Effective Behavioral Treatment of Self-biting by a Child with Lesch-Nyhan Syndrome

Behavior modification consisting of differential reinforcement of incompatible behavior and "punishment' was used for short periods at an early intervention center and was effective in eliminating self-biting of the arms, forearms and backs of the hands by a two-year-old with Lesch-Nyhan syndrome. No side-effects of the "punishment' component were observed. The effectiveness of the treatment was generalized to 3 1/2-hour sessions with his teacher at the early intervention center, and to the child's home. At six-month follow-up the teacher and parents indicated the continued absence of biting of the arms, forearms and back of the hands. The same treatment was applied to biting the fingers and the palms of the hands, without success.     

Long-term safety and tolerability of oxcarbazepine in painful diabetic neuropathy

BACKGROUND: Painful diabetic neuropathy is a common complication of diabetes and often resistant to treatment with standard analgesics. Treatment of diabetic neuropathy with antiepileptic drugs may provide pain relief. AIM: To evaluate the long-term safety and tolerability of oxcarbazepine in two studies investigating the treatment of diabetic neuropathy. OBJECTIVES: Patients with diabetes and a history of neuropathic pain were included. Study 1 was a multicenter, open-label study comprising a screening and 12-month treatment phase. Study 2 was a multicenter, open-label extension to a double-blind, randomized study. Oxcarbazepine was initiated at 300 mg/day and titrated over 4 weeks to tolerability or a maximum dose of 900 mg b.i.d. Safety was assessed by monitoring adverse events (AEs), serious AEs (SAEs), hematology, blood chemistry, urinalysis values, and vital signs. RESULTS: Adverse events were most frequently reported in the nervous and gastrointestinal systems; 20.5% and 21.6% of patients withdrew because of AEs in study 1 and study 2, respectively. SAEs were reported in 13.7% and 14.4% of patients in study 1 and study 2, respectively. CONCLUSIONS: Long-term treatment with oxcarbazepine is generally well tolerated in patients with painful diabetic neuropathy. Rapid titration of oxcarbazepine may be responsible for discontinuations resulting from AEs during early stages of treatment.     

Minocycline improves peripheral and autonomic neuropathy in type 2 diabetes: MIND study

Diabetic peripheral neuropathy and diabetic autonomic neuropathy are serious and common complications of diabetes associated with increased risk of mortality and cardiovascular disease. We sought to evaluate the safety and efficacy of minocycline in type 2 diabetic patients with diabetic peripheral and autonomic neuropathy. In a randomized placebo controlled study, 50 outpatients were randomly assigned to receive 100 mg minocycline or placebo. Outcome measures included the vibration perception threshold (VPT), Leeds assessment of neuropathic symptoms and signs (LANSS), Pain Disability Index (PDI), Visual Analog Scale (VAS), beck depression inventory (BDI), health assessment questionnaire (HAQ) and autonomic neuropathy, assessed by cardiovascular reflex tests according to Ewing and peripheral sympathetic autonomic function was assessed by FDA approved Sudoscan. At baseline there were no significant differences between demographic variables and the neuropathy variables in the minocycline and placebo groups. After treatment, VPT significantly improved in the minocycline group as compared to the placebo group. Mean posttreatment scores on the LANSS, PDI and HAQ were significantly lower in the minocycline group compared with the placebo group. However, BDI and VAS significantly (p = 0.01) improved in both minocycline and placebo groups (Table 2). After treatment with minocycline, heart rate (HR) response to standing significantly improved, while there was a borderline significance toward a reduction in HR response to deep breath. These finding indicate that 6-week oral treatment with minocycline is safe, well tolerated and significantly improves peripheral and autonomic neuropathy in type 2 diabetic patients.     

