Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy.

Ischemic peripheral neuropathy is a frequent, irreversible complication of lower extremity vascular insufficiency. We investigated whether ischemic peripheral neuropathy could be prevented and/or reversed by gene transfer of an endothelial cell mitogen designed to promote therapeutic angiogenesis. Intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor (VEGF) simultaneously with induction of hindlimb ischemia in rabbits abrogated the substantial decrease in motor and sensory nerve parameters, and nerve function recovered promptly. When gene transfer was administered 10 days after induction of ischemia, nerve function was restored earlier and/or recovered faster than in untreated rabbits. These findings are due in part to enhanced hindlimb perfusion. In addition, however, the demonstration of functional VEGF receptor expression by Schwann cells indicates a direct effect of VEGF on neural integrity as well. These findings thus constitute a new paradigm for the treatment of ischemic peripheral neuropathy.

Non-length dependent small fibre neuropathy/ganglionopathy.

OBJECTIVE: To describe the clinical and laboratory features of a painful non-length dependent, small fibre ganglionopathy (SFG). BACKGROUND: The syndrome of generalised SFG with early involvement of the face, trunk or proximal limbs is not well recognised and contrasts with the burning feet syndrome of small fibre neuropathy (SFN) and classical large fibre features of sensory ganglionopathy. METHODS: Retrospective case review including skin biopsies from four neuromuscular centres. Patients with pre-existing diseases associated with ganglionopathies were excluded. RESULTS: 12 men and 11 women, with an average age of 50 years, were studied. Neuropathic pain developed over days in eight and over months in the other patients. The face (n = 12), scalp (n = 10), tongue (n = 6), trunk (n = 15) and acral extremities (n = 21) were involved. Symptoms began in the hands or face before the legs in 10. The pain was characterised as burning (n = 22), prickling (n = 13), shooting (n = 13) or allodynic (n = 11). There was loss of pinprick sensation in affected regions in 19, with minimal or no loss of large fibre sensibility. Laboratory findings included abnormal glucose metabolism in six patients, Sjögren syndrome in three and monoclonal gammopathy, sprue and hepatitis C infection in one each, with the remainder idiopathic. Sensory nerve action potentials were normal in 12 and were reduced in the hands but normal in the legs in six. Skin biopsy in 14 of 17 showed reduced nerve fibre density in the thigh equal to or more prominent than in the calf. Two of seven patients improved with immune therapies, 13 symptomatically with analgesic medications and the remainder had little improvement. Ten considered the pain disabling at the last follow-up (mean 2 years). CONCLUSION: The pattern of symmetric, non-length dependent neuropathic pain with face and trunk involvement suggests a selective disorder of the dorsal ganglia cells subserving small nerve fibres. It can be distinguished from distal SFN. A potential metabolic or immune process was detected in half of the cases and the disorder was often refractory to treatment.

Reversal of experimental diabetic neuropathy by VEGF gene transfer.

The pathogenetic basis for diabetic neuropathy has been enigmatic. Using two different animal models of diabetes, we have investigated the hypothesis that experimental diabetic neuropathy results from destruction of the vasa nervorum and can be reversed by administration of an angiogenic growth factor. Nerve blood flow, as measured by laser Doppler imaging or direct detection of a locally administered fluorescent lectin analogue, was markedly attenuated in rats with streptozotocin-induced diabetes, consistent with a profound reduction in the number of vessels observed. A severe peripheral neuropathy developed in parallel, characterized by significant slowing of motor and sensory nerve conduction velocities, compared with nondiabetic control animals. In contrast, 4 weeks after intramuscular gene transfer of plasmid DNA encoding VEGF-1 or VEGF-2, vascularity and blood flow in the nerves of treated animals were similar to those of nondiabetic control rats; constitutive overexpression of both transgenes resulted in restoration of large and small fiber peripheral nerve function. Similar experiments performed in a rabbit model of alloxan-induced diabetes produced comparable results. These findings support the notion that diabetic neuropathy results from microvascular ischemia involving the vasa nervorum and suggest the feasibility of a novel treatment strategy for patients in whom peripheral neuropathy constitutes a secondary complication of diabetes.

Further regional variants of acute immune polyneuropathy. Bifacial weakness or sixth nerve paresis with paresthesias, lumbar polyradiculopathy, and ataxia with pharyngeal-cervical-brachial weakness.

OBJECTIVE: To describe four syndromes of acute regional weakness with clinical, spinal fluid, and electrophysiologic similarities to the acute immune polyneuropathy of Guillain-Barré syndrome. DESIGN: Case series of personally examined patients. RESULTS: Seven patients are described: four with facial diplegia and distal limb paresthesias, one with sixth nerve palsy and distal paresthesias, one with bilateral lumbar polyradiculopathy, and one with combined Fisher's syndrome and pharyngeal-cervical-brachial weakness. These self-limited illnesses, which evolved over days or weeks, involved acellular cerebrospinal fluid with raised protein concentration and electrophysiologic findings that were consistent with a demyelinating polyneuropathy. CONCLUSIONS: The first three regional variants of Guillain-Barré syndrome may cause diagnostic difficulty, particularly at the onset of illness, and the fourth links Fisher's syndrome with the typical syndrome. The consistently bilateral weakness of Guillain-Barré syndrome and its regional variants and the absence of a monoparetic or hemiparetic pattern suggest that the pathologic process occurs in the same single or contiguous groups of nerves on both sides of the sagittal plane but is not randomly distributed in the peripheral nervous system.

