Eric L. Logigian

Chronic Neurologic Manifestations of Lyme Disease

BACKGROUND AND METHODS Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi, is associated with a wide variety of neurologic manifestations. To define further the chronic neurologic abnormalities of Lyme disease, we studied 27 patients (age range, 25 to 72 years) with previous signs of Lyme disease, current evidence of immunity to B. burgdorferi, and chronic neurologic symptoms with no other identifiable cause. Eight of the patients had been followed prospectively for 8 to 12 years after the onset of infection. RESULTS Of the 27 patients, 24 (89 percent) had a mild encephalopathy that began 1 month to 14 years after the onset of the disease and was characterized by memory loss, mood changes, or sleep disturbance. Of the 24 patients, 14 had memory impairment on neuropsychological tests, and 18 had increased cerebrospinal fluid protein levels, evidence of intrathecal production of antibody to B. burgdorferi, or both. Nineteen of the 27 patients (70 percent) had polyneuropathy with radicular pain or distal paresthesias; all but two of these patients also had encephalopathy. In 16 patients electrophysiologic testing showed an axonal polyneuropathy. One patient had leukoencephalitis with asymmetric spastic diplegia, periventricular white-matter lesions, and intrathecal production of antibody to B. burgdorferi. Among the 27 patients, associated symptoms included fatigue (74 percent), headache (48 percent), arthritis (37 percent), and hearing loss (15 percent). At the time of examination, chronic neurologic abnormalities had been present from 3 months to 14 years, usually with little progression. Six months after a two-week course of intravenous ceftriaxone (2 g daily), 17 patients (63 percent) had improvement, 6 (22 percent) had improvement but then relapsed, and 4 (15 percent) had no change in their condition. CONCLUSIONS Months to years after the initial infection with B. burgdorferi, patients with Lyme disease may have chronic encephalopathy, polyneuropathy, or less commonly, leukoencephalitis. These chronic neurologic abnormalities usually improve with antibiotic therapy.

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 (≥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).

The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study.

