Angelika F. Hahn

Polyneuropathy in critically ill patients

Five patients developed a severe motor and sensory polyneuropathy at the peak of critical illness (sepsis and multiorgan dysfunction complicating a variety of primary illnesses). Difficulties in weaning from the ventilator as the critical illness subsided and the development of flaccid and areflexic limbs were early clinical signs. However, electrophysiological studies, especially needle electrode examination of skeletal muscle, provided the definite evidence of polyneuropathy. The cause is uncertain, but the electrophysiological and morphological features indicate a primary axonal polyneuropathy with sparing of the central nervous system. Nutritional factors may have played a role, since the polyneuropathy improved in all five patients after total parenteral nutrition had been started, including the three patients who later died of unrelated causes. The features allow diagnosis during life, and encourage continued intensive management since recovery from the polyneuropathy may occur.

Critically ill polyneuropathy: electrophysiological studies and differentiation from Guillain-Barré syndrome.

A polyneuropathy of varying severity has been observed in association with sepsis and critical illness in 15 patients. Since clinical evaluation is often difficult, electrophysiological studies provided definitive evidence for polyneuropathy. These revealed reductions in the amplitudes of compound muscle and sensory nerve action potentials, the most marked abnormality. Near-nerve recordings confirmed such reductions for sensory fibres. Needle electromyography revealed signs of denervation of limb muscles. Phrenic nerve conduction and needle electromyographic studies of chest wall muscles suggested that the polyneuropathy partially explained difficulties in weaning patients from the ventilator, an early clinical sign. No defect in neuromuscular transmission was demonstrated, despite the use of aminoglycoside antibiotics in some patients. In those who survived the critical illness, clinical and electrophysiological improvement occurred. The 15 critically ill polyneuropathy patients were compared with 16 Guillain-Barré syndrome patients observed during the same period. The analysis showed that the two polyneuropathies are likely to be separate entities that can be distinguished in most instances by the predisposing illness, electrophysiological features and cerebrospinal fluid results.

European Federation of Neurological Societies/Peripheral Nerve Society Guideline* on management of chronic inflammatory demyelinating polyradiculoneuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society

Abstract  Background: Numerous sets of diagnostic criteria have sought to define chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and randomized trials and systematic reviews of treatment have been published. Objectives: The aim of this guideline was to prepare consensus guidelines on the definition, investigation, and treatment of CIDP. Methods: Disease experts and a representative of patients considered references retrieved from MEDLINE and Cochrane Systematic Reviews in May 2004 and prepared statements that were agreed in an iterative fashion. Recommendations: The Task Force agreed on good practice points to define clinical and electrophysiological diagnostic criteria for CIDP with or without concomitant diseases and investigations to be considered. The principal treatment recommendations were as follows: (1) intravenous immunoglobulin (IVIg) or corticosteroids should be considered in sensory and motor CIDP (level B recommendation); (2) IVIg should be considered as the initial treatment in pure motor CIDP (good practice point); (3) if IVIg and corticosteroids are ineffective, plasma exchange should be considered (level A recommendation); (4) if the response is inadequate or the maintenance doses of the initial treatment are high, combination treatments or adding an immunosuppressant or immunomodulatory drug should be considered (good practice point); and (5) symptomatic treatment and multidisciplinary management should be considered (good practice point).

Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease.

