Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy.

BACKGROUND: Genomic copy number variants have been shown to be responsible for multiple genetic diseases. Recently, a duplication in septin 9 (SEPT9) was shown to be causal for hereditary neuralgic amyotrophy (HNA), an episodic peripheral neuropathy with autosomal dominant inheritance. This duplication was identified in 12 pedigrees that all shared a common founder haplotype. METHODS AND RESULTS: Based on array comparative genomic hybridisation, we identified six additional heterogeneous tandem SEPT9 duplications in patients with HNA that did not possess the founder haplotype. Five of these novel duplications are intragenic and result in larger transcript and protein products, as demonstrated through reverse transcription-PCR and western blotting. One duplication spans the entire SEPT9 gene and does not generate aberrant transcripts and proteins. The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 to 9 bp in size. The duplicated regions contain a conserved 645 bp exon within SEPT9 in which HNA-linked missense mutations have been previously identified, suggesting that the region encoded by this exon is important to the pathogenesis of HNA. CONCLUSIONS: Together with the previously identified founder duplication, a total of seven heterogeneous SEPT9 duplications have been identified in this study as a causative factor of HNA. These duplications account for one third of the patients in our cohort, suggesting that duplications of various sizes within the SEPT9 gene are a common cause of HNA.

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.

Mononeuritis multiplex: the yield of evaluations for occult rheumatic diseases.

We identified 35 patients who had electrodiagnostic evidence of mononeuritis multiplex and did not have diabetes or multiple nerve compressions. Their charts were reviewed to determine the etiologies of the mononeuritis multiplex and to determine how often the laboratory examination revealed a rheumatic disease in patients whose initial history and physical examination did not suggest that a rheumatic disease was present. In 11/35 (31%; CI = 17-49) a disorder capable of causing mononeuritis multiplex was diagnosed before the symptoms of mononeuritis multiplex began. Ten had a rheumatic disease; 1 had lymphoma. Nine of the other patients were suspected, on the basis of the history and physical examination, of having new onset of a rheumatic disease. Subsequent laboratory evaluation showed that 5/9 (56%; CI = 21-86) had a rheumatic disease, and 4/9 (44%; CI = 14-79) were unknowns. In 15/35 (43%; CI = 26-61) patients with mononeuritis multiplex, no rheumatic disease was suspected on the basis of the initial history and physical examination. The subsequent laboratory examination revealed an underlying rheumatic disease in 0/15 (0%; CI = 0-18). Mean clinical follow-up of 16 +/- 16 months in the patients with mononeuritis multiplex of unknown cause also failed to identify a rheumatic disease. Overall 19/35 (54%; CI = 37-71) did not have a rheumatic disease or any other known cause. Of the 14 patients with mononeuritis multiplex associated with a rheumatic disease, 5/14 (36%; CI = 13-15) had systemic lupus erythematosus; an additional patient had both lupus and the CREST syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatosensory evoked potentials in chronic acquired demyelinating peripheral neuropathy.

We recorded somatosensory evoked potentials (SEPs) over the scalp in eight patients with chronic acquired demyelinating peripheral neuropathy. They were obtained from 15 nerves in which sensory nerve action potentials (SNAPs) were absent or not more than 1 microV, but from which motor responses could be elicited. Motor and sensory (SEP-derived) conduction velocity was determined from the difference in response latency with wrist and elbow stimulation. In 11 nerves, afferent conduction velocity was slowed. In 10, there was relatively equal slowing in sensory and motor axons, whereas in 1 there was disproportionate slowing in afferent fibers. In four nerves, afferent conduction velocity was within the normal range despite slowing of motor conduction. We conclude that SEPs may be useful in evaluating peripheral sensory conduction in the absence of SNAPs, but can provide misleadingly normal data, presumably because of central amplification of an attenuated response arising from a few axons that conduct normally.

Piroxicam may reduce the rate of progression of experimental diabetic neuropathy.

We studied the effect of piroxicam, a long acting inhibitor of platelet aggregation, on the evolution of neuropathy in diabetic rats. We treated half of the rats with piroxicam and serially studied sensory and motor nerve conduction during 20 weeks of diabetes. The sensory nerve action potential amplitude was the same in treated and untreated rats before diabetes, and declined steadily as duration of diabetes increased. In treated rats, the amplitude fell more slowly and by 16 weeks and thereafter was significantly higher than in untreated rats. Sensory conduction velocity and motor nerve conduction studies were not affected by piroxicam treatment. The results suggest that piroxicam may slow the rate of progression of neuropathy in diabetic rats, probably by inhibiting platelet aggregation.

