Mikihiro Kihara

Comparison of SSR and QSART in early diabetic neuropathy—the value of length-dependent pattern in QSART

We evaluated postganglionic sympathetic function using the sympathetic skin response (SSR) and quantitative sudomotor axon reflex test (QSART) on the feet of 31 patients with early diabetic neuropathy and 20 age-matched normal controls. The amplitude of SSR and the sweat volume of QSART were significantly decreased in the diabetic patients. We evaluated the sensitivity of the tests in detecting autonomic failure. Out of 31 patients, 14 (45%) had abnormal SSR (14 absent; 17 present), while 16 of 31 patients (52%) had abnormal QSART (1 absent; 5 absolutely reduced and 10 showed a length-dependent pattern of reduction). More important than differences in sensitivity is the specificity of QSART, which specifically evaluates the postganglionic axon (instead of polysynaptic pathways in SSR) and provides quantitative data on the severity and pattern of autonomic deficit. In normal controls under 65 years of age, there was a significant correlation between the amplitude of SSR and the sweat volume of QSART. However, there was no significant relationship between these in diabetic patients. These results suggest that QSART can evaluate early diabetic neuropathy more precisely than SSR.

Altered vasoreactivity to angiotensin II in experimental diabetic neuropathy: role of nitric oxide.

We evaluated the effects of angiotensin II and an angiotensin‐converting enzyme inhibitor (cilazapril) on nerve blood flow (NBF) and electrophysiology in control and diabetic rats. When applied locally to the sciatic nerve, the dose–response curve of angiotensin II was more potent in experimental diabetic neuropathy (EDN) than control rats. No difference existed in plasma angiotensin II levels between EDN and controls. The rats were given typical rat pellets or pellets treated with 10 mg/kg per day cilazapril for 4 weeks. Diabetes caused a significant reduction in NBF, nerve conduction velocity, and compound muscle action potential (CMAP) amplitudes. NBF was significantly increased in diabetic rats supplemented with cilazapril diet, and nerve conduction velocity and amplitudes of the CMAP were also improved after 4 weeks on this diet. Direct application 10−3 mol/L cilazapril on sciatic nerve did not increase NBF in normal and EDN rats. We topically applied the nitric oxide synthase (NOS) inhibitor, NG‐nitro‐L‐arginine, on sciatic nerve and observed reduced inhibition of NBF in EDN, which was correctable with a cilazapril diet. These results suggest that diabetic neuropathy may have an increasing vasopressor action with angiotensin II and this is likely to be the mechanism of NOS inhibition. Angiotensin II‐converting enzyme inhibitors may have potential in the treatment of diabetic neuropathy.

Sensorimotor polyneuropathy associated with chronic lymphocytic leukemia, IgM antigangliosides antibody and human T-cell leukemia virus I infection.

A 65‐year‐old man presented with a sensorimotor polyneuropathy associated with B‐cell chronic lymphocytic leukemia (CLL) and immunoglobulin M (IgM) antibody to various gangliosides. Electrophysiological studies denoted significant abnormalities of motor and sensory nerve conduction. Although the pathology of sural nerve biopsy looked minimally affected, immunohistochemical studies showed specific binding of IgM to the human peripheral nerve. Our patient also had high titer of antibody to human T‐cell leukemia virus I (HTLV‐I) in both serum and cerebrospinal fluid (CSF), which might activate B‐cell–mediated immunity and facilitate the production of IgM antibody. The other unique feature is the reactivity of antibody to gangliosides. The patient had IgM antibody reactivities to gangliosides with disialosyl residue such as GT1b, GQ1b and GD3, but not to GD1b. IgM antibody to gangliosides with disialosyl residue has been reported in ataxic symptoms, but our patient failed to demonstrate ataxia. Without reactivity to GD1b, sensory ataxic neuropathy might not develop even in the presence of antibody reactive to other gangliosides with disialosyl residue.

Hypothermic neuroprotection of peripheral nerve of rats from ischemia-reperfusion injury: intraischemic vs. reperfusion hypothermia.

The pathophysiology of ischemic fiber degeneration (IFD) is not known, but mechanisms involved during nerve ischemia differ from those during reperfusion. We have previously demonstrated hypothermic neuroprotection of peripheral nerve from IFD. We now evaluate the efficacy of hypothermia in the intraischemic vs. the reperfusion period, using our established model of ischemia-reperfusion injury. Intraischemic hypothermia resulted in significant recovery of all indices (behavior score, electrophysiology and histology, P<0.01 or 0.05) while hypothermia during reperfusion period showed less improvement, significant only for the histological score compared to normothermia group (IFD index, P<0.05). Once hypothermia was applied in the ischemic period, the resultant neuroprotection continued into the reperfusion period, even if nerve temperature was then raised during the reperfusion period. These results indicate that hypothermic neuroprotection is more efficacious during the intraischemic period than during reperfusion, when a lesser degree of neuroprotection ensued.

Effect of zenarestat, an aldose reductase inhibitor, on endoneurial blood flow in experimental diabetic neuropathy of rat

The effects of zenarestat, an aldose reductase inhibitor, on endoneurial blood flow (NBF) were explored in streptozotocin-induced diabetic rats. Rats were maintained on a diet of containing 0.09% zenarestat for 8 weeks, then NBF in the sciatic nerve was measured using microelectrode hydrogen polarography. NBF in the diabetic control rats was significantly lower than values in age-matched control rats, however, NBF was not significantly altered in diabetic rats treated with zenarestat. Direct application of nitric oxide synthase inhibitor, NG-nitro-L-arginine, did not affect NBF in diabetic control rats, whereas this application significantly reduced NBF both in age-matched control and zenarestat treated diabetic rats. Considerable levels of zenarestat were confirmed in the sciatic nerve in the drug treated rats. These data suggest that aldose reductase, such as zenarestat, might restore or prevent the alteration of endoneurial blood flow resulting from an impairment of nitric oxide function.

