Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1.

OBJECTIVE: To determine if mexiletine is safe and effective in reducing myotonia in myotonic dystrophy type 1 (DM1). BACKGROUND: Myotonia is an early, prominent symptom in DM1 and contributes to decreased dexterity, gait instability, difficulty with speech/swallowing, and muscle pain. A few preliminary trials have suggested that the antiarrhythmic drug mexiletine is useful, symptomatic treatment for nondystrophic myotonic disorders and DM1. METHODS: We performed 2 randomized, double-blind, placebo-controlled crossover trials, each involving 20 ambulatory DM1 participants with grip or percussion myotonia on examination. The initial trial compared 150 mg of mexiletine 3 times daily to placebo, and the second trial compared 200 mg of mexiletine 3 times daily to placebo. Treatment periods were 7 weeks in duration separated by a 4- to 8-week washout period. The primary measure of myotonia was time for isometric grip force to relax from 90% to 5% of peak force after a 3-second maximum grip contraction. EKG measurements and adverse events were monitored in both trials. RESULTS: There was a significant reduction in grip relaxation time with both 150 and 200 mg dosages of mexiletine. Treatment with mexiletine at either dosage was not associated with any serious adverse events, or with prolongation of the PR or QTc intervals or of QRS duration. Mild adverse events were observed with both placebo and mexiletine treatment. CONCLUSIONS: Mexiletine at dosages of 150 and 200 mg 3 times daily is effective, safe, and well-tolerated over 7 weeks as an antimyotonia treatment in DM1. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that mexiletine at dosages of 150 and 200 mg 3 times daily over 7 weeks is well-tolerated and effective in reducing handgrip relaxation time in DM1.

Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To provide evidence-based recommendations on the treatment of nervous system Lyme disease and post-Lyme syndrome. Three questions were addressed: 1) Which antimicrobial agents are effective? 2) Are different regimens preferred for different manifestations of nervous system Lyme disease? 3) What duration of therapy is needed? METHODS: The authors analyzed published studies (1983-2003) using a structured review process to classify the evidence related to the questions posed. RESULTS: The panel reviewed 353 abstracts which yielded 112 potentially relevant articles that were reviewed, from which 37 articles were identified that were included in the analysis. CONCLUSIONS: There are sufficient data to conclude that, in both adults and children, this nervous system infection responds well to penicillin, ceftriaxone, cefotaxime, and doxycycline (Level B recommendation). Although most studies have used parenteral regimens for neuroborreliosis, several European studies support use of oral doxycycline in adults with meningitis, cranial neuritis, and radiculitis (Level B), reserving parenteral regimens for patients with parenchymal CNS involvement, other severe neurologic symptomatology, or failure to respond to oral regimens. The number of children (> or =8 years of age) enrolled in rigorous studies of oral vs parenteral regimens has been smaller, making conclusions less statistically compelling. However, all available data indicate results are comparable to those observed in adults. In contrast, there is no compelling evidence that prolonged treatment with antibiotics has any beneficial effect in post-Lyme syndrome (Level A).

Painful small-fiber neuropathy in Sjogren syndrome.

Of 20 consecutive patients with Sjögren neuropathy, 16 (80%) presented with burning feet and 12 (60%) with non-length-dependent sensory symptoms. Leg and thigh skin biopsies, performed in 13 patients, including 7 with normal electrophysiology, showed either reduced epidermal nerve fiber (ENF) density or abnormal morphology. ENF loss was frequently non length dependent, suggesting that patients with this disorder commonly have a small-fiber sensory neuronopathy rather than a "dying-back" axonopathy.

Quantitative analysis of the "warm-up" phenomenon in myotonic dystrophy type 1.

To quantitate improvement in hand-grip myotonia and muscle strength (i.e., the "warm-up" phenomenon) in myotonic dystrophy type 1 (DM1), six successive, standardized maximum voluntary isometric contractions (MVICs) were recorded on 2 separate days using a computerized isometric hand-grip myometer in 25 genetically confirmed DM1 patients and in 17 normal controls. An automated computer program placed cursors along the declining (relaxation) phase of the MVICs at 90%, 50%, and 5% of peak force (PF) and calculated relaxation times (RTs) between these points. Mean 90% to 5% RT (a measure of myotonia) rapidly declined from 2.5 s in MVIC 1 to 0.8 s in MVIC 6 (warm-up = 1.7 s) in DM1; in controls, it remained 0.4 s for all six MVICs (warm-up = 0). In DM1, 70% of warm-up occurred between MVIC 1 and 2, almost exclusively in the terminal 50% to 5% phase of muscle relaxation. Day 1 warm-up was highly correlated with the severity of myotonia, and with day 2 warm-up. Improvement in myotonia was not accompanied by either transient paresis or improvement in PF. We conclude that, with this testing paradigm: warm-up of myotonia in DM1 can be reliably measured; is proportional to severity of myotonia; occurs rapidly, being most prominent between the first and second grips; mainly results from shortening of the terminal phase of muscle relaxation; and is not accompanied by significant warm-up in force output.