ABSTRACT: We have studied the relationship between genotype, clinical phenotype, and pathology in 13 families with dominant X‐linked Charcot‐Marie‐Tooth (CMT) neuropathy. Connexin32 (Cx32) gene mutations were spread throughout the coding region and included eight missense mutations, one 8‐bp deletion/4‐bp insertion frame shifting mutation, two nonsense mutations, and one deletion of the entire coding sequence. One hundred sixteen affected CMTX patients (53 males and 63 females) and 63 unaffected, at‐risk individuals were compared by neurological and electrophysiological examinations and analyzed by gender; nerve biopsies were available from seven index cases. It was found that mutations within all regions of the Cx32 gene coding sequence caused an identical clinical phenotype. Male CMTX patients were affected more severely and showed an age‐dependent progression of clinical signs and of the pathology; there was, however, variability in the severity of disease expression, irrespective of age, among males within families of defined genotype. All but 10% of female CMTX patients had only mild signs. Motor nerve conduction velocities were moderately slowed (median nerve MNCV: males 34.5 ± 6.2 m/sec; females 45.8 ± 7.3 m/sec), and motor and sensory nerve amplitudes were reduced (median nerve CMAP: males 3.7 ± 3.7 mV; females 7.8 ± 3.4 mV), with electromyographic evidence of chronic denervation. Differences were significant between gender and between affected and unaffected individuals. In agreement with the electrophysiological observations, pathological studies showed evidence of paranodal demyelination and of a length‐related axonal degeneration in motor and sensory nerve fibers. Correlations between genotype and clinical phenotype suggested that missense mutations located within the second transmembrane domain and/or cytoplasmic loop might be associated with milder clinical phenotype, and therefore might be less disruptive of Connexin32 gap junction function. Missense, chain‐terminating, or deletion mutations in all other locations of the Connexin32 protein caused severe forms of CMTX and disease onset in the first decade. Observed variability of disease severity among males within kinships suggests the influence of other modifying factors.

Pathological findings in the x-linked form of Charcot-Marie-Tooth disease: a morphometric and ultrastructural analysis

Abstract. Mutations in the connexin 32 gene (Cx 32) are associated with the x-linked form of Charcot-Marie-Tooth disease (CMTX) and segregate with a CMT 1 phenotype. The gap junction protein Cx 32 is expressed in myelinating Schwann cells and has been localized to regions of non-compacted cytoplasm in paranodes and in Schmidt-Lanterman incisures. Mutant Cx 32 myelin proteins are predicted to impair Schwann cell functions. We have studied the resulting pathology in motor and sensory nerves from the probands of 13 CMTX kindreds with precisely defined genotype. This report provides a detailed descriptive and morphometric analysis of 14 CMTX nerve biopsy samples, taken at various stages in the development of the neuropathy and studied by light and electron microscopic examination. Findings indicated unusually prominent changes in paranodal myelin with resulting widened nodes of Ranvier, but with segmental demyelination being less common. In parallel early axonal cytoskeletal abnormalities were noted, which were followed later by axonal atrophy, degeneration and loss of myelinated nerve fibers, occurring in a length-dependent fashion. Regenerative sprouting was also unusually prominent. Ultrastructural abnormalities included a frequent dilatation of the adaxonal spaces, prominence of the adaxonal Schwann cell cytoplasm and widening of the Schmidt-Lanterman incisures. We conclude that mutations in Cx 32 gap junction protein lead to a compromise of Schwann cell functions and to impaired Schwann cell-axon interactions with subsequent pathology in both myelin and axons.

Respiratory electrophysiological studies in Guillain-Barré syndrome.

Respiratory failure is a common and potentially life threatening complication in patients with Guillain-Barré syndrome. The incidence of phrenic nerve involvement and the predictive value of phrenic nerve conduction and diaphragmatic needle EMG were studied in 40 patients with Guillain-Barré syndrome within the first three days of admission to hospital. The negative peak onset latency of the diaphragmatic compound muscle action potential (CMAP), and its amplitude, duration, and area were abnormal in 83%. The need for ventilation was correlated with diaphragmatic CMAP amplitude (P = 0.005), and area (P = 0.001), but not with latency or duration. Abnormalities in diaphragmatic needle EMG were found in 45%, mainly a decreased number of motor unit potentials. The abnormalities correlated with the need for ventilation (P = 0.013). Of the 40% who required ventilation, all had either abnormal phrenic conduction, abnormal diaphragmatic needle EMG, or both. Eighty one per cent of the ventilated patients had abnormal forced vital capacity on the day of the electrophysiological examination. The results indicate that phrenic nerve conduction studies and diaphragmatic EMG are useful in detecting respiratory involvement in patients with Guillain-Barré syndrome and in identifying those at risk of respiratory failure.

Complement depletion suppresses lewis rat experimental allergic neuritis

Lewis rats immunized with myelin and complete Freunds adjuvant were treated with cobra venom factor (CVF) which depletes the C3 component of complement. CVF given at day 9 delayed the onset of experimental allergic neuritis (EAN) by 2-3 days and when given at days 9 and 12 delayed the onset of EAN by 4-5 days. Lumbar nerve roots of CVF-treated rats had significantly less demyelination than those from control EAN rats.

