis of CIDP remains fragmentary and insufficient for a unified hypothesis. Activated macrophages and T-cells with the participation of T-1 helper cell related cytokines seem to play a fundamental role in demyelination. The nature of antigen presenting cells, T-cell receptors, adhesion molecules and the proinflammatory cytokines need to be explored to design more specific immunotherapies. Established treatments in GBS include intravenous immunoglobulin and plasma exchange. Randomized trials have shown the efficacy of prednisone, intravenous immunoglobulin and plasma exchange in CIDP. New insight in the pathogenetic role of the cytokine-network in CIDP opens new therapeutical possibilities with the modification of the T-1 helper cell reaction with interferon.