Lyme borreliosis is a tick-borne infection caused by the spirochete Borrelia burgdorferi [1-3]. The disease usually begins with erythema migrans accompanied by viral-like or meningitis-like symptoms. Weeks later meningitis, facial palsy, atrioventricular nodal block, or migratory musculoskeletal pain may develop, followed months to years later by episodes of frank arthritis, encephalopathy, polyneuropathy, or acrodermatitis [4]. Lyme disease is now the most common vector-borne disease in the United States; nearly 50 000 patients have been diagnosed with it since 1982 [5]. Musculoskeletal and neurologic sequelae may occur from Lyme disease. Some of the late consequences of Lyme disease, such as oligoarticular arthritis, axonal polyneuropathy, or active encephalopathy, are thought to be caused by persistent spirochetal infection and are amenable to antibiotic treatment [6-8]. Other syndromes such as persistent arthritis, fibromyalgia, subtle joint pain, or mild encephalopathy do not improve with antibiotic treatment, suggesting a mechanism other than active infection [9-12]. We studied persons residing in an endemic coastal area of Massachusetts who were previously infected with B. burgdorferi in the early 1980s [13]. They contracted Lyme disease while the clinical syndromes and optimal antibiotic therapies were still evolving, which offered a natural experiment for the identification of risk factors for Lyme disease sequelae. We ascertained the prevalence of persistent symptoms in unselected patients with a history of Lyme disease; ascertained their rheumatologic, neurologic, and health status outcomes; and identified potential risk factors for these long-term sequelae. Methods Participants In February l991, we did a follow-up analysis of residents of Argylla Road in Ipswich, Massachusetts, an endemic coastal area for Lyme disease. The incidence and clinical course of Lyme disease among residents of this area have been reported previously [13]. Participants were recruited by calling consecutive households located in the Argylla Road area, the epicenter of infection, to ask if they would be interested in enrolling in a study about Lyme disease in their area. Potential participants were told that the study involved a history, physical examination, and serologic analysis for Lyme disease. Information about whether a person ever had a previous diagnosis of Lyme disease was obtained and used to assign tentative status (with or without Lyme disease) for study participants. We recruited participants until we had 50 tentative persons with Lyme disease and 50 tentative controls. Once the potential Lyme disease group was filled, calls were made consecutively to fill the potential control group. Residents 18 years of age or older were invited to participate in the study. This protocol was approved by the Brigham & Womens Hospital Committee for the Protection of Human Subjects. Confirmation of Lyme Disease For inclusion in the Lyme group, persons needed a previous diagnosis of Lyme disease by a physician and needed to fulfill the Centers for Disease Control and Prevention (CDC) criteria for Lyme disease (a history of physician-documented erythema migrans or a late manifestation of Lyme disease confirmed by a positive Lyme serologic test result, or both [14]). This information was obtained through patient interview and then medical record review to determine if patients fulfilled criteria for Lyme disease. Previous study records, local physician reports, and previous serologic test results were available for confirmation of Lyme disease. Persons without a previous clinical history of Lyme disease were classified as controls. The status of the participants (with or without Lyme disease) was determined independent of the clinical assessment, using a protocol that did not include any outcome data. Assessment of Clinical Outcomes A blinded investigator determined outcomes in a standardized manner independent of Lyme disease status. All patients completed a standardized questionnaire, had electrocardiography, and had a neuropsychological battery of tests. The questionnaire included data on demographics, comorbidity, education, review of systems, medications, memory and cognitive function, and the Short Form-36 health status measure (a reliable, previously validated measure of physical, psychological, social, and role functions [15]). A physical examination was done by one observer blinded to Lyme disease status. It included a joint examination (the American College of Rheumatology Glossary examination) that measured swelling and pain through passive range of motion [16] and a neurologic evaluation of strength and deep tendon reflexes, light touch, and vibration sensation with a 128-Hz tuning fork (at the elbow, wrist, fibula, and ankles). Pain and swelling indices from the joint examination (the American College of Rheumatology Glossary examination) were summed and recorded as a global score. A vibration test result of a distal gradient was considered present if the participant reported diminished vibratory sensation at a distal compared with proximal site. Each participant had an electrocardiographic study that was interpreted blindly by a cardiologist uninvolved with the clinical assessment. All outcomes were determined by one investigator who had no knowledge of whether participants were in the Lyme or control groups. The neuropsychological battery of tests measured immediate and delayed verbal memory, attention, conceptualization, fine motor dexterity, and perceptual discrimination. Tests included the California Verbal Learning Test [17], Wechsler Memory Scale (visual reproduction and verbal paired associates subtests [18]), Shipley abstraction subtest [19], Stroop test [20], Trailmaking test [21], and Purdue Pegboard Test [22]. The California Verbal Learning Test measures verbal memory. Participants are asked to learn a list of 16 words during five trials; recall on the fifth trial is recorded (trial 5). This is then followed by a distracter list. The original list is recalled after the distracter list is learned (short recall) and then recalled again after a 20-minute delay (long recall). This is a challenging test of memory for patients with superior premorbid experience. Normative values are available for young and elderly adults [17]; the range of normal is between 11 and 15 words for trial 5 and is between 10 and 15 words for the long-recall subtest for persons between 45 and 54 years of age. A clinically significant change in the California Verbal Learning Test would be recalling 4 more words or 4 fewer words. All tests were administered according to published procedures. Test scores were transformed into standard scores calculated from published, age-corrected normative data. Participants with a score of 2 or more SDs from age-adjusted means were considered impaired. All results were reviewed by a neuropsychologist (RK) who was not involved with the participants evaluation, to determine those patients who were in need of further clinical evaluation. Participants with swelling or pain (joint examination test result), evidence of a distal gradient (vibration test result) or persistent symptoms of paresthesias in an extremity, or impairment on two or more neurocognitive tests were sent for further clinical evaluation. Nine patients were evaluated at the Lyme disease clinic at Tufts-New England Medical Center and 4 were evaluated by other neurologist or rheumatologist consultants to determine if these abnormal screening test results were accompanied by objective findings. This evaluation included lumbar puncture, electrophysiologic studies, magnetic resonance imaging, detailed neuropsychological tests [8], joint radiographs, or arthrocentesis. Serologic Evaluation All patients had serologic testing after the history and examination. Serum samples were stored at 70C and were tested for IgG antibodies to B. burgdorferi by indirect enzyme-linked immunosorbent assay (ELISA [23]); for IgM, IgG, and IgA antibodies to the spirochete by antibody-capture enzyme immunoassays [24]; and for the pattern of IgG reactivity to spirochetal polypeptides by Western blotting. In general, Western blot reactivity varied with the degree and duration of dissemination of Lyme disease. For example, patients with early localized infection or erythema migrans might react to only 2 to 8 B. burgdorferi polypeptides, those with meningitis might react to at least 8 to 14 polypeptides, and those with arthritis or late central nervous system disease might react to as many as 18 to 25 polypeptides (Berardi VP. Personal communication). The isolate used for antigen preparations was the B. burgdorferi G39/40 strain obtained through low passage [24]. Indirect ELISA titers greater than 400 and ELISA capture ratios (sample optical density/control optical density) of 1.0 or more were considered as increased test results. Western blot reactivity to five or more B. burgdorferi-specific polypeptides indicated previous infection [25]. Silver Stain Method The Dieterle silver impregnation stain used was a modification made by one of us (PHD) in 1985 [26]. This standard approach has yielded a constant clean yellow background of cerebral cortex sections with no silver impregnation of anatomic neural processes and dendrites. Spirochetes are easily seen as black to blue-black cells against the yellow tissue. Specificity for nonstaining of normal tissue fibers (procollagen, elastin, basement membrane material, and neural dendrites and filaments) and documentation of the cytologic structure of Borrelia spirochete strains were further tested in a large extended study [27]. Controls routinely used in each stain assay consisted of NP40 strain that was injected into human normal breast tissue removed for cosmetic surgery and was paraffin-embedded in the usual manner (negative control), and rat gonad tissue infected with the Reiter strain of treponemal spirochetes (positive c