Genotype-phenotype correlation in a family with late onset CMT and an MPZ lys236del mutation.

An in frame, lys236 deletion in the intracytoplasmic domain of myelin protein zero (MPZ) has recently been designated as a mutation possibly associated with Charcot-Marie-Tooth disease (CMT) but requiring further documentation. In this report we present a detailed clinical, electrophysiological, and genotype correlation in three generations of a family with the MPZ lys236del mutation and provide further evidence that this mutation is associated with CMT. The MPZ lys236del mutation is associated with an autosomal dominant, adult onset CMT phenotype, with variable penetrance ranging from an asymptomatic state to foot deformities, pedal numbness, and muscle cramps. Nerve conduction studies disclose intermediate range, somewhat non-uniform slowing of motor nerve conduction, which is accentuated in forelimb rather than distal nerve segments. Based on the contrasting finding of entirely normal conduction velocities (CV) in a genetically affected 15 year old in this family, it remains to be established whether CV slowing with this mutation is progressive in life, a pattern that would contrast with CMT1a (PMP22 gene duplication).

Plantar nerve AP and skin biopsy in sensory neuropathies with normal routine conduction studies.

OBJECTIVE: To assess the medial plantar nerve action potential (NAP) and skin biopsy in the evaluation of suspected distal sensory neuropathies (SN) with normal routine nerve conduction studies (NCS). METHODS: A total of 110 consecutive patients with suspected distal SN and normal routine NCS underwent medial plantar NAP testing and punch skin biopsy. Patients were clinically stratified as having pure small fiber sensory neuropathy (SFSN), or distal SN with large fiber involvement (SN-LFI). RESULTS: A total of 56 patients were classified as SN-LFI and 54 SFSN. The medial plantar NAP, a measure of large fiber function, was abnormal in 31.8% of patients, more frequently in SN-LFI than SFSN. Distal leg epidermal nerve fiber (ENF) density, a measure of small fibers, was reduced in 47.3% of biopsies, with isolated ENF morphologic changes in 29.1% and normal findings in 23.6%. Biopsy abnormalities were more severe and prevalent in SN-LFI than in SFSN. In patients with a normal medial plantar NAP, distal leg biopsy showed reduced ENF density in 34.7%, and isolated morphologic changes in a further 37% of cases. CONCLUSIONS: The medial plantar nerve action potential and skin biopsy are complementary in evaluation of distal SN with normal routine NCS. Small sensory nerve fibers are affected early in SN, and more severely so when large fiber involvement is apparent clinically.

Leukocyte CTG repeat length correlates with severity of myotonia in myotonic dystrophy type 1.

OBJECTIVE: To quantitate hand muscle myotonia and to assess the relationship between CTG repeat length and myotonia in myotonic dystrophy type 1 (DM1). METHODS: First dorsal interosseous twitch and tetanic contractions evoked by single and 10-Hz ulnar nerve stimulation were recorded with a force transducer in 15 patients with genetically confirmed DM1 and 15 control subjects. An automated computer program analyzed three single and three tetanic recordings per subject on 2 successive days by placing cursors along the declining (relaxation) phase of the force recordings at 90, 50, and 5% of peak force (PF) and calculating relaxation times (RT) between these points. RESULTS: Tetanic and twitch RT was longer and PF lower in patients than subjects. RT (90 to 5%) was above the normal mean + 2.5 SD in 13 tetanic (87%) and 11 (73%) twitch patient recordings. In DM1, prolongation of RT was due mainly to delay in the terminal (50 to 5%), rather than the initial (90 to 50%) phase of relaxation, and was much greater in tetanic than single-twitch recordings. Mean test-retest variability was 19% for tetanic RT and 16% for tetanic PF. In DM1, both tetanic and twitch RT were positively correlated with leukocyte CTG repeat length. CONCLUSIONS: In DM1, myotonia of intrinsic hand muscles can be quantitated reliably by automated analysis of tetanic and twitch RT, targeting, in particular, the terminal phase of muscle relaxation after tetanic stimulation. Severity of hand muscle myotonia depends on CTG repeat length consistent with a "triplet repeat dosage" effect on chloride channel mRNA splicing and function.

