Cold-induced sweating syndrome: CISS1 and CISS2: manifestations from infancy to adulthood. Four new cases.

Cold-induced sweating syndrome (CISS), a rare autosomal recessive disorder, is genetically heterogeneous. Deficiency of the CRLF1 and the CLCF1 gene functions results in CISS1 and CISS2, respectively. So far, only a single patient with CISS2 has been reported. Here we describe four new cases of CISS, two additional patients with CISS2 (confirming locus heterogeneity) and two patients with CISS1. Their case histories are given in detail to emphasize the striking similarity of their presentation, which makes a clinical differentiation impossible. All four cases had a uniform presentation in the neonatal period, much like Crisponi syndrome - inability to suckle and swallow due to facial and bulbar weakness; excessive startle and trismus-like facial contractions when crying or being handled; apnoeic spells; episodic unexplained fevers (up to 41 degrees C) and associated seizures or even sudden death; erythematous skin rashes; and camptodactyly. Thus it is evident that Crisponi syndrome is the pediatric manifestation of both CISS1 and CISS2. Signs abate during infancy and most children have a normal psychomotor development. During the first decade all children develop scoliosis and abnormal sweating which is the most disabling symptom in adulthood. We report that cold-induced sweating can be effectively treated. Detailed clinical observations, correlated with the findings from basic science research, may serve to elucidate the role(s) of this important cytokine complex in embryonic and postnatal development.

Derivation and validation of diagnostic criteria for chronic inflammatory demyelinating polyneuropathy.

To develop diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), a retrospective series of patients' records diagnosed by sexpert consensus as CIDP or other chronic polyneuropathies were analyzed. Classification and regression tree analysis was applied to 150 patients to derive a classification rule. According to the rule, diagnosis of CIDP required that a patient have a chronic non-genetic polyneuropathy, progressive for at least eight weeks, without a serum paraprotein and either 1) recordable compound muscle action potentials in > or =75% of motor nerves and either abnormal distal latency in >50% of nerves or abnormal motor conduction velocity in >50% of nerves or abnormal F wave latency in >50% of nerves; or 2) symmetrical onset of motor symptoms, symmetrical weakness of four limbs, and proximal weakness in > or =1 limb. When validated in 117 patients, the rule had 83% sensitivity (95% confidence interval 69%-93%) and 97% specificity (95% confidence interval 89%-99%) and performed better than published criteria.

CMT1X phenotypes represent loss of GJB1 gene function.

OBJECTIVE: To investigate possible genotype-phenotype correlations and to evaluate the natural history of patients with Charcot-Marie-Tooth disease type 1X (CMT1X). BACKGROUND: CMT1X is caused by over 260 distinct mutations in the gap junction beta 1 (GJB1) gene, located on the X chromosome, which encodes the gap junction protein connexin 32 (Cx32). The natural history of CMT1X is poorly understood, and it remains unknown whether particular mutations cause more severe neuropathies through abnormal gain-of-function mechanisms. METHODS: We evaluated 73 male patients with CMT1X, who each have 1 of 28 different GJB1 mutations predicted to affect nearly all domains of Cx32. Disability was evaluated quantitatively by the CMT Neuropathy Score (CMTNS) as well as by the CMT Symptom Score (CMTSS) and the CMT Examination Score (CMTES), which are both based on the CMTNS. Patients were also evaluated by neurophysiology. RESULTS: In all patients, disability increased with age, and the degree of disability was comparable with that observed in patients with a documented GJB1 deletion. Disability correlated with a loss of motor units as assessed by motor unit number estimates. CONCLUSIONS: Taken together, these data suggest that most GJB1 mutations cause neuropathy by a loss of normal connexin 32 function. Therefore, treatment of male patients with Charcot-Marie-Tooth disease type 1X may prove amenable to gene replacement strategies.

Cold-induced sweating syndrome: a report of two cases and demonstration of genetic heterogeneity.

