FK506 ACCELERATES AXONAL REGENERATION THROUGH AN ARTIFICIAL NERVE GUIDE IN THE RAT SCIATIC NERVE TRANSECTION MODEL.
Archibald S.J.(1), Wang M-S(2), and Gold B.G.(2,3) (1)Integra LifeSciences, Plainsboro, NJ, USA, (2)Center for Research on Occup. & Environ. Toxicology, (3)Dept. Cell & Developmental Biology, Oregon Health Sciences University, Portland, OR, USA.
FK506 dose-dependently accelerates nerve regeneration in the sciatic nerve crush model (Gold, Mol Neurobiol 15:285, 1997) via a mechanism distinct from its immunosuppressant activity, as shown by the ability of non-immunosuppressant derivatives to speed regeneration (Steiner et al., Nature Med 3:1, 1997; Gold et al., Exp Neurol, 147:269, 1997). To date, no study has examined whether FK506 can increase regeneration of a severed nerve reconnected by an artificial nerve graft (or guide), a more clinically relevant model. A 4-mm or 10-mm section of the left sciatic nerve was removed and the proximal and distal stumps reconnected with a polyethylene tube (1.2 mm, inner diameter) leaving a 4.5 or 10.5 mm gap, respectively. Rats received daily subcutaneous injections of FK506 (5 mg/kg) or saline and were perfused with 5% glutaraldehyde at 3 weeks. In the 4.5 mm gap group, axons from the FK506-treated rats were larger in size at all levels distal to the transection; axonal areas were increased from 4.4 ± 0.2 mm(exp2) to 5.4 ± 0.1 mm(exp2) (p < 0.005) in the tube and from 0.4 ± 0.04 mm(exp2) to 0.5 ± 0.03 mm(exp2) (p < 0.05) in the soleus nerve. In the 10 mm gap group, the area of the nerve in the tube from the FK506-treated animals was almost doubled, being significantly (p < 0.05) increased from 0.14 ± 0.03 mm(exp2) to 0.27 ± 0.04 mm(exp2). Studies will be also be presented using collagen-based Integra matrixes in combination with systemic FK506 administration. Our results are the first to demonstrate that a neuroimmunophilin ligand increases axonal regeneration through an artificial nerve guide bridging a transected peripheral nerve. These studies demonstrate the utility of combining FK506 (or one of its non-immuno-suppressant derivatives) with artificial nerve guide matrixes for the repair of peripheral nerve injuries.
THE RELIABILITY OF ASSESSMENT OF VIBRATION SENSE
Bienfait H.M.E., Peters E.W., de Visser M., de Haan R.J. Academic Medical Center, Amsterdam, The Netherlands
INTRODUCTION: Quantitative assessment of vibration sense is used to detect and monitor the course of polyneuropathies in multicentre trials. The reliability of vibrametry has not been well established. We investigated the intraobserver and interobserver reliability and assessed the independent impact of effects of age, height and gender on vibration thresholds. MATERIAL AND METHODS: we examined 111 healthy persons (21 - 69 years) with a Vibrameter type III (Somedic, Stockholm). For intraobserver reliability short term (15 minutes between measurements (N=11) and 24 hr. long term (N=28) reliability was tested, For interobserver reliability a second tester performed the second measurement after 15 minutes (N=38). RESULTS: For the short and long term intraobserver reliability the Intra Class Correlation Coefficients (ICC) ranged from 0.73-0.99 (substantial to perfect). For the interobserver reliability the ICC ranged from 0.47-0.85 (moderate). Multiple linear regression analysis showed that age and - to a lesser extent, height - were independently associated with the threshold values of the feet, not the hands. CONCLUSIONS: The intraobserver reliability is good. The interobserver reliability is in our opinion not satisfactory. Therefore we recommend that in trials only one examiner should perform the tests using the same device throughout the study. We confirmed the previously recognized influence of age and height, albeit only for the thresholds of the lower extremities.
A PILOT STUDY OF TOPAMAX® (TOPIRAMATE) IN THE TREATMENT OF PAINFUL PERIPHERAL NEUROPATHY.
Cornblath D.R., Carter K. Johns Hopkins University School of Medicine, Baltimore, MD 21287 USA.
Pain associated with peripheral neuropathy is a difficult clinical
problem, The differential diagnosis for these syndromes is limited.