A Bayesian argument against rigid cut-offs in electrodiagnosis of median neuropathy at the wrist.

BACKGROUND: Nerve conduction (NC) tests, using rigid cut-offs separating normal from abnormal test values, are commonly used to confirm median neuropathy at the wrist (MNW). The authors studied patients with clinically defined mild MNW and a normal median distal motor latency to determine 1) how much sensory or mixed NC test results increase (or decrease) the probability of MNW and 2) the NC test values required to confirm (or exclude) MNW for the range of pretest probabilities of MNW. METHODS: Palmar, digit 4 (D4), and digit 2 (D2) median NC tests were reviewed in 125 hands with mild carpal tunnel syndrome (CTS) and 100 control hands with musculoskeletal pain. Receiver operating characteristic curves and interval likelihood ratios were plotted for the three tests. Using Bayes theorem, post-test probability of MNW was then determined for the range of pretest probabilities and NC test values. RESULTS: Receiver operating characteristic curves showed that for a set specificity of 97%, palmar and D4 studies had higher electrodiagnostic utility than D2 studies with cut-off test values (sensitivities of 0.3 msec, 64.0%; 0.4 msec, 71.2%; and 50 m/sec, 44.8%). However, Bayesian analysis showed that to confirm MNW more conservative cut-off values (palmar 0.5 msec, D4 0.7 msec, D2 44 m/sec) were required for pretest probabilities or=75%. Conversely, normal test values could exclude MNW only for pretest probabilities <25%. CONCLUSIONS: For a given NC test value, post-test probability of MNW can be determined from the estimated pretest probability (derived from clinical data), interval likelihood ratios, and Bayes theorem. Use of rigid cut-off values to confirm MNW is problematic, because more conservative cut-offs are required for low pretest probability. Conversely, NC tests with sensitivity <95% cannot exclude MNW when pretest probability is high.

Evidence in support of a feedback-sensitive central timekeeper for an over-learned repetitive motor behavior (pencil shading).

PURPOSE: To demonstrate the presence of a CNS timekeeper for an over-learned repetitive voluntary movement (pencil shading), and to learn if the timekeeper is influenced by changes in sensory feedback. METHODS: Self-paced pencil shading; fast, maximally-fast, and slow hand waving, as well as enhanced physiologic tremor (EPT) were recorded on 3 separate occasions with a surface-mounted accelerometer placed on the hand in 9 normal volunteers. Variation in inter-trial peak frequency was calculated. Shading and EPT were also recorded with and without visual masking in 9 normals and in 2 deafferented patients. Variation in intra-trial beat-to-beat intervals, a measure of movement regularity, was calculated. RESULTS: Shading and maximally-fast waving displayed preferred frequencies with no more variability in peak frequency between trials than did EPT, while slow and fast waving had significant inter-trial variability. Variation in beat-to-beat intervals for the shading task was less in controls than for EPT, and less in controls than for the patients in both the masked and unmasked conditions. In addition, in the masked condition, pencil shading by the patients was performed with much higher amplitude and lower frequency than by the controls. CONCLUSIONS: These data support the hypothesis that certain repetitive voluntary movements, such as pencil shading, are paced by central timekeepers that are influenced by changes in sensory feedback.

Gentle dorsal root retraction and dissection can cause areflexia: implications for intraoperative monitoring during "selective" partial dorsal rhizotomy.

During partial dorsal rhizotomy (PDR), intraoperative dorsal rootlet stimulation often evokes nonreflex, rather than reflex, motor responses that are due to costimulation of adjacent ventral roots. Intraoperative areflexia typically predicts that motor responses evoked by dorsal rootlet stimulation are nonreflexive. The cause of areflexia during PDR is in part due to anesthesia, but other mechanisms are likely to play a role as well. In this study of three consecutive patients undergoing lumbosacral neurosurgery, soleus H-reflexes evoked by tibial nerve stimulation at the popliteal fossa were found to suddenly decline in amplitude following retraction and gentle dissection of the S-1 dorsal root. In one areflexic patient, dorsal rootlet stimulation proximal to the main site of dissection evoked soleus H-reflexes, although they could not be evoked by tibial nerve stimulation. We conclude that the gentle retraction and dissection of dorsal rootlets that occurs during PDR can induce conduction block of reflex afferents. High-intensity dorsal rootlet stimulation distal to the site of conduction block may then evoke not reflex responses, but rather nonreflex motor responses, due to the costimulation of adjacent ventral roots.

