The PFA-100 ® does not predict delta-granule platelet storage pool deficiencies.

There are no published reports investigating the ability of the platelet function analyzer (PFA-100(®) ) to detect the presence of delta-granule platelet storage pool deficiencies (δ-PSPD), a common mild bleeding disorder. Prior studies of the PFA-100(®) and congenital platelet disorders have been limited by small numbers of patients with a variety of disorders. We examined PFA-100(®) results in a large paediatric patient population diagnosed specifically with δ-PSPD, and determined the relationship between PFA-100(®) and platelet electron microscopy (the gold standard for diagnosis). This study is a retrospective review of patients <19 years of age diagnosed with δ-PSPD at Nationwide Children's Hospital from 2008 to 2010. To examine the correlation between PFA-100(®) and average number of granules per platelet we used Spearman's Rho as a non-parametric measure of dependence. A total of 105 patients diagnosed with δ-PSPD were included, of which 99 patients underwent PFA-100(®) testing. Of those tested 46% had at least one abnormal closure time, whereas 16% had abnormal results for both cartridges. We found no statistical correlation between C-EPI closure time and average number of granules per platelet (ρ= -0.0095, P-value = 0.9328), nor between C-ADP closure time and the average number of granules (ρ = 0.0315, P-value = 0.7798). The PFA-100(®), a widely used screening test for suspected bleeding disorders, did not correlate with presence or severity of δ-PSPD as determined by platelet electron microscopy. When evaluating patients with suspected bleeding disorders, PFA-100(®) alone cannot be used to rule out the presence of a δ-PSPD.

Clinical, electrophysiologic, and pathologic evidence for sensory abnormalities in ALS.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of upper and lower motor neurons. Reports of the nature and frequency of sensory nerve involvement in ALS have varied. METHODS: We reviewed the Emory University motor neuron disease registry between 1997 and 2004 to identify 103 patients with ALS without coexisting diseases that might cause sensory abnormalities and for whom electrodiagnostic studies were available for review. Neurophysiologic studies were interpreted based on age-adjusted normative data from our laboratory. Twelve control biopsies were evaluated alongside 22 samples from patients with ALS to ensure blinded evaluation of pathologic specimens. RESULTS: Sensory symptoms or signs were present in 32% of patients, sural sensory nerve action potential amplitudes were abnormal in 27%, and pathologic abnormalities were present in 91% of patients. Large-caliber myelinated fibers were predominantly affected (reduced in 73%) and small-caliber myelinated fibers were affected less often (23%). Thinly myelinated fibers were present in 95% and regenerating clusters in 77% of the biopsies. Teased fiber analysis showed an increased frequency of axonal degeneration and regeneration as well as excessive myelin irregularity. Morphometry confirmed the loss of large-caliber fibers. CONCLUSIONS: These data indicate that one third of patients with amyotrophic lateral sclerosis report sensory symptoms and sural sensory response amplitudes are reduced in a similar proportion of subjects. Pathologic evidence of sensory nerve pathology was present in 91% of patients who underwent sural nerve biopsy. The electrophysiologic and pathologic findings indicate a pattern of axonal loss that predominantly affects large-caliber myelinated fibers.

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.

Histopathological features of peripheral nerve and muscle in mitochondrial disease.

Despite enormous strides in the molecular diagnosis of mitochondrial disease, this approach is currently applicable to only a minority of patients who are affected with these disorders. The phenotypic spectrum in this category of disease is large and, in the absence of genotypic confirmation, a pattern recognition paradigm is probably the most sensitive means to reinforce the suspicion of mitochondrial disease. Along with clinical, biochemical, radiographic, and electrophysiological markers, histopathological features from nerve and muscle biopsy are useful indices to factor into a complex equation permitting a presumptive diagnosis or to justify more elaborate diagnostic undertakings. The combination of electrophysiological evidence of demyelinating neuropathy on nerve conduction studies and mild myopathic features on electromyography is one such constellation that should instigate a high index of suspicion for mitochondrial disease. The histopathological hallmarks of mitochondrial cytopathies on muscle biopsy are the "ragged-red fiber" on light level evaluation and paracrystalline inclusions at the electron microscopic level. Neither of these is exclusive to mitochondrial disease and both may be identified among other nonspecific changes seen in biopsy specimens. Histopathological evaluation of muscle and nerve can provide information to reinforce the likelihood of mitochondrial disease or to indicate an alternative diagnosis as the more probable cause of a patient's symptoms.