The most common cause is diabetes, but most cases are idiopathic.
Treatment options for the pain itself are limited. Controlled
clinical trials have shown that amitriptyline, nortriptyline,
imipramine, desipramine, carbamazepine, phenytoin, tramadol HCL,
and gabapentin are effective in reducing pain from peripheral
neuropathy. However, none are perfect, and additional agents are
needed. Topamax® is a recently released anticonvulsant that
may be useful in reducing pain. We conducted a randomized, double-blind,
placebo-controlled, single center study of the safety and efficacy
of Topamax® (topiramate) in the treatment of painful peripheral
neuropathy from any cause. Nineteen patients with at least 6 months
of pain from neuropathy were enrolled and randomized to receive
either Topamax® or placebo in a 2:1 allocation. At baseline,
all subjects underwent routine exams, NCS, QST, and blood studies.
The Gracely pain scale was completed daily by all subjects and
was the primary outcome measure. Subjects completing or withdrawing
from the blinded study were allowed to participate in an open-label
extension study. Results will be presented from this trial.
INTRANEURAL NERVE METASTASIS WITH MULTIPLE MONONEUROPATHIES
Grisold W., Piza H., Jahn W. LBI for Neurooncology, and LBI for quality assurance in plastic and reconstructive surgery, Vienna, Austria
Although cancer is a frequent condition, neoplastic involvement of the peripheral nervous system is rare. The mechanisms are heterogeneous and include lesions in the CSF space, local invasion (e.g. brachial plexus), compression rarely direct infiltration, perineural spread and even rarer intranerval metastasis. The 47 year woman was operated from a mediastinal tumor 10 years earlier. She received axillar radiation. 8 years later she complained of weakness of the biceps brachii and severe radiating pain in the C 6 dermatome, with a sensory loss in the distal C 6 dermatome. MRT scan of the cervical vertebral column and brachial plexus was negative. EMG revealed denervation in the biceps brachii and an absent sensory conduction of the superficial radial nerve. A postradiation fibrosis was suspected. Due to increasing pain, the brachial plexus was explored. An intranerval metastasis in the musculocutaneous nerve was found. Soon she presented with numbness and weakness in the ulnar nerve and a second metastasis was discovered in the ulnar nerve. This rare case report demonstrates that multiple mononeuropathies, resembling multiplex neuropathy may be caused by direct tumor invasion or intranerval metastasis. Varieties of neoplastic nerve involvement will be discussed.
NERVE BIOPSY IN PERIPHERAL NEUROPATHIES.
Katifi H., Gad H. Wessex Neurological Centre, Southampton, UK.
Out of 200 patients attending the Wessex Neurological Centre in the period of October 1996-October 1998 with a clinical diagnosis of peripheral neuropathy, an aetiological diagnosis was reached in 133 patients without the need for a nerve biopsy. The remaining 67 patients underwent a nerve biopsy. There were 42 men and 25 women, mean age 56.4 ± 14.7 (17-85) years and a mean duration of symptoms 24.3 ± 24.9 months. The neuropathy was symmetrical in 39, asymmetric in 11 and multifocal in 17 patients. In 7 patients it was purely sensory whilst in 2 it was purely motor, the remaining patients had mixed sensory/motor involvement. The nerve biopsy was diagnostic in 27 patients confirming the following aetiologies: CIDP in 8, paraproteinaemic neuropathy in 4, vasculitis in 14 and hereditary in 1 patient. In 20 patients the biopsy showed abnormal findings that were helpful in supporting the diagnosis in a further 20 patients. The remaining 20 patients remain cryptogenic. Nerve biopsy was particularly helpful in patients with multi-focal neuropathy and more likely to yield diagnostic information when the disability was severe. Electrophysiology showed axonal changes in 40 patients, abnormalities in keeping with demyelinating neuropathies in 12, mixed features in 11 whilst in 4 patients the conduction studies were normal. Patients with cryptogenic neuropathies had a longer mean duration of symptoms of 41 ± 29.7 months and were characterized by mild symmetrical generalized sensory neuropathy with axonal electrophysiology. Their functional disability was also mild. We concluded that nerve biopsy was a useful diagnostic tool particularly in rapidly progressive and disabling neuropathies with a multi-focal pattern whilst patients with mild symmetrical sensory symptoms of longstanding duration were unlikely to be helped by a nerve biopsy.