Localization of ulnar neuropathy with conduction block across the elbow.

We performed short segment incremental stimulation on 13 consecutive patients with ulnar neuropathy across the elbow (UNE) and conduction block. Conduction block occurred proximal to the medial epicondyle in 62%, at the epicondyle in 23%, and below the elbow in 15%. The ulnar nerve may be more prone to external compression above the elbow than previously recognized. Short segment incremental studies are useful to identify conduction block above the elbow in such patients.

Distal myasthenia gravis with a decrement, an increment, and denervation.

We present two patients with distal myasthenia gravis poorly responsive to immunomodulatory therapy. In addition to a typical decrement on slow repetitive nerve stimulation, both had borderline to low compound muscle action potential (CMAP) amplitudes, a large increment in CMAP amplitude and area after exercise, and active denervation in distal muscles. Both had elevated acetylcholine receptor antibody (AChR Ab) levels, but normal voltage-gated calcium channel antibody levels. We hypothesize that these electrophysiological findings represent a more severe form of myasthenia gravis.

Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adult humans, results from expansion of a CTG repeat in the 3' untranslated region of the DMPK gene. The mutant DMPK messenger RNA (mRNA) contains an expanded CUG repeat and is retained in the nucleus. We have expressed an untranslated CUG repeat in an unrelated mRNA in transgenic mice. Mice that expressed expanded CUG repeats developed myotonia and myopathy, whereas mice expressing a nonexpanded repeat did not. Thus, transcripts with expanded CUG repeats are sufficient to generate a DM phenotype. This result supports a role for RNA gain of function in disease pathogenesis.

The overactive bladder in childhood: long-term results with conservative management.

PURPOSE: Idiopathic detrusor overactivity has not been thoroughly investigated and its natural history remains largely anecdotal. Bladder overactivity resulting from a neurogenic, anatomical or medical condition has been well described. Therefore, we assessed the long-term results of conservative treatment of children with idiopathic symptomatic refractory detrusor instability. MATERIALS AND METHODS: We reviewed the records of 58 patients who had an isolated finding of uninhibited contractions on urodynamics performed for refractory enuresis and daytime wetting between 1988 and 1994. Study exclusion criteria were chronic urinary tract infection, neurological lesion, anatomical abnormality of the lower urinary tract and less than 12 months of followup. RESULTS: Of the 30 children who met our study inclusion criteria 26 (87%) had complete (21) or significant (5) symptom resolution. Average time to resolution was 2.7 years (range 0.2 to 6.6). Patients with a 50% to 90% bladder capacity expected for age were more likely to benefit from therapy than those with a bladder capacity outside of this range. Age and gender were not significant predictors of resolution although girls were more likely to have resolution than boys. CONCLUSIONS: Idiopathic detrusor instability is amenable to conservative management in the majority of patients during a prolonged period. We advocate thorough urological and urodynamic evaluation to identify idiopathic detrusor instability as an etiology of enuresis and daytime wetting in complicated cases.

Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease.

BACKGROUND: Previous follow-up studies of patients with Lyme disease suggest that disseminated infection may be associated with long-term neurologic and musculoskeletal morbidity. OBJECTIVE: To determine clinical and functional outcomes in persons who were treated for Lyme disease in the late 1980s. DESIGN: Population-based, retrospective cohort study. SETTING: Nantucket Island, Massachusetts. PARTICIPANTS: 186 persons who had a history of Lyme disease (case-patients) and 167 persons who did not (controls). MEASUREMENTS: Standardized medical history, physical examination, functional status measure (Medical Outcomes Study 36-item Short Form Health Survey [SF-36]), mood state assessment (Profile of Mood States), neurocognitive tests, and serologic examination. RESULTS: The prevalence of Lyme disease among adults on Nantucket Island was estimated to be 14.3% (95% CI, 9.3% to 19.1%). In multivariate analyses, persons with previous Lyme disease (mean time from infection to study evaluation, 6.0 years) had more joint pain (odds ratio for having joint pain in any joint, 2.1 [CI, 1.2 to 3.5]; P = 0.007), more symptoms of memory impairment (odds ratio for having any memory problem, 1.9 [CI, 1.1 to 3.5]; P = 0.003), and poorer functional status due to pain (odds ratio for 1 point on the SF-36 scale, 1.02 [CI, 1.01 to 1.03]; P < 0.001) than persons without previous Lyme disease. However, on physical examination, case-patients and controls did not differ in musculoskeletal abnormalities, neurologic abnormalities, or neurocognitive performance. Persons with previous Lyme disease who had persistent symptoms after receiving treatment (n = 67) were more likely than those who had completely recovered to have had fever, headache, photosensitivity, or neck stiffness during their acute illness (87% compared with 13%; odds ratio, 2.4 [CI, 1.0 to 5.5]; P = 0.045); however, the performance of the two groups on neurocognitive tests did not significantly differ. CONCLUSIONS: Because persons with previous Lyme disease exhibited no sequelae on physical examination and neurocognitive tests a mean of 6.0 years after infection, musculoskeletal and neurocognitive outcomes seem to be favorable. However, long-term impairment of functional status can occur.