Acute changes in blood glucose affect resistance to ischemic nerve conduction failure.

We studied resistance to ischemic nerve conduction failure (RINCF) following rapid alterations of blood glucose in normal and diabetic rats. We measured RINCF hourly for 4 hours in normal and diabetic rats. We then made normal rats hyperglycemic and diabetics euglycemic. In normal rats, we measured RINCF sequentially for 4 hours immediately after glucose injection and once after 1, 2, 3, or 4 hours of hyperglycemia. In diabetics, we measured RINCF sequentially for 4 hours after insulin injection. In normal rats, in sequential measurements, RINCF progressively fell but glucose injection prevented this fall. Hyperglycemia without preceding ischemia increased RINCF. In diabetic rats, sequential measurements also produced a decline in RINCF, accentuated with insulin injection. The results suggest that both glucose and insulin are important in determining the response of peripheral nerve to ischemia. They also underscore the importance of knowing the blood glucose and time of most recent insulin injection when measuring RINCF.

Diabetic truncal neuropathy presenting as abdominal hernia.

Two patients with longstanding type II diabetes mellitus presented with focal, unilateral protrusion of the abdominal wall, thought to be due to abdominal hernia. They were evaluated extensively for intra-abdominal pathology but none was found. In one patient, the protrusion was associated with spontaneous burning pain and hyperpathia, but in the other it was painless. In the patient seen during the acute phase there was denervation in paraspinal and abdominal muscles on EMG examination. In both patients, the protrusion subsided without specific treatment in 2 to 4 months. This seldom-described manifestation of diabetic truncal neuropathy masquerading as abdominal hernia needs a higher profile to avoid misdiagnosis and unnecessary investigation. Diagnosis may be quickly established by EMG examination of the paraspinal and abdominal muscles.

Sensory neuropathy with low-dose pyridoxine.

We describe 16 patients with neuropathy associated with pyridoxine abuse. The clinical picture of a pure sensory central-peripheral distal axonopathy was consistent. Pyridoxine dose was 0.2 to 5 g/d, and duration of consumption before symptoms was inversely proportional to the daily intake. In all patients with adequate follow-up, improvement followed discontinuation of pyridoxine. The ready availability of up to 1-gram tablets makes it likely that this neuropathy will continue to be seen.

Distinctive pathologic findings in proximal diabetic neuropathy (diabetic amyotrophy).

OBJECTIVE: To investigate the pathogenesis of proximal diabetic neuropathy (PDN) with nerve and muscle biopsies. BACKGROUND: Recent evidence suggests that nerve ischemia secondary to immune-mediated vasculopathy rather than diabetic microangiopathy may be responsible for PDN. METHOD: - Fifteen patients with PDN and two diabetic controls underwent nerve and muscle biopsy and clinical, electrophysiologic, and laboratory evaluation. There were eight men and seven women between 49 and 79 years of age with type II diabetes. All had progressive, painful, asymmetric, proximal weakness with duration of 5 weeks to 12 months. None had evidence of systemic autoimmune disorder. RESULTS: Four patients showed the distinctive findings of polymorphonuclear small-vessel vasculitis affecting epineurial vessels with transmural infiltration of postcapillary venules with polymorphonuclear leukocytes. Immunoglobulin M (IgM) deposits were found along the endothelium and intramurally in affected vessels. IgM staining was seen in the subperineurial space and in the endoneurium. Activated complement deposition was seen along endothelium of small vessels. Three of these four patients were evaluated within 6 seeks of onset of PDN, and the fourth patient during acute flare of PDN 6 months after the initial onset. Six patients showed "perivasculitis" with mononuclear cell infiltrates around small epineurial vessels without vasculitis (fibrinoid necrosis or transmural inflammation). One patient showed recanalized vessels with transmural lymphocytes without fibrinoid necrosis, possibly suggesting healed vasculitis. CONCLUSION: These distinctive pathologic findings support that proximal diabetic neuropathy has an immune-mediated inflammatory basis and suggest that polymorphonuclear vasculitis with immune complex and complement deposition may be the primary event in the acute phase of proximal diabetic neuropathy.

MRI in juvenile ALS: a patient report.

We describe the MR images of a patient with juvenile ALS. MRI of the brain showed bilateral hyperintensities along the corticospinal tracts extending from the corona radiata to the brainstem on T2-weighted images. These findings should be differentiated from the slight hyperintensities seen in the posterior limbs of the internal capsules in normal subjects.