OBJECTIVES: To characterize the specific autonomic disturbances underlying the cold-induced sweating syndrome (CISS), and to describe a novel genetic variant of this rare recessive disorder. The two not previously reported patients had similar dysmorphic features: abnormal facial appearance, high arched palate, low set rotated ears, flexion deformities of elbows and fingers and scoliosis. Most noticeable were their paradoxical sweat responses: cold ambient temperature induced a profuse sweating over the face, arms and trunk but not over the lower limbs; while in the heat very little sweating occurred primarily on the legs. Testing of autonomic functions demonstrated normal cardiovascular reflexes and postganglionic sympathetic efferent functions. Sural nerve morphology and number of unmyelinated fibers was normal and skin biopsies showed normal appearing eccrine sweat glands. MRI scans revealed no structural brain abnormalities. Oral clonidine, prescribed in one patient, completely suppressed cold-induced sweating. Observed clinical features matched those of two sisters reported from Israel and of two brothers reported from Norway. All six cases presented a similar phenotype. The Norwegian, Israeli and Canadian cases were homozygous or compound heterozygous, respectively, for mutations in the CRLF1 gene on chromosome 19p12 (CISS1). The Australian case, however, had no pathogenic sequence variants in the CRLF1 gene, but was compound heterozygous for mutations in the CLCF1 gene on chromosome 11q13.3 (CISS2). CONCLUSION: The rare cold-induced sweating syndrome is genetically heterogeneous and is probably caused by central and peripheral impairment of sudomotor functions. This is the first detailed report on the clinical consequences of mutations in the CLCF1 gene in humans. Directions for medical therapies are outlined to achieve long term symptom control.

Reliability and validity of the CMT neuropathy score as a measure of disability.

OBJECTIVE: To determine the validity and reliability of the Charcot-Marie-Tooth disease (CMT) neuropathy score (CMTNS) in patients with inherited neuropathy. BACKGROUND: Natural history studies and potential treatment trials for patients with various forms of CMT are limited by the lack of quantitative methodologies to monitor disease progression. Most cases of CMT can be considered length-dependent axonal neuropathies because disability for even the demyelinating forms correlates with length-dependent axonal degeneration. The total neuropathy score (TNS) is a validated composite measure of disability in length-dependent axonal neuropathies but is weighted toward predominantly sensory neuropathies. Thus, the authors have devised a CMTNS, modified from the TNS, to provide a single measure to quantify CMT disability. METHODS: The authors measured inter- and intrainvestigator reliability of the CMTNS and performed a validation of the score with the Neuropathy Impairment Score (NIS), patient self-assessment scores, an ambulation index, and other measures of disability. RESULTS: Inter- and intrainvestigator reliability was more than 95% in the 60 patients evaluated. Patients could be divided into mild (CMTNS, < or =10), moderate (CMTNS, 11 to 20), and severe (CMTNS, > or =21) categories and demonstrated excellent correlations among all measures of disability. CONCLUSION: The Charcot-Marie-Tooth disease (CMT) neuropathy score is a validated measure of length-dependent axonal and demyelinating CMT disability and can be investigated as an end point for longitudinal studies and clinical trials of CMT.

Practice parameter: immunotherapy for Guillain-Barré syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To provide an evidence-based statement to guide physicians in the management of Guillain-Barré syndrome (GBS). METHODS: Literature search and derivation of evidence-based statements concerning the use of immunotherapy were performed. RESULTS: Treatment with plasma exchange (PE) or IV immunoglobulin (IVIg) hastens recovery from GBS. Combining the two treatments is not beneficial. Steroid treatment given alone is not beneficial. RECOMMENDATIONS: 1) PE is recommended for nonambulant adult patients with GBS who seek treatment within 4 weeks of the onset of neuropathic symptoms. PE should also be considered for ambulant patients examined within 2 weeks of the onset of neuropathic symptoms; 2) IVIg is recommended for nonambulant adult patients with GBS within 2 or possibly 4 weeks of the onset of neuropathic symptoms. The effects of PE and IVIg are equivalent; 3) Corticosteroids are not recommended for the management of GBS; 4) Sequential treatment with PE followed by IVIg, or immunoabsorption followed by IVIg is not recommended for patients with GBS; and 5) PE and IVIg are treatment options for children with severe GBS.