Teaching in the field: the model of a one-day trip to an outreach clinic.

A trip to an outreach clinic in a 15-passenger van is presented as part of the answer to the forces negatively affecting the practice of academic medicine today. Any subspecialist in a medical center can use the model if a community can be identified that has a hospital or clinic building able to host the university group. County- or state-funded facilities are well suited to a periodic clinic, and public health nurses are well trained in their management. The Muscular Dystrophy Association is a private supporter of clinics like this, allowing specialty doctor visits close to home for patients with disabling weakness who might otherwise be excluded from our increasingly restricted health care system.

Abnormal fatty acid metabolism in childhood spinal muscular atrophy.

Our previous experience with abnormal fatty acid metabolism in several children with spinal muscular atrophy (SMA) prompted evaluation of fatty acid metabolism in a larger cohort. Thirty-three infants with severe infantile SMA were shown to have a significantly increased ratio of dodecanoic to tetradecanoic acid in plasma compared with normal infants and 6 infants affected with equally debilitating, non-SMA denervating disorders. Seventeen children with milder forms of SMA had normal fatty acid profiles. In addition, all 5 infants with severe SMA evaluated in a fasting state developed a distinctive and marked dicarboxylic aciduria, including saturated, unsaturated, and 3-hydroxy forms, comparable in severity with the dicarboxylic aciduria of children with primary defects of mitochondrial fatty acid beta-oxidation. Nine children with chronic SMA and 23 control patients did not develop an abnormal dicarboxylic aciduria during fasting. No known disorder of fatty acid metabolism explains all of the abnormalities we find in SMA. Our data suggest, however, that the abnormalities are not a consequence of SMA-related immobility, systemic illness, muscle denervation, or muscle atrophy. These abnormalities in fatty acid metabolism may be caused by changes in cellular physiology related to the molecular defects of the SMA-pathogenic survival motor neuron gene or neighboring genes.

Heterozygous P0 knockout mice develop a peripheral neuropathy that resembles chronic inflammatory demyelinating polyneuropathy (CIDP).

Demyelinating peripheral neuropathies are clinically divided into inherited and acquired types. Inherited demyelinating neuropathies are caused by mutations in genes expressed by myelinating Schwann cells, whereas acquired ones, including chronic inflammatory demyelinating polyneuropathy (CIDP), are probably caused by autoimmune mechanisms. We find that heterozygous P0 knockout (P0+/-) mice develop a neuropathy that resembles CIDP. By one year of age, P0+/- mice develop severe, asymmetric slowing of motor nerves, with temporal dispersion or conduction block, which are features of acquired demyelinating neuropathies including CIDP. Moreover, morphological analysis of affected nerves reveals severe and selective demyelination of motor fibers, focal regions of demyelination, and inflammatory cells. These data suggest that immune-mediated mechanisms may contribute to the pathogenesis of the neuropathy in P0+/- mice.

Prominent proptosis in childhood thyroid eye disease.

BACKGROUND: Orbital signs and symptoms occur in approximately one half of children with Graves disease, but the symptoms are usually minor and limited to the eyelids. Prominent proptosis is uncommon in children with this disorder. METHODS: Review of eight children with prominent proptosis associated with thyroid eye disease. Four patients were treated at the Children's Hospital of Philadelphia, the other four at the Columbia Presbyterian Medical Center. RESULTS: At initial presentation, children ranged in age from 3 to 16 years. There were five girls and three boys. Seven of eight children had hyperthyroidism at ophthalmic presentation. Four patients had restrictive myopathy, and all of the seven patients who underwent neuroimaging had extraocular muscle enlargement. Five patients were treated with lubrication. Two underwent orbital fat decompression. One patient had thyroid eye disease and myasthenia gravis. CONCLUSIONS: Proptosis in childhood thyroid eye disease usually is associated with a hyperthyroid state. The proptosis may be dramatic, but corneal exposure and restrictive myopathy are seen in only some of the patients. Neuroimaging shows enlarged extraocular muscles. Most children with this complication can be treated conservatively with topical lubrication, but orbital fat decompression may be considered in patients with more advanced conditions.