Neuropsychological deficits in Lyme disease patients with and without other evidence of central nervous system pathology.

A small percentage of Lyme patients develop mild to moderate encephalopathic symptoms months to years after diagnosis and treatment. Their symptoms typically include fatigue, memory loss, sleep disturbance, and depression. However, the etiology of this syndrome remains controversial. It is generally thought that Lyme patients with abnormal cerebral spinal fluid (CSF) have a neurological basis to their illness. To further examine this question, we compared Lyme patients with evidence of abnormal CSF, intrathecal antibody to Borrelia burgdorferi, elevated protein, or a positive polymerase chain reaction for B. burgdorferi DNA (n = 14); Lyme patients with normal CSF (n = 18); and healthy controls (n = 15) on a battery of neuropsychological and personality tests. Although both Lyme groups reported memory problems, only the Lyme group with abnormal CSF had measurable memory deficits. Both Lyme groups had higher depression scores than the normal control group, although depression was not correlated with memory scores. It appears that Lyme patients with abnormal CSF may have a neurological basis to their illness, whereas affective symptoms, common to many chronic disorders, may predispose other Lyme patients to the perception of cognitive dysfunction.

Radial neuropathy.

The radial nerve is the largest branch of the brachial plexus, and is commonly involved in upper extremity mononeuropathies. The radial nerve is primarily responsible for motor innervation of the upper extremity extensors, as well as receiving cutaneous innervation from most of the posterior arm, forearm, and hand. There are a variety of sites at which the radial nerve is susceptible to trauma and entrapment. Localizing radial nerve lesions is dependent on clinical knowledge of radial nerve anatomy, and sensory and motor examination.

Successful treatment of Lyme encephalopathy with intravenous ceftriaxone.

The efficacy of intravenous ceftriaxone, 2 g per day for 30 days, was evaluated in a case series of 18 consecutive patients who met strict criteria for Lyme encephalopathy. Months to years after classic manifestations of Lyme disease, the 18 patients presented with memory difficulty, minor depression, somnolence, or headache. Sixteen (89%) had abnormal memory scores; 16 (89%) had cerebrospinal fluid (CSF) abnormalities, and all 7 patients tested had frontotemporal perfusion defects on single photon emission computed tomographic (SPECT) imaging. Six months after treatment, memory scores in the 15 patients who completed the study according to protocol were significantly improved (P<.01). In the 10 patients who had follow-up CSF analyses, total protein levels were significantly lower (P<.05). In the 7 patients who had SPECT imaging, posttreatment perfusion was significantly better (P<.01). Twelve to 24 months after treatment, all 18 patients rated themselves as back to normal or improved. We conclude that Lyme encephalopathy can be treated successfully with ceftriaxone.

Amplitude-dependent slowing of conduction in amyotrophic lateral sclerosis and polyneuropathy.

The mechanism of motor nerve conduction slowing in amyotrophic lateral sclerosis (ALS) is thought primarily to be loss of large, fast-conducting motor fibers; this is less certain in axonal polyneuropathy. We compared motor conduction studies in 64 patients with axonal polyneuropathy with 72 patients with ALS. Compound motor action potential amplitude, distal motor latency, and conduction velocity were converted to a percentage of the upper or lower limit of normal and then represented as a square root (SQRT) transformation, plotted with SQRT amplitude as the independent variable and SQRT latency or SQRT conduction velocity as the dependent variables. Regression analysis of the lower extremity nerve data showed that prolongation of latency and slowing of velocity were amplitude-dependent and were virtually identical in ALS and polyneuropathy. In the upper extremity, amplitude-dependent prolongation of latency was similar in both groups, but amplitude-dependent slowing of velocity was seen in ALS and not in axonal polyneuropathy. Our data support the hypothesis that the major mechanism of slowing is similar in both polyneuropathy and ALS and is the loss of large, fast-conducting fibers. However, the presence of distal but not proximal slowing in the upper extremity of axonal polyneuropathy suggests that additional mechanisms may be contributory.