Assessment of sudomotor dysfunction in early Parkinson's disease.

We performed a quantitative sudomotor function test on 10 patients with early Parkinsons disease (PD) and 11 age-matched control subjects. Thermal warming increased the sweat rate in both PD and controls. There was no difference in sweat rate between the forearm and the thigh in either PD or controls. In PD, thyrotropin-releasing hormone (TRH) did not increase the sweat rate, whereas it did so in the controls. These results suggest that sudomotor dysfunction in early PD is minor but that there may be an impairment of TRH-induced sympathetic response in the early stages of PD.

Comparison of electrophysiologic and autonomic tests in sensory diabetic neuropathy

We examined autonomic function in 46 patients with symmetric sensory non-insulin dependent diabetic neuropathy without autonomic symptoms and 31 age-matched control patients using the composite autonomic scoring scale (CASS) and electrophysiologic examination. The patients were divided into three groups by subjective severity of pain or numbness; 17 had slight pain or numbness, 15 had mild pain or numbness, and 14 had moderate pain or numbness. The patients in the moderate group had the following: a mild reduction in systolic and mean blood pressure (BP) within 1 minute of head-up tilt and a partial recovery after 5 minutes; an excessive fall in early phase II (IIe), an absence of late phase II (III) and reduced phase IV beat-to-beat BP responses to Valsalva maneuver (VM); a poor heart rate response to deep breathing; a reduced quantitative sudomotor axon reflex test (QSART) response in distal leg and foot; the highest CASS among the 3 groups; and reduced conduction velocity and amplitude in post-tibial nerve and sural nerve. The mild group had a mild reduction in BP during phase IIe and an absent phase III but normal phase IV overshoot during VM; a reduced QSART in the foot; a CASS between the moderate and slight groups; and reduced conduction velocity and amplitude in post-tibial nerve and reduced amplitude in sural nerve. The slight pain group had no abnormalities except for mild cardiovagal dysfunction. CASS gathered from all cases had a significant correlation with amplitude of sural nerve. These results suggest that the patients with symmetric sensory diabetic neuropathy may also have autonomic dysfunction, although they did not have any obvious autonomic symptoms, and that abnormalities in autonomic function parallel changes in somatic function in peripheral nerve. The CASS may be a sensitive tool, similar to the neurophysiologic test, for assessing diabetic neuropathy.

A small dose of the immunosuppressive agent FK506 (tacrolimus) protects peripheral nerve from ischemic fiber degeneration

The immunosuppressant agent FK506 (tacrolimus) has proven to be neuroprotective against brain ischemia, but there are no data on potential neuroprotective effects of FK506 in peripheral nerve ischemia. We examined the potential effects of two doses of FK506 in protecting peripheral nerve from ischemic fiber degeneration. Ischemia in the left sciatic nerve of the rat was produced by injecting 2 × 106 microspheres (14 μm) into the left femoral, hypogastric, and superior gluteal arteries in proportions of 47%, 37%, and 17%, respectively. After embolization, FK506 was injected into the left femoral, hypogastric, and superior gluteal arteries in doses of 9.4, 7.4, and 3.4 μg, respectively, for the high‐dose group and 4.7, 3.7, and 1.7 μg, respectively, for the low‐dose group. The control rats were injected with saline. FK506 treatment resulted in dramatic behavioral improvement in nerve function, in the number of functioning nerve fibers, and in the salvage of a majority of nerve fibers from ischemic fiber degeneration in a dose‐dependent fashion. These results suggest that a small dose of FK506 protects peripheral nerve from ischemic fiber degeneration and that it may have potential in the treatment of ischemic neuropathy.

Aging differentially modifies sensitivity of nerve blood flow to vasocontractile agents (endothelin-1, noradrenaline and angiotensin II) in sciatic nerve

This study examined the influence of the vaso-constricting agents (noradrenaline, endothelin-1 and angiotensin II) in Sprague-Dawley rats aged 2, 6 and 24 months by evaluating epineurial arteriolar vasoreactivity in response to superfused teat agents. Nerve blood flow (NBF) was measured using microelectrode H2 polarography. In 24-month-old rats, NBF was decreased and vascular resistance (VR) was increased compared with 2- and 6-month-old rats. All of the constricting agents reduced NBF in the 2-, 6- and 24-month groups, however, the effects of the constricting agents reduced significantly with age. These results suggest that during aging, there is a decline of vasoconstrictive responses to noradrenaline, endothelin-1 and angiotensin II in peripheral nerve and that these changes may be due to altered function of receptors.

A dysautonomia case of Guillain–Barré syndrome with recovery: Monitored by Composite Autonomic Scoring Scale

To investigate the usefulness of the Composite Autonomic Scoring Scale (CASS) as an indication for autonomic dysfunction with Guillain-Barré syndrome, we quantitated autonomic deficits on follow-up using CASS in a patient with Guillain-Barré syndrome who did not have any autonomic symptoms and had good clinical recovery. Using the CASS we found the patient to have mild autonomic dysfunction but with a period of recovery. The scale showed that adrenergic deficits improved quickly, sudomotor deficits recovered moderately and cardiovagal deficits did not improve. These results suggested that the patient with Guillain-Barré syndrome might have dysautonomia although she did not have any autonomic symptoms. Results also suggest that there might be difference on the degree of improvement among adrenergic, sudomotor and cardiovagal deficits in Guillain-Barré syndrome. The CASS may be a sensitive tool for the detection of autonomic dysfunction in Guillain-Barre syndrome.