Bimoclomol (BRLP-42) Ameliorates Peripheral Neuropathy in Streptozotocin-Induced Diabetic Rats

A reduction in nerve conduction velocity and an increase in resistance to ischemic conduction failure are early signs of neural dysfunction in both diabetic patients and animal models of diabetes. The effect of Bimoclomol (BRLP-42), a drug under clinical development for the treatment of diabetic complications, on experimental peripheral neuropathy was examined in rats made diabetic by injection of streptozotocin. Daily oral doses of Bimoclomol (10 or 20 mg/kg) or control dose of γ-linolenic acid (260 mg/kg), an agent with known neuropathy-improving effects, were administered for 3 months. Treatments began 1 day after diabetes induction to assess the prophylactic efficacy of Bimoclomol. Neuropathy was evaluated electrophysiologically by measuring motor and sensory nerve conduction velocities and resistance to ischemic conduction failure of sciatic nerve in vivo. Bimoclomol significantly reduced nerve conduction slowing and retarded the typical elevated ischaemic resistance due to streptozotocin-induced neuropathy, suggesting that the drug might be a useful treatment for diabetic peripheral neuropathies.     

Modes and patterns of self-mutilation in persons with Lesch-Nyhan disease

Lesch-Nyhan disease (LND) is a rare X-linked recessive genetic disorder associated with cognitive impairment, choreoathetosis, hyperuricemia, and the hallmark symptom of severe and involuntary self-mutilation. This study examines data gathered from a survey of 64 families in the USA and abroad regarding the self-injury of their family members who have LND. The individuals with LND ranged in age from 1 to 40 years (mean 16 years 7 months, SD 11 years 2 months) and, with the exception of one, were males. The most common initial mode of self-mutilation, and the most frequently cited past or current behavior, was biting of lips and/or fingers. Other behaviors, in order of frequency, included head banging, extension of arms when being wheeled through doorways, tipping of wheelchairs, eye-poking, fingers in wheelchair spokes, and rubbing behaviors. Hierarchical cluster analysis identified patterns of association among the types of self-mutilation. Modes of self-mutilation in which external surfaces (such as a wheelchair component) served as instruments of self-injury tended to co-occur, as did biting of lips and fingers.     

Evaluation of thermography in the diagnosis of selected entrapment neuropathies

We studied 20 normal subjects, 22 patients with carpal tunnel syndrome, and 15 with ulnar neuropathy at the elbow to compare the diagnostic accuracy of infrared thermography with that of conventional electrodiagnostic studies. We found abnormal thermograms in 55% of patients with carpal tunnel syndrome and 47% with ulnar neuropathy, using 2.5 SD from the normal mean as criteria for abnormality. The abnormalities consisted of either an increase in interside temperature difference in the fingers and hands or an alteration of the normal thenar-hypothenar temperature gradient in the fingers. The sensitivity of thermography was considerably lower than that of conventional electrodiagnostic methods. Moreover, the thermographic abnormalities were nonspecific, and could be misleading as they did not reliably identify the side of lesion or distinguish between median or ulnar nerve involvement. Thus, thermography is not helpful in the diagnosis of these two common entrapment neuropathies.     

Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study

OBJECTIVE: To study the efficacy of lamotrigine in relieving the pain associated with diabetic neuropathy. METHODS: The authors randomly assigned 59 patients to receive either lamotrigine (titrated from 25 to 400 mg/day) or placebo over a 6-week period. Primary outcome measure was self-recording of pain intensity twice daily with a 0 to 10 numerical pain scale (NPS). Secondary efficacy measures included daily consumption of rescue analgesics, the McGill Pain Questionnaire (MPQ), the Beck Depression Inventory (BDI), the Pain Disability Index (PDI), and global assessment of efficacy and tolerability. RESULTS: Twenty-four of 29 patients (83%) receiving lamotrigine and 22 of 30 (73%) patients receiving placebo completed the study. Daily NPS in the lamotrigine-treated group was reduced from 6.4 +/- 0.1 to 4.2 +/- 0.1 and in the control group from 6.5 +/- 0.1 to 5.3 +/- 0.1 (p < 0.001 for lamotrigine doses of 200, 300, and 400 mg). The results of the MPQ, PDI, and BDI remained unchanged in both groups. The global assessment of efficacy favored lamotrigine treatment over placebo, and the adverse events profile was similar in both groups. CONCLUSIONS: Lamotrigine is effective and safe in relieving the pain associated with diabetic neuropathy.     