SERIAL ASSESSMENT OF SEVERITY OF NEUROPATHIC SYMPTOMS AS A MARKER FOR CHANGE IN PERIPHERAL NEUROPATHY
Klein CM., Dyck P.J. Mayo Clinic, Rochester, MN 55905 USA
BACKGROUND: The Neuropathy Symptoms and Change (NSC) score is based on standardized questions asking a patient about number of neuropathic symptoms, current severity, and relative severity compared to an earlier time point. The Neuropathy Impairment Score (NIS) is a score derived from the patient's neurological examination. OBJECTIVE: To investigate the value of each component of the NSC over time compared to the NIS as markers for change in peripheral neuropathy. METHODS: Patients with chronic inflammatory demyelinating polyneuropathy (CIDP, N = 33) and multifocal mononeuropathy with persistent conduction block (MM-PCB, N = 9) were evaluated at intervals of 6 weeks to 4 months, while undergoing treatment. Patients were judged to be improved or worsened at the time of each evaluation by the percentage change in the NIS from initial values. We compared this with the percentages of patients with improvement, worsening or no change in symptoms as assessed by the change in each component of their NSC scores. RESULTS: For treatment intervals with improvement or worsening of neuropathy as measured by NIS, the change in the patient's reported number of symptoms correctly identified that change in 64% of measured intervals. Change in the reported severity of neuropathic symptoms at the time of evaluation corresponded to NIS change in 83% of intervals. Change in the reported relative severity of symptoms corresponded to the NIS change in 70% of measured intervals. CONCLUSIONS: Serial assessment of the patient's reported severity of current neuropathic symptoms corresponds best to changes in the neurological examination (NIS) as a marker for change in peripheral neuropathy.
EXTRANODAL SOLITARY LYMPHOMA OF THE MEDIAN NERVE. A CASE REPORT
Mignogna T., Sabatelli M., Lippi G., De Armas L., Madia F., Mereu M.L., Tonali P. Istituto di Neurologia. Università Cattolica. Rome, Italy
Infiltration of nerves by lymphoma is a rare cause of monomultineuropathy. In literature there are two reports about primary solitary lymphoma of nerve trunks (J. Neurol Sci 1986; 74:23; Neurosurgery 1988, 23:370). We report on a 54 year-old-man who was examined in our electrophysiologic laboratory because of paresthesias and weakness in his right hand since six months. Clinical examination showed a complete paralysis of all muscles innervated by the right median nerve and anesthesia was found on the volar side of the thumb and of the index and middle fingers. Electrophysiological studies showed: absent sensory action potentials from the median nerve, denervation potentials from ronator teres, flexor pollicis longus and abductor pollicis brevis. No CMAP could be elicited from abductor pollicis brevis stimulating the median nerve at the wrist. Echography of the right arm disclosed an enlargement of the median nerve. A biopsy of nerve enlargement showed a non-Hodgkin's lymphoma. Routine blood examinations, chest and abdominal CT, bone marrow biopsy were normal. He was treated with a chemiotherapy. After 8 months echographic evaluation showed the disappearance of median nerve enlargement; EMG evaluation showed low amplitude, polyphasic and long duration potentials in the pronator teres and flexor longus pollicis, suggesting nerve regeneration.
THE DIAGNOSTIC VALUE OF ELECTROPHYSIOLOGICAL STUDIES IN THE DIAGNOSTIC WORK-UP OF PATIENTS WITH A PERIPHERAL NEUROPATHY
Rosenberg N.R., de Visser M., Portegies P., Vermeulen M. Department of Neurology, Academic Medical Center, PO Box 22700, 1100 DE Amsterdam, The Netherlands
BACKGROUND: We investigated whether electro-physiological studies direct the clinician in a focused search for an aetiology in patients with peripheral neuropathy of at least 6 weeks. METHODS: We reviewed medical records of 209 patients referred with a possible peripheral neuro-pathy. Excluded were patients who were sent for a second opinion. RESULTS: Final diagnoses were diabetic neuropathy (n = 52), chronic idiopathic axonal neuropathy (26), neuropathy caused by HIV (20), alcoholism (12), uraemia (7) or medication (7), and miscellaneous (57). Twenty eight patients had no neuropathy. Electrodiag-nostic studies were performed in 168 patients of which 48% (80 of 168) was not contributing, since there was a plausible explanation for the distal symmetrical polyneuropathy (diabetes mellitus, alcoholism, HIV, uraemia or medication) and the diagnosis had not changed after these studies. In patients with electrophysiological studies, 12/168 (7%) fulfilled the criteria of a demyelinating neuropathy. There was only one unexpected electrophysiological result. CONCLUSIONS: 1) Electrophysiological studies do not contribute to the diagnosis if a patient with symmetrical distal polyneuropathy is known with diabetes, alcohol-abuse, HIV, uraemia or neurotoxic drugs. 2) The distinction between demyelinating and axonal neuropathies does rarely direct the clinician in a focused search of a definitive aetiology since a demyelinating neuropathy occurred in only 7%.