Immune neuropathies in childhood.

In contradistinction to older populations, immune-mediated disorders (principally demyelinating processes) account for nearly half of peripheral neuropathies in childhood. The largest single diagnostic entity is GBS, which makes up approximately 25% of sensorimotor neuropathies in patients under 18 years of age. The clinical features are similar to those encountered in adults, although the prognosis in youngsters appears to be better than in older populations. Despite the absence of prospective data, plasmapheresis seems to be an effective modality for hastening recovery during GBS in children. The use of human immunoglobulin has gained acceptance for the treatment of GBS in adults, but insufficient data exist to draw firm conclusions about it role in the management of paediatric GBS. CIDP is the second most common cause of chronic sensorimotor neuropathy in children. The clinical manifestations of this disorder are extremely variable, and it can mimic the phenotype of several genetically determined neuropathies. The prognosis in this disorder is also relatively good, although a small number of children have significant neurological disability or treatment side-effects. Other immune-mediated neuropathies are relatively infrequent in our experience. When they occur, they are often associated with collagen-vascular diseases or bone marrow transplantation. Peripheral neuropathy in association with HIV infection in children appears to be rare.

Developmental profile in a patient with monosomy 10q and dup(17p) associated with a peripheral neuropathy.

We report on a patient with dup(17p) and monosomy (10q) resulting from a familial translocation. Manifestations typical of both syndromes were present. The overall development of this patient was better by comparison with similar reported cases of either anomaly. Our evaluation detected severe gross motor delay and signs of a demyelinating peripheral neuropathy. This patient is trisomic for the region of 17p which includes the peripheral myelin protein-22 (PMP-22) gene, known to be duplicated in Charcot-Marie-Tooth neuropathy type 1A (CMT1A). Our analysis in this patient suggests that trisomy for the PMP-22 gene led to the demyelinating neuropathy and contributed to his severe motor developmental delay.

Neurologic manifestations in children with Lyme disease.

OBJECTIVE: Lyme disease (LD) is a tick-borne spirochetal infection with a wide range of neurologic and non-neurologic manifestations. The clinical diversity of LD and limitations in serologic diagnosis often make it difficult to document the diagnosis of neuroborreliosis with certainty. METHODS: We reviewed clinical manifestations in 97 seropositive children with particular attention to neurologic manifestations. Diagnostic criteria used in other case surveys were applied to determine how often a definitive diagnosis of neuroborreliosis could be made in children. RESULTS: Of 69 children who met criteria for LD, 32% (22) had new neurologic signs, 73% (16) of which were accounted for by facial palsy and aseptic meningitis. Five of those with neurologic findings also had erythema migrans (EM), and one had both EM and arthritis. Among those with neurologic involvement, boys outnumbered girls two to one. Neurologic abnormalities resolved spontaneously in five children before their serologic results were known. CONCLUSION: In our series, only 27% of children with neurologic abnormalities due to LD had a history of EM or arthritis. Seropositivity commonly constituted the primary basis for diagnosis of LD. Despite its nonspecificity, seropositivity for LD in children with neurologic symptoms usually signifies active neuroborreliosis.

A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene.

We report a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) who harbored a novel missense mutation at mtDNA position 9957 in the gene specifying subunit III of cytochrome c oxidase (COX III). This T-->C transition converted Phe-251, a highly conserved amino acid in the C-terminus of the polypeptide, to Leu. The mutation, which was not present in 107 normal controls or in 57 patients with various mitochondrial diseases, was heteroplasmic in both muscle and blood of the proband and in blood from his asymptomatic mother. These results provide evidence that the MELAS clinical phenotype can be due not only to mutations in mtDNA-encoded tRNA genes, but in polypeptide-coding genes as well.

Neuromuscular complications of bone marrow transplantation.

Six children are reported with neuromuscular complications of allogenic bone marrow transplantation. Myositis occurred in 4, chronic inflammatory demyelinating neuropathy in 1, and myasthenia gravis in 1. Chronic graft-versus-host disease was present in 3. The onset following bone marrow transplant may be delayed.

Reversible metabolic myopathy in biotinidase deficiency: its possible role in causing hypotonia.