Non-ketotic hyperglycaemia-related paroxysmal bilateral hand paraesthesia misdiagnosed as diabetic neuropathy

Abstract Non-ketotic hyperglycaemia (NKH)-related partial seizure disorders are not uncommon in clinical practice but still deserve attention as they significantly affect neurologic outcome if unnoticed. The atypical presentation of sensorimotor symptoms can be seen in this setting, with paroxysmal character as the rule. Atypical manifestations could cause confusion and might lead to improper diagnosis and treatment. We report a case of inadequately controlled diabetes mellitus and NKH presenting as paroxysmal paraesthesia of both hands, which was misdiagnosed as diabetic neuropathy.     

Oxcarbazepine in painful diabetic neuropathy: results of a dose-ranging study

OBJECTIVES: To evaluate the efficacy and safety of oxcarbazepine in patients with diabetic neuropathy in a multicenter, double-blind, placebo-controlled, dose-ranging 16-week study. METHODS: A total of 347 patients were randomized to oxcarbazepine 600 mg/day (n = 83), 1,200 mg/day (n = 87), 1,800 mg/day (n = 88), or placebo (n = 89). The primary efficacy variable was change in mean visual analog scale (VAS) score from baseline to the last week of the study. RESULTS: No difference between any oxcarbazepine group and the placebo group was noted for the primary efficacy variable. Both the 1,200- and 1,800-mg/day groups showed a trend toward statistical significance (P = 0.101, P = 0.096, respectively). Statistically significant differences were found between the oxcarbazepine 1,200-mg/day (P = 0.038) and 1,800-mg/day (P = 0.005) groups and placebo in the overall mean weekly VAS scores for the entire double-blind treatment phase. CONCLUSIONS: Although the primary efficacy variable did not reach statistical significance, patients taking oxcarbazepine 1,200 and 1,800 mg/day showed improvements in VAS scores compared with placebo. Oxcarbazepine may provide clinically meaningful pain relief in patients with painful diabetic neuropathy.     

Isolated finger flexion caused by continuous muscle fiber activity]

We report two patients who presented with progressive involuntary flexion of fingers. Both of them were women (Case 1 and 2 were 23 year old and 86 year old, respectively), and developed involuntary finger flexions, particularly of the ring and little fingers, following a localized pain of their hands and forearms. The other neurological findings were not present. There was no abnormal finding in their serum, and anti-voltage-gated potassium channel antibodies were negative. Nerve conduction velocity studies revealed no obvious peripheral neuropathy or conduction block. EMG studies revealed continuous muscle fiber activities only in the flexor digitorum superficialis muscles in both patients. Additionally, in Case 1, neuromyotonic discharges at frequencies of 100-200 Hz were recorded only from the flexor digitorum superficialis muscle. The present findings are likely to be similar to those of a novel form of focal neuromytonia reported recently as 'isolated finger flexion'.     

Differential response to intravenous immunoglobulin (IVIg) therapy among multifocal and polyneuropathy types of painful diabetic neuropathy

Peripheral neuropathy associated with diabetes mellitus often causes severe neuropathic pain that is difficult to alleviate. We evaluated the effect of intravenous immunoglobulin (IVIg) therapy on six patients with two phenotypes of painful diabetic neuropathy: three patients with multifocal neuropathy and three with symmetric polyneuropathy. All patients were treated with IVIg therapy and pain levels were evaluated on the Visual Analog Scale. Three patients were also assessed by quantitative sensory testing. All three patients with multifocal neuropathy showed a marked improvement in severe pain, while the patients with symmetric polyneuropathy did not respond to IVIg therapy. Pain associated with diabetic neuropathy is multifactorial and causative factors are heterogeneous. Our results show that IVIg therapy can alleviate pain in patients with multifocal diabetic neuropathy.     

