Richard L. Barbano

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.

Botulinum neurotoxin versus tizanidine in upper limb spasticity: a placebo-controlled study

Background: While spasticity is commonly treated with oral agents or botulinum neurotoxin (BoNT) injection, these treatments have not been systematically compared. Methods: This study performed a randomised, double-blind, placebo-controlled trial to compare injection of BoNT-Type A into spastic upper limb muscles versus oral tizanidine (TZD), or placebo, in 60 subjects with upper-limb spasticity due to stroke or traumatic brain injury (TBI). Wrist flexors were systematically injected, while other upper limb muscles were injected as per investigator judgement. Participants were randomised into three groups: (1) intramuscular BoNT plus oral placebo; (2) oral TZD plus intramuscular placebo; (3) intramuscular placebo plus oral placebo. The primary outcome was the difference in change in wrist flexor modified Ashworth score (MAS) between groups. Other outcome measures included MAS at elbow and finger joints, Disability Assessment Scale (DAS) and adverse events (AE). Results: BoNT produced greater tone reduction than TZD or placebo in finger and wrist flexors at week 3 (p<0.001 vs TZD; p<0.02 vs placebo) and 6 (p = 0.001 vs TZD; p = 0.08 vs placebo), and greater improvement in the cosmesis domain of the DAS at week 6 (p<0.01). TZD was not superior to placebo in tone reduction at either time point (p⩾0.09). The incidence of AE related to study treatment was higher with TZD than in the BoNT (p<0.01) or placebo groups (p = 0.001). Conclusions: BoNT is safer and more effective than TZD in reducing tone and disfigurement in upper-extremity spasticity, and may be considered as first-line therapy for this disorder.

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.

A randomized, placebo-controlled trial of oxycodone and of gabapentin for acute pain in herpes zoster.

ABSTRACT Although acute pain in patients with herpes zoster can be severe and has a substantial impact on health‐related quality of life, there have been no randomized clinical trials of oral medications specifically for its ongoing treatment. A randomized clinical trial was conducted in which 87 subjects ⩾50 years of age with herpes zoster within 6 calendar days of rash onset and with worst pain in the past 24 h ⩾ 3 on a 0–10 rating scale initiated 7 days of treatment with famciclovir in combination with 28 days of treatment with either controlled‐release (CR) oxycodone, gabapentin, or placebo. Subjects were evaluated for adverse effects of treatment, acute pain, and health‐related quality of life. The results showed that CR‐oxycodone and gabapentin were generally safe and were associated with adverse events that reflect well‐known effects of these medications. Discontinuing participation in the trial, primarily associated with constipation, occurred more frequently in subjects randomized to CR‐oxycodone (27.6%) compared with placebo (6.9%). Treatment with CR‐oxycodone reduced the mean worst pain over days 1–8 (p = 0.01) and days 1–14 (p = 0.02) relative to placebo but not throughout the entire 28‐day treatment period as pain resolved in most subjects. Gabapentin did not provide significantly greater pain relief than placebo, although the data for the first week were consistent with a modest benefit. By demonstrating that CR‐oxycodone is safe, generally adequately tolerated, and appears to have efficacy for relieving acute pain, the results of this clinical trial provide a foundation for evidence‐based treatment for acute pain in herpes zoster.

Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies

Predictors of response to neuropathic pain treatment in patients with painful distal sensory neuropathies are lacking. The 5% lidocaine patch is believed to exert its effects on neuropathic pain via a local stabilizing effect on cutaneous sensory afferents. As such, it provides a model to assess whether the status of epidermal innervation as determined by skin biopsy or quantitative sensory testing (QST) of small‐ and large‐diameter sensory afferents might serve as predictors of response to topical, locally active treatment. In this study we assessed associations between epidermal nerve fiber (ENF) densities, sensory nerve conduction studies (NCS), QST, and response to a 5% lidocaine patch in patients with painful distal sensory neuropathies. We observed no association between distal leg epidermal and subepidermal innervation and response to the lidocaine patch. Several patients with complete loss of distal leg ENF showed a response to the lidocaine patch. Similarly we observed no consistent association between treatment response and QST for vibration, cooling, warm, heat‐pain, and cold‐pain thresholds, or distal sensory NCS. Thus, distal‐leg skin biopsy, QST, and sensory NCS cannot be used to identify patients with painful polyneuropathy likely to respond to a lidocaine patch in clinical practice. Further studies are required to clarify precisely the mechanism and site of action of the lidocaine patch in patients with peripheral neuropathic pain. Muscle Nerve, 2005

Epidermal reinnervation concomitant with symptomatic improvement in a sensory neuropathy

