Steven H. Horowitz

Early stroke treatment associated with better outcome The NINDS rt-PA Stroke Study

Background The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study showed a similar percentage of intracranial hemorrhage and good outcome in patients 3 months after stroke treatment given 0 to 90 minutes and 91 to 180 minutes after stroke onset. At 24 hours after stroke onset more patients treated 0 to 90 compared to 91 to 180 minutes after stroke onset had improved by four or more points on the NIH Stroke Scale (NIHSS). The authors performed further analyses to characterize the relationship of onset-to-treatment time (OTT) to outcome at 3 months, early improvement at 24 hours, and intracranial hemorrhage within 36 hours. Methods Univariate analyses identified potentially confounding variables associated with OTT that could mask an OTT–treatment interaction. Tests for OTT–treatment interactions adjusting for potential masking confounders were performed. An OTT–treatment interaction was considered significant if p ≤ 0.10, implying that treatment effectiveness was related to OTT. Results For 24-hour improvement, there were no masking confounders identified and there was an OTT–treatment interaction (p = 0.08). For 3-month favorable outcome, the NIHSS met criteria for a masking confounder. After adjusting for NIHSS as a covariate, an OTT–treatment interaction was detected (p = 0.09): the adjusted OR (95% CI) for a favorable 3-month outcome associated with recombinant tissue-type plasminogen activator (rt-PA) was 2.11 (1.33 to 3.35) in the 0 to 90 minute stratum and 1.69 (1.09 to 2.62) in the 91 to 180 minute stratum. In the group treated with rt-PA, after adjusting for baseline NIHSS, an effect of OTT on the occurrence of intracranial hemorrhage was not detected. Conclusions If the NINDS rt-PA Stroke Trial treatment protocol is followed, this analysis suggests that patients treated 0 to 90 minutes from stroke onset with rt-PA have an increased odds of improvement at 24 hours and favorable 3-month outcome compared to patients treated later than 90 minutes. No effect of OTT on intracranial hemorrhage was detected within the group treated with rt-PA, possibly due to low power.

Peripheral nerve injury and causalgia secondary to routine venipuncture

Article abstract I examined 11 patients with upper-extremity causalgia secondary to peripheral nerve injury occurring during routine venipuncture. The nerves affected were the medial (n = 5) and lateral (n = 2) antebrachial cutaneous in the antecubital fossa, the superficial radial at the wrist (n = 2), and the dorsal sensory branches in the hand (n = 2). Anatomically, nerves lie on a plane just beneath and in close proximity to veins, making them vulnerable to injury during the procedure.

Thymomas in patients with myasthenia gravis.

The records of 141 patients with myasthenia gravis who had thymomas were reviewed. In this series there were 69 noninvasive tumors and 52 invasive tumors. The five year survival for all patients was 60%, with the invasive group demonstrating a poorer prognosis than the noninvasive. The remission rates for the whole group (both invasive and noninvasive) of myasthenics was quite low (7%). Although the overall survival of this series of patients was relatively high, it is felt that by earlier diagnosis and a more aggressive surgical approach their prognosis will be even better.

Treatment of sporadic hemiplegic migraine with calcium-channel blocker verapamil

Gene mutations within the P/Q type neuronal calcium channel in familial hemiplegic migraine (FHM) suggest a therapeutic role for calcium-channel blockade. The authors have previously reported abortive therapy of FHM with IV verapamil. Here the authors describe four cases of sporadic hemiplegic migraine (SHM) responsive to verapamil, administered either orally or IV. The findings indicate that verapamil is effective therapy for both SHM and FHM.

Ischemia and sensory nerve conduction in diabetes mellitus

Sensory conduction along the median nerve was evaluated during 30 minutes of ischemia in patients with diabetes mellitus. There was abnormal persistence of the sensory evoked potential in 19 of 22 diabetic patients, but not in normal controls, patients with nonmetabolic neuropathies, or 5 of 6 patients with motor neuron diseases. There was an excellent correlation between ischemic resistance and effective control of glucose metabolism, as manifested by Hb A1C levels. These data suggest that abnormal ischemic resistance in diabetes may be the most sensitive indicator of peripheral neural dysfunction even when there are no other electrophysiologic or clinical abnormalities.

Cholinergic dysautonomia and Eaton-Lambert syndrome.

Cholinergic autonomic function was abnormal in a 47-year-old woman with Eaton-Lambert syndrome (ELS), not associated with carcinoma. Pupillary constriction to light and accommodation, sweating, lacrimation, and salivation were all affected. There was no evidence of Sjogren syndrome or botulinum intoxication. The defect of acetylcholine release from presynaptic terminals in the Eaton-Lambert syndrome may not be restricted to the neuromuscular junction of skeletal muscle.

Electrophysiologic diagnosis of myasthenia gravis and the regional curare test

Two hundred and fifty consecutive patients were evaluated for myasthenia gravis with repetitive supramaximal stimulation of peripheral nerves and regional curare administration when necessary. Among patients with definite generalized myasthenia gravis, 72 percent had abnormal responses to repetitive supramaximal stimulation alone and another 17 percent had abnormal responses after regional curare administration. Among those with possible generalized myasthenia gravis, 15 percent had abnormal responses to repetitive supramaximal stimulation and another 12 percent had abnormal responses after regional curare administration. Of those with only ocular symptoms, 46 percent had abnormal responses to repetitive supramaximal stimulation before or after regional curare administration, suggesting generalized involvement. Myasthenia gravis has not developed subsequently in any of the equivocal patients with negative electric tests. We have found these electric procedures to be simple, safe, and at least as effective as other methods in diagnosing myasthenia gravis.