Sympathetic skin response in idiopathic and diabetic carpal tunnel syndrome

BACKGROUND: In carpal tunnel syndrome (CTS), certain changes were expected in sympathetic skin response (SSR) because median nerve carries postganglionic unmyelinated fibres. PURPOSE: To investigate the median and ulnar SSR in idiopathic and diabetic CTS without autonomic dysfunction in hands and to find possible relations with electrophysiological features of these diseases. PATIENTS AND METHODS: SSRs were elicited by electrical stimulation on the supraorbital nerve and recorded from the median and ulnar territories in the hand from 20 diabetic patients with only CTS (29 hands), 24 idiopathic CTS patients (42 hands) and 13 normal subjects (26 hands). Hands with ulnar neuropathy at the wrist without symptoms and normal hands of unilateral CTS were excluded. In addition to classical parameters and comparative methods, SSR waveform changes and percentile method was used in finding abnormality. RESULTS: Median SSRs had significant delayed latency compared to ulnar latency in both CTS patients but this was not important clinically (1.38/1.37 s for idiopatic CTS; 1.43/1.36 s for diabetic CTS). Median and ulnar SSR amplitude, area, median/ulnar latency difference, amplitude and area ratio were compared and only median/ulnar latency difference and median/ulnar latency ratio were found different between the three groups. Four idiopathic CTS hands were outside of the limits or absent (9.5%). SSR waveforms were significantly different from normal subjects in CTS patients. P type SSR replaced M type in idiopathic CTS and N type in diabetic CTS. CONCLUSIONS: Findings regarding SSR parameters suggest that unmyelinated C fibers were affected in CTS. These values were not useful because they were too small. Data on SSR were not normally distributed and the percentile method seems to be more convenient for finding any abnormality in clinical practice. Also, SSR waveform analysis could give us valuable data and should add to the SSR examination parameters.     

Dopaminergic regulation of quiet biting attack behavior in the cat.

The present study provides evidence for the involvement of dopamine in the regulation of quiet biting attack behavior. Utilizing monopolar electrodes, quiet biting attack was elicited by electrical stimulation of lateral hypothalamus in five cats. After stable baseline response latency values were established, the nonselective dopamine agonist, apomorphine, was administered peripherally (IP, 1.0, 1.4 and 1.8 mg/kg), and its effects upon the attack response were identified. Apomorphine significantly facilitated the occurrence of quiet biting attack in a dose- and time-dependent manner. Conversely, quiet biting attack behavior was also suppressed in a dose- and time-dependent manner by the selective D2 antagonist, spiperone (0.2, 0.4 and 0.8 mg/kg), but not by the selective D1 antagonist, SCH 23390 (0.8 mg/kg). Moreover, pretreatment with spiperone (0.2 mg/kg) completely blocked the facilitatory effects of 1.4 mg/kg of apomorphine, while SCH 23390 (0.8 mg/kg) pretreatment failed to alter apomorphine-induced facilitation of the attack response. In addition, neither apomorphine nor spiperone altered response latencies for hypothalamically elicited circling behavior. The results suggest that dopamine plays a significant role in the regulation of quiet biting attack behavior.     

Self-injurious behavior in acquired sensory neuropathy

Self-abusive behavior, noted frequently in congenital sensory neuropathy, was observed in two children with acquired peripheral nerve dysfunction. In one case a laceration over the median nerve was followed by self-induced trauma to the fingers distal to the cut, while the other patient developed self-mutilation in all the extremities following insecticide poisoning and presented with signs of diffuse peripheral neuropathy. Improvement of the self-injurious behavior in each case seemed temporally related to the use of anticonvulsant medications, a treatment that is often suggested for older patients with paresthesias related to peripheral neuropathy. The apparent improvement in these two patients suggests that a trial of these drugs in additional patients with self-abusive behavior associated with peripheral neuropathy would be justified.     