Conduction block as an early sign of reversible injury in ischemic monomelic neuropathy.

We report three patients with reversible motor conduction block in the forearm associated with ischemic monomelic neuropathy (IMN), which occurred in two patients following placement of brachial artery-cephalic vein shunts for hemodialysis. In the third patient, IMN resulted from spontaneous, probably embolic, brachial artery occlusion. Conduction block was observed shortly after the onset of symptoms, and preferentially involved the median nerve. Slowing of conduction velocity was seen in the same nerve segments. Electrophysiologic resolution, correlating with clinical improvement following treatment, occurred promptly in one patient and over several weeks in the others. Recognition of conduction block is important in the evaluation of IMN, and indicates the need for prompt treatment of likely reversible nerve injury.

Gammopathy with proximal motor axonopathy simulating motor neuron disease.

We report a 38-year-old man with a pure motor syndrome and IgM gammopathy leading to flaccid quadriplegia. Improvement followed treatment with dexamethasone, cyclophosphamide, and plasmapheresis, but he died of pulmonary embolism. At autopsy, he had a proximal motor axonopathy with lymphocytic infiltration of ventral roots. Proximal motor neuropathy may masquerade as motor neuron disease. The association with gammopathy and response to treatment suggest that patients with motor neuron disease should be routinely screened for serum protein abnormalities.

Uniform slowing of conduction velocities in Charcot-Marie-Tooth polyneuropathy type 1.

We evaluated motor conduction studies in 129 patients with Charcot-Marie-Tooth disease type 1 (CMT1) to assess the uniformity of conduction slowing within individual patients. Conduction velocities were nearly identical in proximal and distal nerve segments (r = 0.86), from side to side (r = 0.95), in ipsilateral median and ulnar nerves (r = 0.94), and even in the median and peroneal nerves (r = 0.70). Segmental amplitude reductions suggestive of possible conduction block or differential dispersion were present in only 19 of 360 nerve segments studied (5.3%), and interphase cancellation or focal compression were likely alternative explanations in these cases. These findings support the concept that uniform conduction slowing characterizes CMT1, in distinction to acquired demyelinating polyneuropathies, which feature multifocal conduction abnormalities. We conclude that normal nerve conduction velocity in a single motor nerve can reliably exclude CMT1, but evaluation of several nerves and nerve segments to establish uniformity of conduction slowing is important in making this diagnosis. The homogeneity of the disturbance of nerve conduction favors a primary Schwann-cell disorder as the basis of CMT1.

Nerve conduction studies in Charcot-Marie-Tooth polyneuropathy associated with a segmental duplication of chromosome 17.

We evaluated motor conduction velocities in a large group of patients and their unaffected kin from five families in which a segmental duplication of chromosome 17p has shown complete linkage to Charcot-Marie-Tooth disease type 1 (CMT1A). Slowing of conduction was completely concordant with the presence of the segmental duplication; two clinically normal patients had slowed conduction. Nonetheless, among the patients with the CMT1A duplication, conduction velocities varied widely, by > 30 m/sec overall, by > 20 m/sec within families, and often by more than 10 m/sec between siblings and between parents and children. One patient was homozygous for the chromosome 17p duplication and had the slowest conduction velocity observed. Conduction slowing was not age-dependent and was present early in childhood. Our findings demonstrate complete penetrance at an early age of the electrophysiologic phenotype associated with the chromosome 17p duplication and confirm the reliability of nerve conduction studies in establishing the affection status in CMT1A. The great variation in conduction velocity among CMT1A patients emphasizes the influence of factors apart from the shared genetic mutation on phenotypic expression.

Relative utility of different electrophysiologic techniques in the evaluation of brachial plexopathies.

We report the results of detailed electrophysiologic studies in 23 patients with suspected brachial plexopathies. In five with neurogenic thoracic outlet syndrome, needle EMG and determination of size of ulnar sensory nerve action potentials (SNAPs) and thenar M waves were important in localizing the lesion; F-response and somatosensory evoked potential (SEP) studies were of more limited utility. All electrodiagnostic studies were normal in 10 patients with nonneurogenic thoracic outlet syndrome. In traumatic (three patients) or idiopathic brachial plexopathy (five patients), needle EMG was especially helpful but, in the former, SEP studies helped to guide management and, in the latter, to confirm the proximal site of the lesion when peripheral SNAPs were normal. The presence of preserved but small SNAPs but absent M waves in patients with traumatic plexopathies suggested a combined pre- and postganglionic lesion.

Neuropathy in erythropoietic protoporphyrias.

