David R. Cornblath

SeminarGuillain-Barré syndrome

Guillain-Barré syndrome has now become recognized as a clinical syndrome that may be due to several pathological entities, consisting of an acute inflammatory demyelinating polyradiculoneuropathy as well as an acute motor axonal neuropathy. Campylobacter jejuni infection is a common preceding event and, together with anti-ganglioside GM1 antibodies, is associated with axonal damage and a poor outcome. The mechanism by which such antibodies damage axons is not clear. The Miller Fisher syndrome is very closely associated with antibodies to ganglioside CQ1b that may be important in pathogenesis. Treatment of Guillain-Barre syndrome with intravenous immunoglobulin appears to be as effective as plasma exchange in one controlled trial. Two small series have reported a high incidence of early relapses following intravenous immunoglobulin, and its efficacy is being reexamined in a further controlled trial.

DNA/RNA Helicase Gene Mutations in a Form of Juvenile Amyotrophic Lateral Sclerosis (ALS4)

Juvenile amyotrophic lateral sclerosis (ALS4) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS) characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span. The ALS4 locus maps to a 1.7-Mb interval on chromosome 9q34 flanked by D9S64 and D9S1198. To identify the molecular basis of ALS4, we tested 19 genes within the ALS4 interval and detected missense mutations (T3I, L389S, and R2136H) in the Senataxin gene (SETX). The SETX gene encodes a novel 302.8-kD protein. Although its function remains unknown, SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing. These observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing.

The spectrum of neuropathy in diabetes and impaired glucose tolerance

Objective: To compare the neuropathy associated with impaired glucose tolerance (IGT) and diabetes mellitus (DM) determined by oral glucose tolerance testing (OGTT). Methods: Patients with peripheral neuropathy of unknown cause were prescribed OGTT. Duration of neuropathic symptoms, neuropathic pain, neuropathy classification, nerve conduction test results, and intraepidermal nerve fiber densities (IENFD) were compared between IGT and DM groups. Results: Seventy-three patients completed OGTT; 41 (56%) had abnormal results. Of these 41 patients, 26 had IGT and 15 had DM. Patients with IGT had less severe neuropathy than patients with diabetes, as measured by sural nerve amplitudes (p = 0.056), sural nerve conduction velocities (p = 0.03), and distal leg IENFD (p = 0.01). Patients with IGT had predominantly small fiber neuropathy, compared to patients with DM (p = 0.05), who had more involvement of large nerve fibers. Conclusions: The neuropathy associated with IGT is milder than the neuropathy associated with DM. Small nerve fibers are prominently affected and may be the earliest detectable sign of neuropathy in glucose dysmetabolism. OGTT is appropriate in patients with idiopathic neuropathy.

Double‐blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy

Objective The objective of this study was to evaluate the efficacy and safety of tramadol in treating the pain of diabetic neuropathy. Background The pain of diabetic neuropathy is a major cause of morbidity among these patients and treatment, as with other small-fiber neuropathies, is often unsatisfactory. Tramadol is a centrally acting analgesic for use in treating moderate to moderately severe pain. Methods This multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group study consisted of a washoutlscreening phase, during which all analgesics were discontinued, and a 42-day double-blind treatment phase. A total of 131 patients with painful diabetic neuropathy were treated with tramadol (n = 65) or placebo (n = 66) tramadol, which were administered as identical capsules in divided doses four times daily. The primary efficacy analysis compared the mean pain intensity scores in the tramadol and placebo groups obtained at day 42 of the study or at the time of discontinuation. Secondary efficacy assessments were the pain relief rating scores and a quality of life evaluation based on daily activities and sleep characteristics. Results Tramadol, at an average dosage of 210 mg/day, was significantly (p < 0.001) more effective than placebo for treating the pain of diabetic neuropathy. Patients in the tramadol group scored significantly better in physical (p = 0.02) and social functioning (p = 0.04) ratings than patients in the placebo group. No statistically significant treatment effects on sleep were identified. The most frequently occurring adverse events with tramadol were nausea, constipation, headache, and somnolence. Conclusions The results of this placebo-controlled trial showed that tramadol was effective and safe in treating the pain of diabetic neuropathy.

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 - First Revision

Background:  Consensus guidelines on the definition, investigation, and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been previously published in European Journal of Neurology and Journal of the Peripheral Nervous System.