The Absence of Synergism between the Effects of an Aldose Reductase Inhibitor, Epalrestat, and a Vasodilator, Cilostazol, on the Nerve Conduction Slowing and the Myelinated Fiber Atrophy in Streptozotocin-Induced Diabetic Rats

The preventive effects of combined or separate treatment for 10 weeks with an aldose reductase inhibitor, epalrestat (50 mg/kg/day), and a vasodilator, cilostazol (30 mg/kg/day), on nerve conduction deficits and morphometric alterations were examined in streptozotocin-induced diabetic rats. The average motor nerve conduction velocities (MNCV) in the tail nerve of the untreated diabetic (DM) group, the group treated with epalrestat (ES), the group treated with cilostazol (CZ), the group with both agents together (ES&CZ), and the normal control group were 34.7, 37.7, 39.3, 39.0 and 42.1 m/s, respectively. All treatments partially but significantly prevented a reduction in MNCV. The MNCV in the ES&CZ group was almost the same as in the CZ group. In a morphometric study of the sural nerve, the DM group showed a reduction in the average diameter of myelinated fiber and in occupancy (percentage of the fascicular area occupied by myelinated fibers), and a shift in the diameter–frequency histogram to smaller diameters. Only the CZ group showed evidence of a partial but significant preventive effect on the decrease in occupancy. In the CS and ES&CZ groups, there was a significant tendency away from the shift of histograms to smaller diameters. The ES&CZ group did not show any fewer morphometric changes than the CZ group. Thus, there was no synergism between the effects of epalrestat and cilostazol on the development of experimental diabetic neuropathy. This finding may provide a useful clue to the mechanisms of action of ES and CZ in diabetic neuropathy.     

A case of malignant rheumatoid arthritis with severe peripheral neuropathy

A 72-year-old woman of definite type of malignant rheumatoid arthritis (MRA) with severe peripheral neuropathy. She has often noted pain of both shoulders or knee joints since some years ago. At the age of 71, she noticed numbness of the feet with pain and swelling of knee joints. She was diagnosed as definite type of rheumatoid arthritis by one podiatrist. Although she took some medications, she subsequently developed general fatigue, appetite loss, exacerbation of arthritis, drop feet and hands with prominent coldness. She was admitted to our hospital on March 22, 1985. On examination, she revealed purpura, decubitis, heart murmur, arthritis of knee joints, and fingers necrosis with skin ulcer. She had severe muscle weakness, and wasting of four limbs. Moderate impairment of all-modality sensations were noted in all extremities. Distal involvement was greater than proximal. Laboratory data during administration of prednisolone (60 mg/day) were as follows: glucose in urine, 2+; occult blood in urine, 1+; white blood cells count, 18600 with 92% polymorphonuclear leukocytes; erythrocyte sedimentation rate, 60 mm in an hour; CRP, 14.62 mg/dl (normal 0.5 greater than); RA test, 2+; RAHA, 10240; CH50, 10 U/ml (normal 32-42); C3, 37 mg/dl (normal 55-75); C4, 9 mg/dl (normal 15-28); immune complex, 4.4 micrograms/ml (normal 3.0): Chest X-ray film showed cardiomegaly (CTR, 57%). ECG disclosed atrial premature contraction, and echo cardiography suggested epicarditis with aortic valve insufficiency. 99mTc RI angiogram revealed impairment of peripheral circulation. SCV on sural nerve was not elicited. Sural nerve biopsy showed obliterans type of endoarteritis and axonal degeneration with loss of myelinated fiber.     

Sympathetic skin response in idiopathic and diabetic carpal tunnel syndrome

BackgroundIn carpal tunnel syndrome (CTS), certain changes were expected in sympathetic skin response (SSR) because median nerve carries postganglionic unmyelinated fibres.PurposeTo investigate the median and ulnar SSR in idiopathic and diabetic CTS without autonomic dysfunction in hands and to find possible relations with electrophysiological features of these diseases.Patients and methodsSSRs were elicited by electrical stimulation on the supraorbital nerve and recorded from the median and ulnar territories in the hand from 20 diabetic patients with only CTS (29 hands), 24 idiopathic CTS patients (42 hands) and 13 normal subjects (26 hands). Hands with ulnar neuropathy at the wrist without symptoms and normal hands of unilateral CTS were excluded. In addition to classical parameters and comparative methods, SSR waveform changes and percentile method was used in finding abnormality.ResultsMedian SSRs had significant delayed latency compared to ulnar latency in both CTS patients but this was not important clinically (1.38/1.37 s for idiopatic CTS; 1.43/1.36 s for diabetic CTS). Median and ulnar SSR amplitude, area, median/ulnar latency difference, amplitude and area ratio were compared and only median/ulnar latency difference and median/ulnar latency ratio were found different between the three groups. Four idiopathic CTS hands were outside of the limits or absent (9.5%). SSR waveforms were significantly different from normal subjects in CTS patients. P type SSR replaced M type in idiopathic CTS and N type in diabetic CTS.ConclusionsFindings regarding SSR parameters suggest that unmyelinated C fibers were affected in CTS. These values were not useful because they were too small. Data on SSR were not normally distributed and the percentile method seems to be more convenient for finding any abnormality in clinical practice. Also, SSR waveform analysis could give us valuable data and should add to the SSR examination parameters.     