Interferon beta-1a as an investigational treatment for CIDP.

A prospective, multicenter, open-label study was conducted to determine the safety and efficacy of intramuscular (IM) interferon beta-1a (IFNbeta-1a) (Avonex) for treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Eligible patients received IM IFNbeta-1a 30 microg once weekly for 6 months. Safety and tolerability were evaluated by reporting of adverse events, measurement of vital signs, and results of blood chemistry, hematology, and urinalysis. The primary efficacy end points were changed from baseline to month 6 on a quantitative Neurologic Disability Score (NDS), a clinical grading (CG) scale, and grip strength (GS) measures. Electrophysiologic measurements were performed at baseline and month 6. A total of 20 treatment-resistant patients with CIDP were enrolled in the study. The tolerability of IFNbeta-1a in patients with CIDP was similar to that seen with its use in MS. There were no serious adverse events, and no patients discontinued treatment due to adverse events. Seven patients (35%) showed clinical improvement, 10 (50%) had stable disease, and 3 (15%) continued to deteriorate. Significant improvements from baseline were observed in NDS in both the intent-to-treat and per protocol analyses (p=0.0005). For CG, significant improvement from baseline was observed in the per protocol analysis (p<0.05) but not in the intent-to-treat analysis. There was no significant effect of treatment on GS. Clinical improvement was not dependent on age, gender, clinical form of CIDP, or duration of symptoms. Electrophysiologic data showed improvements in mean median, ulnar, and tibial motor nerve potential areas. There was no correlation between clinical improvement and electrophysiologic data. The promising results of this study, especially given the refractory nature of the patient population, suggest that a larger placebo-controlled study should be performed to further evaluate the efficacy of IM IFNbeta-1a for the treatment of CIDP.

Use of intravenous gamma globulins in neuroimmunologic diseases.

Intravenous gamma globulin (IVIg) is used in the treatment of immunologic diseases that affect the entire neuroaxis, including the brain, spinal cord, peripheral nerves, muscles, and neuromuscular junction. The panel reviewed the available literature on the use of IVIg in order to evaluate the efficacy of this therapy in neuroimmunologic diseases. In prospective, rigorously controlled, double-blinded clinical trials, IVIg was found to have proven efficacy in the Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, dermatomyositis, and Lambert-Eaton myasthenic syndrome. It was found to be probably effective in myasthenia gravis and polymyositis, and possibly effective in several other neuroimmunologic diseases. Further studies are needed to evaluate the use of IVIg for neuroimmunologic diseases in which its efficacy is suspected but not proven and to elucidate its mechanisms of action.

Severe infantile axonal neuropathy with respiratory failure.

We describe 5 infants (4 male, 1 female) with a severe intractable form of motor-sensory axonal neuropathy. All became ventilator-dependent, 4 have since died and 1 remains static. Diaphragmatic paralysis was an early feature with generalized neuropathy evolving rapidly. Nerve conduction studies and biopsies were consistent with axonal disease. This disorder could be a new condition or part of the spectrum of inherited neuropathies of the axonal degenerative type. It may be that there is a "switching-off" in the infant's Schwann cell-axonal interactions in utero or in the early postnatal period, resulting in severe progressive deterioration and then a static period without recovery.

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

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.

Multifocal motor neuropathy improved by IVIg: randomized, double-blind, placebo-controlled study.