A 5-year-old girl diagnosed with biotinidase deficiency at 9 months of age demonstrated limb and axial hypotonia which improved on biotin therapy. In this patient, electromyographic (EMG) studies prior to treatment were compatible with a mild myopathic process. Serial EMGs performed on biotin therapy demonstrated a gradual resolution of the myopathy. This is the first documented case of a reversible myopathy in a patient with biotinidase deficiency, which may contribute to the clinical findings of hypotonia.

Paternal transmission of congenital myotonic dystrophy.

The congenital form of myotonic dystrophy is reported to be almost exclusively, if not exclusively, maternally transmitted. We present a case of congenital myotonic dystrophy which was inherited from a mildly affected father. This family illustrates that the congenital form of myotonic dystrophy can occur without intrauterine or other maternal factors related to the disease. The possibility of paternal transmission of the congenital form of myotonic dystrophy could be considered when counselling myotonic dystrophy patients and their families.

Prolonged effects of MK-801 in the cat during focal cerebral ischemia and recovery: survival, EEG activity and histopathology.

Previously we reported an improvement in histological outcome in cats treated with MK-801 shortly after the induction of temporary middle cerebral artery occlusion, and examined after 2 h of ischemia followed by 4 h of reperfusion. This study investigates the prolonged effects of the same drug treatment. Focal cerebral ischemia was produced in 34 cats by temporary occlusion of the left middle cerebral artery for 2 h. Stroke severity was determined using the ratio of the EEG amplitude from the ipsilateral to that of the contralateral hemisphere. Thirty minutes after the onset of ischemia, cats were treated i.v. with either 1 mg/kg MK-801 or saline. Electrocortical activity of the animals who survived were followed for 6 days postocclusion at which point they were sacrificed for histopathological analysis. Twelve of the animals died during recovery, of which 4 were MK-801 treated, and 8 were saline controls. The EEG ratios in the non-surviving animals were more depressed than in the animals that survived, whereas the depression in the EEG amplitude in both the treated and the control surviving animals was equal. Among the survivors no reduction in infarct size with MK-801 treatment was observed. Thus treatment with MK-801 in the middle cerebral artery occlusion model in the cat leads to a significant increase in the rate of survival (P < 0.05), but no prolonged improvement in late histopathology, in contrast with acute histological findings using this model. MK-801 treatment may be shifting the stroke model towards the survival of animals with larger infarcts. Histological recovery during prolonged reperfusion may eliminate the early neuroprotective effects seen with MK-801 treatment.

Acute improvement in histological outcome by MK-801 following focal cerebral ischemia and reperfusion in the cat independent of blood flow changes.

The present study reports on the acute effects of MK-801 on the histopathological outcome and blood flow changes during focal cerebral ischemia and reperfusion. In addition, acute changes in the EEG and blood pressure are also reported. In 16 halothane-anesthetized cats, the left middle cerebral artery (MCA) was occluded for 2 h followed by 4 h of reperfusion. Thirty minutes after the onset of ischemia, eight animals were treated with 1 mg/kg of MK-801, while eight animals received saline. Blood flow from the peripheral MCA territory was measured with H2 clearance. There was a comparable reduction in blood flow (down to 20% of control) in the ischemic gyri of the two groups followed by a partial recovery after recirculation. There was a similar decrease in the EEG amplitude over the ischemic central MCA territory in the treated and the untreated group. Treatment with MK-801 induced a burst suppression in the EEG and a transient drop (11.4 +/- 6.5 mm Hg) in the mean arterial pressure. The volume of early ischemic damage decreased by one-third in the MK-801-treated group compared to the untreated one, both in the total hemisphere (from 29 +/- 10 to 20 +/- 5%) and in the hemispheric cortex (range 36 +/- 8 to 24 +/- 13%). A major fraction of this improvement was localized to the middle and posterior parietal (mainly perifocal) regions of the MCA territory. These results show that in our model, MK-801 improves histopathological outcome despite the lack of apparent effect on the cortical blood flow, and an adverse effect on the systemic blood pressure. This is the first report that describes data on a reproducible model of reperfusion after temporary occlusion of the MCA in a cat, extending the findings of the Glasgow group, who observed similar neuroprotection in models of permanent MCA occlusion.