Familial hemiplegic migraine and its abortive therapy with intravenous verapamil

Familial hemiplegic migraine (FHM) is an inheritable subset of migraine headache with motor paralysis. In 1996, gene mutations within the P/Q gated neuronal calcium channel α1A subunit (CACNA1A) were identified in patients with FHM.1 Subsequent genetic studies established multiple missense mutations in CACNA1A and genetic linkage to chromosomes 19p13 and 1q in various families with FHM.2-4⇓⇓ These findings suggest calcium channel dysfunction and implicate a role for calcium channel blockers in the treatment of hemiplegic migraine. We report a case of FHM and its abortive therapy with IV verapamil. A 28-year-old white woman had classic migraine headaches with visual aura since age 11. The headaches were throbbing in nature and accompanied by nausea and vomiting. They usually lasted for 3 to 4 hours and occurred every 4 to 5 months. However, during the past few months the patient started to have progressively …

Venipuncture-induced neuropathic pain: the clinical syndrome, with comparisons to experimental nerve injury models

Venipuncture, the most frequently performed invasive medical procedure (Horowitz, 1994), is usually benign, producing only transitory mild discomfort. However, several case series (Berry and Wallis, 1977; Newman and Waxman, 1996; Horowitz, 1994, 2000; Newman, 2001) and individual patient reports (see Horowitz, 1994) document nerve injuries consequent to the procedure. While such injuries are reportedly rare, 1:21 000–26 700 (Berry and Wallis, 1977; Newman and Waxman, 1996) or 1:6250–6928 (Newman, 2001), some can be severe with permanent residua, the most disturbing being chronic neuropathic pain – the Complex Regional Pain Syndrome Type 2 (CRPS-II), or causalgia. It is defined (Merskey and Bogduk, 1994), as a persistent shooting, electrical, burning pain in the distribution of the affected nerve with frequent spread to adjoining areas, often in association with autonomic and motor dysfunctions. Recent articles in this journal (Eliav et al., 1999; Pitcher et al., 1999; Li et al., 2000; Eschenfelder et al., 2000; Decosterd and Woolf, 2000; Han et al., 2000; Liu et al., 2000a,b,c; Habler et al., 2000; Lindenlaub and Sommer, 2000), employing various peripheral nerve injury models and methodologies in the rat, have studied the pathophysiology of injury-induced neuropathic pain and associated phenomena (mechanosensitivity, allodynia, hyperalgesia). While sites and types of experimental injury differ, each study links the pain to ectopic discharges in primary afferent neurons and ‘central sensitization’, i.e. increased excitability of spinal cord dorsal horn neurons – changes in receptive field properties, decreased thresholds and increased responsiveness to peripheral input (Woolf, 1996). Two sources of discharges are currently favored (Gold, 2000): (1) injured afferent fibers at the lesion site and/or their dorsal root ganglia (DRG) soma (Devor and Seltzer, 1999; Han et al., 2000; Liu et al., 2000a,c); or (2) uninjured afferent fibers consequent to peripheral interactions with injured afferents undergoing Wallerian degeneration (Li et al., 2000; Eschenfelder et al., 2000). In either case, post-injury, spontaneous pain appears due to spontaneous electrogenesis, and pain with movement or palpation secondary to mechanosensitivity at these sites. Innocuous or noxious stimulation in the dermatomal distribution of surviving uninjured Ab low threshold afferent mechanoreceptors trigger heightened sensitivity (allodynia or hyperalgesia, respectively) (Woolf, 1996), due to spinal amplification. This central sensitization may be initiated and maintained by peripheral impulse generation (‘ectopia’) from injured fibers (Devor and Seltzer, 1999; Tal et al, 1999; Liu et al., 2000b), or, conversely, a loss of input to the dorsal horn (deafferentation hypersensitivity) (Eschenfelder et al., 2000). Venipuncture-induced CRPS-II/causalgia is, perhaps, the most paradigmatic human neuropathic pain that can follow acute nerve trauma. It has many similarities to the experimental situation: the procedure – venipuncture – and instrument involved – hypodermic needle – are always identical; the exact timing of injury is known; and the same cutaneous sensory nerves are always involved, i.e. medial or lateral antebrachial cutaneous nerves in the antecubital fossa, superficial radial nerve at the wrist, or dorsal sensory nerves of the hand. As our current concepts of the pathophysiology and treatment of human neuropathic pain are inadequate, it is useful to relate the hypotheses discussed to the clinical venipuncture syndrome, specifically the onset and duration of symptoms and signs, type of nerve fibers affected, and sympathetic nervous system effects.

Recent clinical advances in diabetic polyneuropathy

Purpose of review Recent dramatic increases in the incidence and prevalence of diabetes make an understanding of chronic symmetric sensorimotor diabetic polyneuropathy, the most common and problematic of chronic diabetic complications, essential for a wide range of medical practitioners. Recent findings The demonstration of neuropathic dysfunction in patients with prediabetes or impaired glucose tolerance emphasizes the susceptibility of peripheral nerve fibers, especially small A delta fibers and C fibers, to relatively mild, short-duration hyperglycemia. New testing can reveal peripheral nerve dysfunction prior to clinical neuropathic symptoms and signs. In the absence of effective medications to halt or reverse nerve damage or promote nerve regeneration, early diagnosis of diabetic polyneuropathy, followed by tight glycemic control with diet and exercise, offers the best opportunity to prevent progressive symptoms of sensory loss, pain, autonomic dysfunction, ulcerations, and amputations. Some patients with impaired glucose tolerance have a reversal of neuropathic features with tight glycemic control. Nonpharmacologic therapies for neuropathic pain in diabetic polyneuropathy appear promising. Summary Tight glycemic control, especially early in diabetes, is the best approach to minimizing the prevalence and severity of diabetic polyneuropathy and makes research into the deleterious effects of even mild hyperglycemia imperative.