Peripheral neuropathy (PN) has rarely been described as a complication of erythropoietic protoporphyria (EPP). We describe three episodes of PN and the electrophysiologic findings in two patients with EPP. PN is seen in patients with EPP and hepatic failure and raised free erythrocyte protoporphyrin or serum protoporphyrin levels and is identical to that seen in acute intermittent porphyria. Recognition is important because of the good eventual prognosis.

Lower motor neuron disease in a patient with autoantibodies against Gal(beta 1-3)GalNAc in gangliosides GM1 and GD1b: improvement following immunotherapy.

We followed a patient with a lower motor neuron form of motor neuron disease whose neurologic disorder improved following immunotherapy. The patient did not have an M protein but did have IgM antibodies to ganglioside GM1 detectable at serum titers of 1:2,000 by ELISA. These antibodies were found only in the IgM fraction with lambda light chains and immunoreacted with GD1b and Gal (beta 1-3) GalNAc.

Electrophysiologic evaluation of lumbosacral radiculopathies: electromyography, late responses, and somatosensory evoked potentials.

We compared the diagnostic utility of EMG, F wave and H-reflex studies, and peroneal and dermatomal SEPs in evaluating 28 patients with clinically unequivocal L-5 or S-1 compressive root lesions. The single most useful electrophysiologic technique was EMG, which often provided evidence of denervation in a myotomal pattern when other electrophysiologic findings were normal. We found abnormal late responses in 14 patients, but always in association with EMG abnormalities. Peroneal-derived SEPs were always normal. Dermatomal SEPs confirmed the diagnosis in seven patients, including two in whom other electrophysiologic studies were normal.

Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group.

We designed a phase II trial to evaluate the efficacy of gabapentin in slowing the rate of decline in muscle strength of patients with amyotrophic lateral sclerosis (ALS) and to assess safety and tolerability. Gabapentin (800 mg) or placebo was administered t.i.d. in a randomized, double-blinded, placebo-controlled, trial for 6 months. We enrolled 152 patients at eight sites in the United States. The primary outcome measure was the slope of the arm megascore, the average maximum voluntary isometric strength from eight arm muscles standardized against a reference ALS population. A secondary outcome measure was forced vital capacity. Slopes of arm megascores for patients on gabapentin were compared with slopes of those taking placebo using a two-way ANOVA. We observed a nonstatistically significant trend (p = 0.057-0.08) toward slower decline of arm strength in patients taking gabapentin compared with those taking placebo (mean difference 24%, median 37%). We observed no treatment effect on forced vital capacity. Gabapentin was well tolerated by patients with ALS. These results suggest that further studies of gabapentin in ALS are warranted.

Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: To determine the efficacy of IV immunoglobulin (IVIg) given patients with untreated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: A randomized, double-blind, multicenter, investigator-initiated study compared IVIg (Aventis Behring LLC, King of Prussia, PA) with placebo (5% albumin). On days 1, 2, and 21, IVIg (1 g/kg) or placebo was given. The primary outcome measure was the change in muscle strength from baseline to day 42, using the average muscle score (AMS). Secondary outcome measures included change from baseline AMS at days 10 and 21, the Hughes' functional disability scale, forced vital capacity (FVC), and nerve conduction studies (NCS) of four motor nerves (median, ulnar, peroneal, and tibial). RESULTS: The patients (n = 33) were randomized. Of these, 30 (14 women, 16 men, aged 54 +/- 20 years, range 13 to 82) received IVIg and 23 were given placebo (12 women, 11 men, aged 50 +/- 18 years, range 23 to 73). Baseline AMS values of the groups were similar (IVIg 7.06 +/- 1.31 versus placebo 7.28 +/- 1.18, p = 0.53). There were two dropouts in placebo group and one in the IVIg group. Mean AMS improved at day 42 comparing IVIg with placebo (0.63 versus -0.1, p = 0.006). Improved strength was seen by day 10. The placebo group lost strength over this same interval. In the IVIg, 11 subjects improved by the functional disability scale; none worsened. This differed (p = 0.019) from those in the placebo-treated group (two improved, two got worse, remainder unchanged). Forced vital capacity did not improve with IVIg treatment. IVIg improved ulnar motor distal latency (p = 0.005), tibial distal compound muscle amplitude (p = 0.003), and peroneal nerve conduction velocity (p = 0.03). CONCLUSIONS: IVIg improves strength in patients with untreated CIDP by day 10 with continued benefit through day 42; more than one third improve by at least a functional grade on a disability scale. This study provides data supporting IVIg as the initial treatment for CIDP.