CLINICAL ANALYSIS OF FACTORS TO INFLUENCE ON PAINFUL INTOLERANCE IN REPLANTED DIGITS
Takamatsu K., Hidaka N., Gotani N., Egi T., Yano H., Yamano Y. Osaka City University, Osaka City, OSAKA 545-8585 JAPAN
A lot of investigators have reported that some factors have related to cold intolerance (C.I.) in replanted digit. The purpose of this study is to investigate factors retrospectively to prevent cold intolerance. PATIENTS AND METHOD: We consulted 31 patients (42 replanted digits; complete 36, incomplete 6), age- 7~72(averaged 38.9)years old, the period of the follow up- averaged 23.2 months. We interviewed about the presence of painful cold intolerance in cold water or weather and investigated age, amputated level (according to Tamai's zone), condition (clean/blunt cut or crush/ avulsion), numbers of repaired arteries and nerves and sensory recovery (Semmes-Weinstein test, 2 point discrimination). RESULTS: Patients under 30 years old showed cold intolerance in 6/17 patients (35%), patients over 30 years old in 16/24 (67%) (p=0.03). There are no significant differences in level, condition and numbers of arteries. Concerning about numbers of nerves, the rates with cold intolerance are 72.2% (no nerve repaired), 83.3 (only one nerve repaired) and 41.1 (two nerves repaired) (p=0.01). In sensory recovery patients with and without cold intolerance showed averaged 9.4mm and 12.7mm in 2PD respectively (p=0.048). CONCLUSION: This study indicated the fact that age and numbers of repaired nerves are considered as factors to influence cold intolerance, and the possibility that positive nerve reconstruction could prevent or reduce cold intolerance.
CORNEAL PARAPROTEIN DEPOSITION IN A PATIENT WITH CIDP AND MGUS
Vriesendorp F.J., Juneja H.S., Yee R.W. University of Texas Health Science Center, Houston TX 77030
A 36 year old man developed weakness, numbness and areflexia
following a respiratory tract infection. Relevant findings included
a demyelinating neuropathy by nerve conduction studies and sural
nerve biopsy, a CSF protein of 413 mg% and an IgG kappa gammopathy.
Skeletal survey and bone marrow biopsy were normal. He was treated
with prednisolone. Blurred vision developed and crystalline paraprotein
deposits were found in the cornea. A diagnosis of CIDP with MGUS,
complicated by corneal paraprotein deposition was made. Two years
later, the patient had only moderate intrinsic hand muscle weakness
and a mild sensory deficit, but increasing visual problems. Repeated
plasmapheresis did not reduce the paraprotein level (0.3 g/dl)
long-term and melphalan and dexamethasone were given. Paraprotein
levels became undetectable during melphalan but increased again
afterwards. Cytoxan and dexamethasone had a similar effect. Four
years after onset the neuropathy has improved but vision has deteriorated.
Other organs have not been affected. Currently, high-dose chemotherapy
with autologous stem cell rescue is being considered for this
patients unusual light-chain deposition disease. Light chain deposition
disease is rare and the combination of demyelinating neuropathy
and corneal deposits has not been reported previously. The exact
mechanism of corneal deposition is unknown, but paraprotein has
been documented in tear film and aqueous humor. Differences in
target tissue binding between ocular tissues and peripheral nerve
myelin may have influenced the differences in treatment response.
Effective treatment remains difficult.