Changing outcome in inflammatory neuropathies Rasch–comparative responsiveness

Objectives: We performed responsiveness comparison between the patient-reported Inflammatory Rasch-built Overall Disability Scale (I-RODS) and the widely used clinician-reported Inflammatory Neuropathy Cause and Treatment–Overall Neuropathy Limitation Scale (INCAT-ONLS) in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and immunoglobulin M–monoclonal gammopathy of undetermined significance related polyneuropathy (IgM-MGUSP). Methods: One hundred thirty-seven patients (GBS: 55, CIDP: 59, IgM-MGUSP: 23) with a new diagnosis or clinical relapse assessed both scales. Patients with GBS/CIDP were examined at 0, 1, 3, 6, and 12 months; patients with IgM-MGUSP at 0, 3, and 12. We subjected all data to Rasch analyses, and calculated for each patient the magnitude of change on both scales using the minimal clinically important difference (MCID) related to the individual standard errors (SEs). A responder was defined as having an MCID-SE ≥1.96. Individual scores on both measures were correlated with the EuroQoL thermometer (heuristic responsiveness). Results: The I-RODS showed a significantly higher proportion of meaningful improvement compared with the INCAT-ONLS findings in GBS/CIDP. For IgM-MGUSP, the lack of responsiveness during the 1-year study did not allow a clear separation. Heuristic responsiveness was consistently higher with the I-RODS. Conclusion: The I-RODS more often captures clinically meaningful changes over time, with a greater magnitude of change, compared with the INCAT-ONLS disability scale in patients with GBS and CIDP. The I-RODS offers promise for being a more sensitive measure and its use is therefore suggested in future trials involving patients with GBS and CIDP.

European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of paraproteinaemic demyelinating neuropathies: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society*

Background. Paraprotein‐associated neuropathies have heterogeneous clinical, neurophysiological, neuropathological and haematological features. Objectives. To prepare evidence‐based and consensus guidelines on the clinical management of patients with both a demyelinating neuropathy and a paraprotein (paraproteinaemic demyelinating neuropathy, PDN). Methods. Search of MEDLINE and the Cochrane library, review of evidence and consensus agreement of an expert panel. Recommendations. In the absence of adequate data, evidence based recommendations were not possible but the panel agreed the following good practice points: (1) Patients with PDN should be investigated for a malignant plasma cell dyscrasia. (2) The paraprotein is more likely to be causing the neuropathy if the paraprotein is immunoglobulin (Ig)M, antibodies are present in serum or on biopsy, or the clinical phenotype is chronic distal sensory neuropathy. (3) Patients with IgM PDN usually have predominantly distal and sensory impairment, with prolonged distal motor latencies, and often anti‐myelin associated glycoprotein antibodies. (4) IgM PDN sometimes responds to immune therapies. Their potential benefit should be balanced against their possible side‐effects and the usually slow disease progression. (5) IgG and IgA PDN may be indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy, clinically, electrophysiologically, and in response to treatment. (6) For POEMS syndrome, local irradiation or resection of an isolated plasmacytoma, or melphalan with or without corticosteroids, should be considered, with haemato‐oncology advice.

Genotype/phenotype correlation in affected individuals of a family with a deletion of the entire coding sequence of the connexin 32 gene

Abstract X-linked Charcot-Marie-Tooth disease (CMTX) is a peripheral nerve disorder that has been linked to mutations in the connexin 32 gene (Cx32). These mutations have been shown to be genetically heterogeneous, though recurrences of specific mutations in apparently unrelated families have been seen. The majority of mutations have been shown to be missense, resulting in non-conservative amino acid changes. A few mutations resulting in a premature termination of protein translation, including both nonsense mutations as well as frameshifting microdeletions, have been documented. We would like to report a deletion mutation that appears to eliminate the entire coding sequence of the Cx32 gene, but which has been shown to segregate with a clinical phenotype not unlike that seen in individuals with a less severe alteration of the Cx32 gene. The causes at a cellular level of the CMTX phenotype are still not fully clear, though there has been speculation that these may involve a dominant negative effect where the mutant connexin 32 suppresses the function of other connexins. Studies of kindreds such as this, where in CMTX-affected males the Cx32 gene product is totally absent, will help us to better understand the molecular mechanisms underlying the clinical phenotype associated with this disorder.