OBJECTIVE: To determine the effect of IV immunoglobulin (IVIg) on neurologic function and electrophysiologic studies in multifocal motor neuropathy with conduction block (MMN). BACKGROUND: MMN is characterized by progressive, asymmetric, lower motor neuron weakness and is probably immune-mediated. IVIg treatment has been shown to have beneficial effects in several open-label studies and in one small controlled trial. However, larger randomized controlled studies are lacking. METHODS: The authors recruited 16 patients with MMN. All subjects were given each of two treatments (IVIg [0.4 g/kg/d for 5 consecutive days] or placebo [dextrose or saline]) that were assigned according to a randomized, crossover design under double-blind conditions. Patients were evaluated before and about 28 days after trial treatment for subjective functional improvement, neurologic disability score, grip strength, distal and proximal compound muscle action potential amplitude, and conduction block. RESULTS: Subjective functional improvement with IVIg treatment was rated as dramatic or very good in nine patients, moderate in one, mild in one, and absent in five patients. This improvement was absent after placebo. The neurologic disability score improved by 6.7+/-3.3 points with IVIg treatment, whereas it decreased by 2.1+/-3.0 with placebo (p = 0.038). Grip strength on the weaker side was increased by 6.4+/-1.9 kg with IVIg treatment; it decreased by 1.0+/-0.8 kg with placebo (p = 0.0021). Conduction block worsened by 12.98+/-6.52 % with placebo, but improved by 12.68+/-5.62 % with IVIg treatment (p = 0.037). Conduction block was reversed in five patients with IVIg but not placebo. CONCLUSION: IVIg improved conduction block as well as subjective and objective clinical measures of function in patients with MMN.

Intravenous immunoglobulin treatment in peripheral nerve disorders--indications, mechanisms of action and side-effects.

This review summarizes observations of clinical use of high dose intravenous immunoglobulin G (IVIg) in regards to administration, kinetics, known or postulated mechanisms of action, and adverse reactions. Indications and value of IVIg for the treatment of various neuropathies with presumed autoimmune aetiology are examined. New knowledge that advances the understanding of the pathogenesis of the neuropathies and of the mechanisms of action of IVIg is discussed.

A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation.

Hyperkalemic periodic paralysis (HyperKPP) is an autosomal dominant skeletal muscle disorder caused by single mutations in the SCN4A gene, encoding the human skeletal muscle voltage-gated Na(+) channel. We have now identified one allele with two novel mutations occurring simultaneously in the SCN4A gene. These mutations are found in two distinct families that had symptoms of periodic paralysis and malignant hyperthermia susceptibility. The two nucleotide transitions predict phenylalanine 1490-->leucine and methionine 1493-->isoleucine changes located in the transmembrane segment S5 in the fourth repeat of the alpha-subunit Na(+) channel. Surprisingly, this mutation did not affect fast inactivation parameters. The only defect produced by the double mutant (F1490L-M1493I, expressed in human embryonic kidney 293 cells) is an enhancement of slow inactivation, a unique behavior not seen in the 24 other disease-causing mutations. The behavior observed in these mutant channels demonstrates that manifestation of HyperKPP does not necessarily require disruption of slow inactivation. Our findings may also shed light on the molecular determinants and mechanism of Na(+) channel slow inactivation and help clarify the relationship between Na(+) channel defects and the long-term paralytic attacks experienced by patients with HyperKPP.

[Acquired demyelinating neuropathies]. / Neuropathies démyélinisantes acquises.

The acquired demyelinating polyneuropathies with either acute or chronic clinical presentation are considered autoimmune disorders. The Guillain-Barré syndrome is viewed as an acutely reactive and self-limited autoimmune disease, triggered by preceding bacterial or viral infections. There is a particularly strong association with the gastroenteric pathogen, Campylobacter jejuni, and with Cytomegalovirus and Epstein-Barr virus. It is likely that immune response directed towards the infecting organisms are involved in the pathogenesis of Guillain-Barré syndrome by cross-reaction with neural tissues. In the susceptible individual, the infecting organism induces humoral and cellular immune responses that, because of the sharing of homologous epitopes (molecular mimicry), cross-react with ganglioside surface components of peripheral nerve. Immune reactions against target epitopes in the Schwann cell surface membrane or myelin result in acute inflammatory demyelinating neuropathy (90% of cases); reactions against epitopes contained in the axonal membrane cause the acute axonal forms of Guillain-Barré syndrome. Immunomodulation with infusions of IgG or plasma exchange treatments effectively foreshorten the disease course. The immunopathogenesis of the chronic disease forms, chronic inflammatory demyelinating peripheral neuropathy and multifocal motor neuropathy are less well-known. Immunomodulatory treatments with corticosteroid or cytotoxic drug treatments, infusion of Ig or therapeutic plasma exchanges are variably effective. The article outlines the principles and practices of an individualized approach to therapy.

Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis.

Although the carbonic anhydrase inhibitors have been used in the treatment of the primary periodic paralyses (PPs), their efficacy has not been demonstrated in double-blind, placebo-controlled trials. Therefore, we tested the efficacy of dichlorphenamide (DCP; Daranide), a potent carbonic anhydrase inhibitor, in the treatment of episodic weakness in the primary PPs. We performed two multicenter, randomized, double-blind, placebo-controlled crossover trials, one involving 42 subjects with hypokalemic periodic paralysis (HypoPP) and the other involving 31 subjects with potassium-sensitive periodic paralysis (PSPP). In each trial, two 8-week treatment periods were separated by an active washout period of at least 9 weeks. The primary outcome variable in the HypoPP trial was the occurrence of an intolerable increase in attack severity or frequency (end point). The primary outcome variable in the PSPP trial was the number of attacks per week. In the HypoPP trial, there were 13 subjects who exhibited a preference (in terms of the end point) for either DCP or placebo, and 11 of these preferred DCP. In the PSPP trial, DCP significantly reduced attack rates relative to placebo. DCP also significantly reduced attack rates relative to placebo in the HypoPP subjects. We conclude that DCP is effective in the prevention of episodic weakness in both HypoPP and PSPP.

Impact of plasma exchange on indices of demyelination in chronic inflammatory demyelinating polyradiculoneuropathy.

We studied the impact of plasma exchange (PE) on indices of primary demyelination in patients of the Canadian multicenter trial of PE in chronic inflammatory demyelinating polyneuropathy (CIDP). Individual motor nerves (median, ulnar, peroneal, tibial) were studied: distal motor latencies (DMLs), proximal and distal compound muscle action potential (M-wave) amplitudes, negative peak areas and durations, and motor conduction velocities (CVs). Proximal M-wave amplitudes in individual motor territories, particularly in the ulnar nerve (from below elbow, above elbow, and axillary stimulating sites) demonstrated significant improvement with PE, but not sham exchange. Proximal ulnar M-wave areas also had significant improvement with PE. Trends toward improvement of individual nerve motor CVs, M-wave durations, and DMLs did not achieve statistical significance. Proximal M-wave amplitudes, particularly in the ulnar motor territory, and proximal M-wave areas (providing a measure of conduction block) were the most sensitive indices of improvement conferred by PE in CIDP. In individual patients, these indices may help judge the efficacy of therapy.

Clinical and pathological observations in men lacking the gap junction protein connexin 32.

The X-linked form of Charcot-Marie-Tooth disease has been associated with mutations in the connexin 32 (Cx 32) gene, which encodes a gap junction protein. The majority of identified mutations are missense, but a few nonsense mutations or frame-shifting microdeletions have been encountered. Functional assessments of the mutated gap junction protein have demonstrated altered or simple losses of function. Mutations segregate with a typical clinical phenotype, which is the result of an age-related, progressive neuropathy. The mechanisms that cause the nerve damage are unknown. This report describes the consequences of a unique deletion mutation that eliminates the entire coding sequence of Cx 32, resulting in the absence of the Cx 32 gap junction protein in affected, hemizygous men. The clinical expression of this unique mutation was studied by the clinical, electrophysiological, and pathological evaluation of this kinship of five generations. The resulting severe neuropathy combines features of demyelination, notably in paranodal distribution, and distal accentuated axonal degeneration. The predicted absence of Cx 32 gap junctions is shown to be associated with a severe dysfunction of the axon-Schwann cell unit. Observed changes resemble those of Cx 32-null mice. No central nervous system changes were demonstrated.