Assessment of epidermal innervation using polyclonal antibodies to the pan-axonal marker, protein gene product (PGP) 9.5, is gaining acceptance as a diagnostic tool for small-fiber sensory neuropathies (SFSN).1,6,7 However, few reports demonstrate the utility of serial skin biopsy as a clinical marker of treatment responses.4 We thus report our experience in such a case, which supports the potential utility of serial punch skin biopsy to objectively demonstrate and monitor treatment responses in the clinic. A 47-year-old man with no prior neurological history developed right shoulder aching, electric-like sensations (from his right shoulder to the elbow), and intermittent tingling and pain in both feet over a 1-week period in March 1998. Over 3 months the paresthesias and pain spread to his anterior chest, abdomen, and legs. Physical examination disclosed right scapular winging and decreased temperature and pinprick sensation in the right lateral forearm and the feet. Vibratory sense, cutaneous sensation over the trunk, limb strength, and deep tendon reflexes were normal. Initial electrodiagnostic studies showed a 76% reduction in amplitude of the sensory nerve action potentials (SNAPs) of the right lateral antebrachial cutaneous nerve (5.4 V) compared with the contralateral side (21.9 V), and evidence of active denervation (positive waves/fibrillation potentials) and reduced recruitment within the right serratus anterior muscle. All other nerve conduction studies including the right median motor response and minimum F-wave latency, right median (digit 2) and radial SNAPs, and the right sural SNAP amplitude were normal. Needle examination of the right infraspinatus, deltoid, biceps, triceps, pronator teres, and first dorsal interosseous muscles was normal. Antinuclear antibodies, sedimentation rate, lipid profile, anti-Ro/La antibodies, glucose tolerance test, and PMP-22 genetic studies were unremarkable. Between August and December 1998, the patient received low-dose oral colchicine (0.6 mg daily) for Peyronie’s disease without benefit. Electrodiagnostic studies in June 1999 revealed normal medial plantar and sural nerve action potentials and tibial motor studies. Although the right brachial plexopathy improved, his trunk and limb pain and paresthesias continued over the next 2 years, especially in his feet. Sensory examination in July 2000 revealed decreased pinprick sensation in the fingertips and thighs bilaterally as well as below the knees. Motor (tibial) and sensory (sural and medial plantar) nerve conduction studies (April 2001) were again in the normal range. In April 2001, 3-mm punch skin biopsies, with assessment of epidermal nerve fiber (ENF) density according to previously validated techniques,1,3,8,9 showed a reduced ENF density (Fig. 1) at the right lateral ankle (5.8 fibers/mm; laboratory normal,2 16.7 5.2 fibers/mm; range, 8 –25 fibers/mm) and proximal thigh (9.3 fibers/mm; normal, 21.2 5.87 fibers/mm; range, 11.7– 33.8 fibers/mm) with abnormal morphology (axonal swellings) of some of the remaining fibers at both sites.7 Prednisone 60 mg daily was started empirically because of progressive paresthesias and pain despite symptomatic treatment. Pain and paresthesias over the trunk and thighs resolved entirely, whereas distal leg symptoms improved but persisted. Examination showed mildly decreased touch and pinprick sensation restricted to the feet. Prednisone was tapered to 20 mg daily over 12 months. Follow-up skin biopsies in April 2002 (1 inch from the initial biopsy sites) showed (Fig. 1) clear repopulation of ENF at the thigh (27.7 fibers/mm, 200% increase) but only a slightly increased density at the ankle (7.0 fibers/mm, 18% increase). However, focal epidermal axonal swellings were still seen at the thigh and ankle (Fig. 1D). This is one of the first illustrations of epidermal reinnervation coinciding with clinical and symptomatic improvement of a painful SFSN following long-term immunosuppression. The etiology of our patient’s SFSN and brachial plexopathy is unknown, but his clinical

Serum and cells from Theiler's virus-infected mice fail to injure myelinating cultures or to produce in vivo transfer of disease: The pathogenesis of Theiler's virus-induced demyelination appears to differ from that of EAE

Intracerebral inoculation of SJL mice with Theilers Murine Encephalomyelitis virus (TMEV) results in a biphasic disease characterized by early grey matter involvement followed by late, chronic white matter inflammation and demyelination. Morphological parameters of TMEV-induced demyelination are essentially identical to those of experimental allergic encephalomyelitis (EAE) and immunosuppression has been shown to prevent demyelination. To test whether the pathogenesis of demyelination in TMEV infection is based on an autoimmune attack on myelin as in EAE, we tested sera and cells from infected animals for their ability to produce in vitro demyelination and cells for their ability to transfer disease in vivo. Isogeneic organotypic cultures were exposed to either serum or splenocytes from diseased animals. Neither serum nor splenocytes demyelinated or prevented myelination in these cultures. Splenocytes from diseased animals were also incubated with basic protein or whole spinal cord and assayed for their proliferative response or their ability to transfer disease to naive recipients. Neither proliferation nor transfer of disease was observed. These results show that the immunopathology of demyelination in the Theilers model differs from that of EAE in a number of important parameters and support the contention that demyelination in this viral infection is produced by immunological mechanisms different from those operating in EAE.