Cutaneous innervation in sensory neuropathies Evaluation by skin biopsy

Objective: To use punch skin biopsies to evaluate the loss of intra-epidermal nerve fibers in sensory neuropathies. Background: Previous assessments of epidermal nerve fibers have been constrained by relatively insensitive staining techniques and variability in quantification. Methods: Punch skin biopsies were performed on the heel and leg of HIV-seronegative controls, HIV-seropositive individuals without neuropathy, and patients with sensory neuropathies, including HIV-seronegative and HIV-positive individuals. After formalin fixation, 50-micro meter free-floating sections were stained with a monoclonal antibody to neuron-specific ubiquitin hydrolase, PGP9.5. The number of intraepidermal fibers/mm in at least three sections from each patient was counted by one observer blinded to site and clinical status. Results: Dermal and epidermal nerve fibers were readily identified and quantified. The immunostaining technique reliably demonstrated a dermal plexus of myelinated and unmyelinated fibers parallel to the surface of the skin. In the epidermis, unmyelinated fibers ascended vertically between the keratinocytes to reach the stratum corneum. The number of intra-epidermal fibers/mm in the distal leg (mean plus minus SEM) was 17.84 plus minus 3.03 in seven HIV-seronegative controls. Epidermal fiber number was significantly reduced (p equals 0.01) in five HIV-infected patients with sensory neuropathies associated with didanosine or zalcitabine therapy (1.07 plus minus 0.40) and in eight HIV-seronegative patients with sensory neuropathies (3.1 plus minus 3.1). Four of five neurologically normal HIV-seropositive subjects had reduced numbers of epidermal fibers, suggesting a subclinical neuropathy. Serial biopsies in one individual demonstrated the evolution of degenerating epidermal fibers after development of zalcitabine-induced sensory neuropathy. Conclusion: Skin biopsies stained with the sensitive panaxonal marker anti-PGP9.5 demonstrated significant reduction in intraepidermal fibers in sensory neuropathies. This simple and repeatable technique is a reliable method for quantitation of small cutaneous sensory fibers. In addition, skin biopsies may be useful in assessing the course and spatial distribution of involvement in peripheral nerve disease. NEUROLOGY 1995;45: 1848-1855

Sequences of taxol and cisplatin: a phase I and pharmacologic study.

Untreated and minimally pretreated solid tumor patients received alternating sequences of taxol and cisplatin. Sequential dose escalation of each agent using taxol doses of 110 or 135 mg/m2 and cisplatin doses of 50 or 75 mg/m2 resulted in four dosage permutations that induced grades 3 and 4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively. Neutropenia was brief, and hospitalization for neutropenia and fever was required in 13% to 24% of courses. However, further escalation of taxol to 170 or 200 mg/m2 induced grade 4 neutropenia in 79% to 82% of courses. At the highest taxol-cisplatin dose level (200 mg/m2 to 75 mg/m2), the mean neutrophil count nadir was 98/microL, and hospitalization for neutropenia and fever was required in 64% of courses. The sequence of cisplatin before taxol, which has less antitumor activity in vitro, induced more profound neutropenia than the alternate sequence. Pharmacologic studies indicated that this difference was probably due to 25% lower taxol clearance rates when cisplatin preceded taxol. Although neurotoxicity was initially thought to be a potentially serious effect of the combination, mild to modest neurotoxicity occurred in only 27% of patients. Adverse effects also included myalgias, alopecia, vomiting, diarrhea, bradycardia, and asymptomatic ventricular tachycardia. Objective responses were noted in melanoma, as well as non-small-cell lung, ovarian, breast, head and neck, colon, and pancreatic carcinomas. Based on these results, the sequence of taxol before cisplatin at doses of 135 and 75 mg/m2, respectively, is recommended for phase II/III trials, with escalation of taxol to 170 mg/m2 if treatment is well tolerated.

Quantitative sensory testing Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Objective: This assessment evaluates the clinical utility, efficacy, and safety of quantitative sensory testing (QST). Methods: By searching MEDLINE, Current Contents, and their personal files, the authors identified 350 articles. Selected articles utilized computer operated threshold systems, manually operated threshold systems, and electrical threshold devices. The authors evaluated the use of normal values and the degree of reproducibility between the same and different systems. Articles were rated using a standard classification of evidence scheme. Results: Because of differences between systems, normal values from one system cannot be transposed to others. Reproducibility of results was also an important concern, and there is no consensus on how it should be defined. The authors identified no adequately powered class I studies demonstrating the effectiveness of QST in evaluating any particular disorder. A number of class II and III studies demonstrated that QST is probably or possibly useful in identifying small or large fiber sensory abnormalities in patients with diabetic neuropathy, small fiber neuropathies, uremic neuropathies, and demyelinating neuropathy. Conclusions: QST is a potentially useful tool for measuring sensory impairment for clinical and research studies. However, QST results should not be the sole criteria used to diagnose pathology. Because malingering and other nonorganic factors can influence the test results, QST is not currently useful for the purpose of resolving medicolegal matters. Well-designed studies comparing different QST devices and methodologies are needed and should include patients with abnormalities detected solely by QST.

EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy

Skin biopsy has become a widely used tool to investigate small calibre sensory nerves including somatic unmyelinated intraepidermal nerve fibres (IENF), dermal myelinated nerve fibres, and autonomic nerve fibres in peripheral neuropathies and other conditions. Different techniques for tissue processing and nerve fibre evaluation have been used. In March 2004, a Task Force was set up under the auspices of the European Federation of Neurological Societies (EFNS) with the aim of developing guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathies. We searched the Medline database from 1989, the year of the first publication describing the innervation of human skin using immunostaining with anti‐protein‐gene‐product 9.5 (PGP 9.5) antibodies, to 31 March 2005. All pertinent papers were rated according to the EFNS guidance. The final version of the guidelines was elaborated after consensus amongst members of the Task Force was reached. For diagnostic purposes in peripheral neuropathies, we recommend performing a 3‐mm punch skin biopsy at the distal leg and quantifying the linear density of IENF in at least three 50‐μm thick sections per biopsy, fixed in 2% PLP or Zambonis solution, by bright‐field immunohistochemistry or immunofluorescence with anti‐PGP 9.5 antibodies (level A recommendation). Quantification of IENF density closely correlated with warm and heat‐pain threshold, and appeared more sensitive than sensory nerve conduction study and sural nerve biopsy in diagnosing small‐fibre sensory neuropathy. Diagnostic efficiency and predictive values of this technique were very high (level A recommendation). Confocal microscopy may be particularly useful to investigate myelinated nerve fibres, dermal receptors and dermal annex innervation. In future, the diagnostic yield of dermal myelinated nerve fibre quantification and of sweat gland innervation should be addressed. Longitudinal studies of IENF density and regeneration rate are warranted to correlate neuropathological changes with progression of neuropathy and to assess the potential usefulness of skin biopsy as an outcome measure in peripheral neuropathy trials (level B recommendation). In conclusion, punch skin biopsy is a safe and reliable technique (level A recommendation). Training in an established cutaneous nerve laboratory is recommended before using skin biopsy as a diagnostic tool in peripheral neuropathies. Quality control at all levels is mandatory.

Rhabdomyolysis: an evaluation of 475 hospitalized patients.

Abstract: Rhabdomyolysis is a common and potentially lethal clinical syndrome that results from acute muscle fiber necrosis with leakage of muscle constituents into blood. Myoglobinuria is the most significant consequence, leading to acute renal failure (ARF) in 15%-33% of patients with rhabdomyolysis. Rhabdomyolysis occurs from inherited diseases, toxins, muscle compression or overexertion, or inflammatory processes, among other disorders. In some cases, no cause is found. We describe 475 patients from the Johns Hopkins Hospital inpatient records between January 1993 and December 2001 for the following discharge diagnosis codes: myoglobinuria, rhabdomyolysis, myopathy, toxic myopathy, malignant hyperthermia, neuroleptic malignant syndrome, and polymyositis. Of 1362 patients, 475 patients with an acute neuromuscular illness with serum creatine kinase (CK) more than 5 times the upper limit of normal (>975 IU/L) were included. Patients with recent myocardial infarction or stroke were excluded. The etiology was assigned by chart review. For all, the highest values of serum CK, serum creatinine and urine myoglobin, hemoglobin, and red blood cells were recorded. Forty-one patients had muscle biopsy within at least 2 months from the onset of rhabdomyolysis. Of the 475 patients, 151 were female and 324 were male (median age, 47 yr; range, 4-95 yr). Exogenous toxins were the most common cause of rhabdomyolysis, with illicit drugs, alcohol, and prescribed drugs responsible for 46%. Among the medical drugs, antipsychotics, statins, zidovudine, colchicine, selective serotonin reuptake inhibitors, and lithium were the most frequently involved. In 60% of all cases, multiple factors were present. In 11% of all cases, rhabdomyolysis was recurrent. Underlying myopathy or muscle metabolic defects were responsible for 10% of cases, in which there was a high percentage of recurrence, only 1 etiologic factor, and a low incidence of ARF. In 7%, no cause was found. ARF was present in 218 (46%) patients, and 16 died (3.4%). A linear correlation was found between CK and creatinine and between multiple factors and ARF, but there was no correlation between ARF and death or between multiple factors and death. Urine myoglobin detected by dipstick/ultrafiltration was positive in only 19%. Toxins are the most frequent cause of rhabdomyolysis, but in most cases more than 1 etiologic factor was present. Patients using illicit drugs or on prescribed polytherapy are at risk for rhabdomyolysis. The absence of urine myoglobin, by qualitative assay, does not exclude rhabdomyolysis. With appropriate care, death is rare. Abbreviations: ARF = acute renal failure, CK = creatine kinase, ICU = intensive care unit, NMS = neuroleptic malignant syndrome.