Dispersion of the distal compound muscle action potential as a diagnostic criterion for chronic inflammatory demyelinating polyneuropathy

Objective: To assess distal compound muscle action potential (DCMAP) duration as a diagnostic criterion for chronic inflammatory demyelinating polyneuropathy (CIDP). Background: Current electrodiagnostic criteria for CIDP have high specificity but limited sensitivity. Prolonged DCMAP duration has been reported in acute inflammatory demyelinating polyneuropathy. The authors have compared DCMAP duration in patients with CIDP, diabetic polyneuropathy (DP), ALS, and musculoskeletal pain syndrome (MSP) to determine whether it enhances the sensitivity of electrodiagnostic criteria for CIDP. Methods: Data from 23 CIDP, 34 DP, 34 ALS, and 54 MSP patients were reviewed. The time interval between onset of the first negative peak and return to baseline of the last negative peak of the DCMAP was calculated for each nerve. To distinguish CIDP from DP, ALS, and MSP, optimal cutoff values for DCMAP duration were achieved with receiver-operating characteristic curves. The sensitivity and specificity of these cutoff values were compared with each of four sets of electrodiagnostic criteria for CIDP. Results: Mean DCMAP duration in CIDP was significantly longer than in DP, ALS, and MSP. The sensitivity of existing electrodiagnostic criteria for CIDP ranged between 0.43 and 0.61. Their specificity vs DP or ALS was 0.91 to 1. Using DCMAP duration of ≥9 milliseconds for any of four motor nerves yielded a sensitivity of 0.78 for CIDP and specificity of 0.94 vs DP or ALS. Adding DCMAP duration criteria to any one of the three accepted criteria enhanced their sensitivity with little sacrifice of specificity. Conclusion: Quantitation of DCMAP dispersion shows promise as a sensitive and specific adjunctive electrodiagnostic criterion for CIDP.

Painful small-fiber neuropathy in Sjögren 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.

Abnormal most-rapid isometric contractions in patients with Parkinson's disease.

Fast isometric elbow flexor muscle contractions of specified amplitude in six normal subjects were compared with those of 11 patients with Parkinsons disease. Despite treatment, all patients exhibited deficits in this motor task. Three patients were able to produce rapid force pulses with normal contraction times, but the variability of their force responses was increased in comparison with the highly stereotyped responses produced by normal subjects. The other eight patients had prolonged contraction times and segmentation of the force profiles. The integrated area of the first agonist EMG burst and the rate of development of force (dF/dt) were less at any target level than what was needed to produce a fast response. The area of the EMG burst, however, did increase with target amplitude, and the relative increase of dF/dt, with target amplitude, was normal. It is concluded that the motor program subserving fast muscle contraction is preserved in Parkinsons disease, but its execution is characterised by improper scaling of motor output.