Treatment recommendations and practical applications of botulinum toxin treatment of cervical dystonia

CD is a complex disorder that can have significant impact on a patients quality of life and physical well-being. BoNTs are a very effective and well-tolerated first-line therapy in relieving CD symptoms over long-term treatment. BoNT treatment should be administered at the lowest effective dose with a minimum of 3 months between treatments. As the incidence of immunoresistance is low, a reassessment of muscle selection, dosing, and diagnosis should take place in the event of suboptimal patient response. Optimal treatment may involve a combination of oral pharmacologic treatment with BoNTs to maintain the use of lowest possible dosing and to extend effectiveness to the recommended 3-month dosing interval. Physical therapy in conjunction with BoNT treatment can also extend treatment efficacy as well. Comorbidities such as insomnia, depression, and anxiety can interfere with successful CD treatment and should be actively managed along with the symptoms of CD. Although our understanding of CD is incomplete, it is ever expanding. As a deeper understanding of disease pathophysiology and disease progression is gained, treatment efforts will be refined for optimal outcome and patient satisfaction.

Needle EMG guidance is useful

Botulinum toxin (BTX) is used increasingly in neurologic practice. Needle electromyographic (EMG) analysis of muscles in disorders treated with BTX is often useful in diagnosis, assessing treatment response, and searching for denervation when neutralizing antibodies are suspected. These are important uses of needle EMG. Although needle EMG guidance for injection of BTX is an accepted technique, some argue over whether this technique increases treatment efficacy. Needle EMG guidance is more important in some diseases than others. For example, it is hard to argue in support of needle EMG–guided BTX injection for the treatment of cosmetic wrinkles (although a recent review in the dermatologic literature claimed benefits for its use). By contrast, it would be difficult to treat laryngeal dysphonia without it. The essential difference between these examples is the location and accessibility of the target muscles, being easily accessible in patients with wrinkles, but difficult in the setting of spasmodic dysphonia. The main advantage of needle EMG guidance is precision of toxin placement. Does precision improve treatment efficacy? There are theoretical advantages of needle EMG– guided delivery of BTX. First, clinical examination alone is often incapable of detecting dystonic muscles. Examination has a sensitivity of only 0.35 and specificity of 0.74 — a finding that holds even for superficial muscles such as the trapezius and scalenus posterior. The sensitivity of clinical examination would be lower for deeper muscles, where needle EMG guidance would likely improve injection accuracy. The importance of targeting the motor endplate has been emphasized in animal models. Using rat anterior tibialis muscle, Shaari and Sanders demonstrated that toxin injection into the motor endplate region produces the greatest paralysis. Injections only 0.5 cm away from the region resulted in a 50% decrease in paralysis. In a canine model, placement of BTX at the motor endplate potentiated the toxic effect and decreased muscle force generation. These results support the premise that the closer the toxin is placed to the motor endplate, the greater the effect and the lower the toxin requirement. It is known that BTX diffuses outside of target muscles even when these muscles are localized by electrical stimulation. This spread is estimated to be 2.5–4.5 cm, with the size of the diffusion field being proportional to the amount of toxin delivered, and can occur across fascial planes. It makes sense that the toxin should be delivered to the target muscle; the further off-target the injection, the more that uninvolved, nondystonic muscles will be weakened. In one series of patients with upper limb dystonia, weakness of uninjected muscles adjacent to those injected was found in 63% of patients. Spread to and weakness of the uninjected muscles was the primary cause of a suboptimal response in 15% of these patients. Is exact localization of muscles advantageous? The answer probably depends on the disease. In blepharospasm and hemifacial spasm (HFS), the involved muscles are superficial and needle EMG may not be necessary. The small lower facial muscles in HFS may be hard to locate exactly, and any misinjection may lead to more extensive diffusion of toxin along fascial planes and increase unwanted cosmetic side effects. Limb dystonia, such as occupational cramp, often involves small extrinsic and intrinsic hand muscles that lie in close proximity to one another. Inappropriate toxin placement can worsen the functional outcome by weakening nondystonic adjacent muscles. Furthermore, it is occasionally important to weaken particular fascicles of individual Abbreviations: BTX, botulinum toxin; EMG, electromyography; HFS, hemifacial spasm

Acute and delayed cerebral infarction after wasp sting anaphylaxis

A 52-year-old man developed a severe anaphylactic reaction after a wasp sting. Slurred speech and left hemiparesis were noted a few hours later. Three-and-one-half weeks later, he became acutely obtunded and quadriparetic. Angiographic studies demonstrated complete and near-complete occlusions of the right and left internal carotid arteries, respectively. A mechanism is suggested for delayed ischemic stroke after wasp sting anaphylaxis that involves cerebrovascular sympathetic innervation.