Segmental median nerve conduction measurements discriminate carpal tunnel syndrome from diabetic polyneuropathy

Median nerve conduction has been compared in CTS, with or without diabetes, and diabetic polyneuropathy. Approximately 90% of hands were correctly predicted as CTS or diabetic polyneuropathy by a comparison including the median antidromic sensory nerve conduction velocities in the elbow-to-wrist segment, wrist-to-palm segment, palm-to-finger segment, and the amplitude of the sensory nerve action potential. CTS with diabetes could not be distinguished from CTS without diabetes. The association between proximal and distal nerve conduction velocities was similar in CTS and diabetic polyneuropathy. A study in motor fibers showed that the hands could be classified through a combination of M-wave latency and the more proximal motor nerve conduction velocity measurements. Independent of severity, motor and sensory nerve conduction was influenced to an equal degree in CTS and diabetic polyneuropathy. The hypothesis that both CTS and diabetic polyneuropathy can be associated with neural ischemia is discussed. © 1995 John Wiley & Sons, Inc.     

Vibration-induced neuropathy among forestry workers

The neurological findings of 217 forestry workers were evaluated during a compulsory annual health examination. Vibration detection thresholds were determined for the left hand and foot. The handgrip forces were measured for both hands. A reduction in the vibration detection threshold or handgrip force was not associated with clinical neuropathy. Polyneuropathy was found in 4% of the lumberjacks whereas neuropathy restricted to the arms was found in 7.5% of the lumberjacks. The neuropathic findings were not linked with alcohol consumption but were associated with a history of numbness in the hands and diminished muscle force. The findings support the concept that local vibration can cause neuropathy in the arms, but the mechanism of vibration-induced neuropathy still remains uncertain.     

Interleukin‐6 attenuates the development of experimental diabetes‐related neuropathy

Neuropathy is the most severe and the least understood complication of diabetes. We investigated the potential neuroprotective effect of IL‐6 therapy in an experimental model of diabetic neuropathy. A single i.v. injection of streptozotocin (STZ, 55 mg/kg) was used to induce experimental diabetes in adult males. IL‐6 (1, 10 or 30 µg/kg) was administrated either intraperitoneally on a daily basis or subcutaneously (s.c.) on a daily, on a three times or one time per week basis, starting at day 10 post‐STZ. A decrease in sensory nerve conduction velocity (SNCV), indicative of neuropathy, is seen in STZ rats as early as day 10 post‐STZ, a time at which blood glycaemia is already maximal. At later time points, this electrophysiological impairment became severe and clinically apparent by affecting tail flick latency. Motor dysfunction defined by a significant increase in compound muscle action potential (CMAP) latency was also recorded. At the completion of the study (day 40 post‐STZ), histological examination revealed significant axonopathy and myelin loss, along with an increase in the proportion of fibers with abnormal appearance in sciatic nerves of STZ rats. These changes were not observed in non‐diabetic rats and were significantly prevented by IL‐6 treatment. The optimal dose appeared to be 10 µg/kg s.c. three injections per week, which showed a better effect in most of the parameters studied than 4‐methylcatechol, a NGF‐like neuroprotective compound. Once weekly and three times weekly administrations of IL‐6 were as effective as daily treatment. Taken together, these results support the potential neuroprotective actions of IL‐6. The fact that the half‐life of IL‐6 is only approximately 5 h while weekly dosing was neuroprotective strongly suggests activation by IL‐6 of effector molecule(s) with longer duration of action.