Clinical and electrophysiologic findings in chronic neuropathy of Lyme disease

We evaluated 25 patients with Lyme disease and chronic peripheral neuropathy. All had immunologic evidence of exposure to Borrelia burgdorferi and no other identifiable cause of neuropathy. Neuropathic symptoms began a median of 8 months (range, 0 to 165) after erythema migrans and had been present for a median of 12 months (range, 2 to 168) prior to evaluation. Twelve patients (48%) had generally symmetric distal, nonpainful pares-thesia, and another 12 (48%) had generally asymmetric radicular pain. One patient (4%) had asymptomatic neuropathy. The most common physical finding was multimodal sensory loss, which was observed in 13 patients (52%); weakness and hyporeflexia were less common. Motor or sensory nerve conduction was slightly slow in 16 patients (64%). The paresthesia group more often had abnormalities on physical examination and on nerve conduction testing than did the radicular group. In 75% to 80% of patients from both groups, however, needle examination showed denervation in paraspinal and limb muscles. Among 20 patients who underwent lumbar puncture, only one had a slight spinal fluid pleocytosis. Six months after treatment with intravenous ceftriaxone, 19 patients (76%) were clinically improved. We conclude that Lyme disease can be associated with a reversible, mild chronic axonal sensorimotor polyradiculoneuropathy or polyradiculopathy.

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.

Memory impairment and depression in patients with Lyme encephalopathy Comparison with fibromyalgia and nonpsychotically depressed patients

Lyme encephalopathy, primarily manifested by disturbances in memory, mood, and sleep, is a common late neurologic manifestation of Lyme disease. We compared 20 patients with Lyme encephalopathy with 11 fibromyalgia patients and 11 nonpsychotically depressed patients using the California Verbal Learning Test, Wechsler Memory Scale, Rey-Osterrieth Complex Figure Test, Minnesota Multiphasic Personality Inventory (MMPI), and Beck Depression Inventory. Compared with patients with fibromyalgia or depression, the Lyme encephalopathy group showed mild, but statistically significant, memory deficits on two of the three memory tests. In contrast, the patients with fibromyalgia scored significantly higher than both other groups on the MMPI scale most sensitive to somatic concerns (scale l), while the depressed patients scored higher than the Lyme patients on the scales most sensitive to depression (scale 2) and anxiety (scale 7). Physical complaints and depression were not major factors in memory performance among Lyme patients. These data support the hypothesis that Lyme encephalopathy is caused by CNS dysfunction and cannot be explained as a psychological response to chronic illness.

Neurological manifestations of primary Sjogren's syndrome.

PURPOSE OF REVIEW This review summarizes our current understanding of the neurological manifestations of primary Sjogrens syndrome (PSS), their pathophysiology, and treatment. RECENT FINDINGS Prevalence of neurological manifestations in PSS varies widely from 10 to 60%, with pure or predominantly sensory polyneuropathies as the most common neurologic manifestation (e.g. sensory ataxic or small fiber sensory painful neuropathy). Mononeuropathy multiplex, polyradiculopathy, symptomatic dysautonomia, cranial neuropathy, myopathy, and central nervous system involvement are less common. PSS-associated sensory neuropathy is often the presenting feature of Sjogrens syndrome and, therefore, a high index of suspicion is required, particularly in female patients with nonlength-dependent, painful, or ataxic sensory neuropathies or those with trigeminal sensory and autonomic involvement. The pathophysiological basis of PSS-associated neuropathy is still unclear. Dorsal root ganglionitis and peripheral nerve vasculitis have been observed on histological examination of biopsy and autopsy samples. A few studies have explored the fundamental role of humoral autoimmune mechanisms. Small, uncontrolled, treatment trials with numerous immunomodulatory agents have reported variable benefit in PSS-associated neuropathy, particularly corticosteroids for mononeuritis multiplex and intravenous immunoglobulin for small fiber or sensory ataxic neuropathy. SUMMARY The clinical and histological spectrum of neurological manifestations of Sjogrens syndrome is becoming clear. The field needs further exploration of basic neuroimmunological mechanisms of neural injury, and controlled treatment trials.