Unusual clinical variants and signs in Guillain-Barré syndrome.

Limited regional forms of the Guillain-Barré syndrome (GBS) and unusual focal signs or symptoms that resemble other illnesses are described: pharyngeal-cervical-brachial weakness with ptosis, sparing power, and reflexes in the legs; paraparesis with normal power and reflexes in the arms; early severe ptosis without other signs of oculomotor weakness; and acute severe midline back pain at the onset. The first two variants did not progress to typical generalized GBS, delaying the proper diagnosis. Regional and functional variants suggest that the pathologic, and perhaps immunologic abnormalities of GBS can be localized and selective.

Accelerated neuropathy of renal failure.

OBJECTIVE: To describe a syndrome of rapidly evolving polyneuropathy in patients with severe renal failure. DESIGN: Retrospective case series of four patients. SETTING: In-hospital evaluations and personal examinations of patients. PATIENTS: Four patients with severe or end-stage renal failure who were receiving peritoneal dialysis. RESULTS: These patients had an acute or subacute syndrome characterized by generalized limb weakness over days or weeks, severe imbalance, diminished reflexes, and numbness. Spinal fluid protein levels were elevated and some demyelinating features were noted on electrophysiological testing. Improvement occurred with more frequent peritoneal dialysis in one patient and transplantation in another, but the neuropathy progressed in the other two in whom diabetes may have played a role. CONCLUSION: This partly reversible acute uremic neuropathy, which is probably caused by the metabolic disturbances of end-stage renal failure, simulates Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy and may be complicated by diabetic neuropathy.

Campylobacter diarrhea and Guillain-Barré syndrome.

Four of 106 consecutive patients with acute Guillain-Barré syndrome had preceding bacterial enteritis caused by Campylobacter jejuni. One had a severe illness with axonal damage and poor outcome; three had typical courses with good recovery. Preceding illnesses in the other 102 patients were the following: diarrhea in nine (with negative stool cultures in five), upper respiratory tract infections in 46, hepatitis in six, other infectious illnesses in eight, and none in 33. Eight patients previously reported with Campylobacter associated with Guillain-Barré syndrome, and the serologic and clinical diagnosis of Campylobacter enteritis in this context, are reviewed.

Ocular dipping in anoxic coma.

Patients with anoxic coma had a cyclic, downward dipping motion of the eyes. The sign is different from ocular bobbing, seizure-related eye deviation, oculogyric crisis, and roving eye movement. Its distinguishing characteristics are slow downward with rapid upward movement, a nadir at the extreme of downgaze, and spontaneous roving horizontal eye movements. Based on necropsy findings in one case and lesions of the basal ganglia evident on computerized tomographic scan in another, it is proposed that cortical dysfunction with damage to the basal ganglia may cause ocular dipping.

Ischemic compression paresthesias in Guillain-Barré syndrome.

An experiment in nine patients tested the similarities and interactions between the paresthesias of Guillain-Barré syndrome (GBS) and tourniquet-induced compression paresthesias. During brachial compression, GBS paresthesias diminished in five of seven patients and new paresthesias occurred in two patients with purely motor GBS. Beginning 1 to 4 minutes after release of the cuff, all patients had new paresthesias, distinguishable from GBS symptoms. The novel finding was that GBS paresthesias diminished or ceased during the postcompression period in five of seven patients. Demyelinated peripheral nerves in GBS apparently can generate and transmit the spontaneous activity associated with paresthesias in the postcompression period. Interference occurs between the two types of paresthesias, possibly because both are caused by spontaneous ectopic activity in tactile nerves.

Self-audible venous bruits and high jugular bulb.

The association between self-audible bruits and ipsilateral high jugular bulbs was demonstrated in five patients, emphasizing the benign nature of the condition. Symptoms included a unilateral pulsatile "whooshing" that was eliminated by gentle pressure on the neck or extreme head rotation to the symptomatic side and was enhanced by conditions that increased cardiac output. The bruits were not audible to examiners. On the basis of one patient with an intracranial tumor, it is proposed that raised intracranial pressure alone, in the absence of a jugular bulb abnormality, is an insufficient explanation for a venous self-audible bruit.

Early Guillain-Barré syndrome without inflammation.

A patient with typical acute Guillain-Barré syndrome died 72 hours after his first symptoms occurred, and an autopsy was performed 8 hours after his death. Extensive sampling of cranial and peripheral nerves, sensory ganglia, and autonomic nerves showed only minimal inflammatory lymphocytic and macrophage infiltrates. This case, one of the earliest studied extensively, represents an extreme example of a noninflammatory mechanism that has been proposed in some cases of Gullain-Barré syndrome.

Proposed mechanism of ataxia in Fisher's syndrome.

A patient with Fisher's variant of Guillain-Barré syndrome had severe limb ataxia. Joint position sense was diminished proximally but normal distally. In contrast, muscle proprioceptive function, studied electrophysiologically by recording silent periods in proximal muscles, appeared to be normal. A disparity between proprioceptive information from muscle spindles and kinesthetic information from joints and other proprioceptors may be a mechanism of ataxia, based solely on abnormalities of peripheral nerve function. A CNS lesion is, therefore, not necessary to explain cerebellar ataxia in Fisher's syndrome.

Progressive necrotic myelopathy: clinical course in 9 patients.

OBJECTIVE: To review the clinical, laboratory, and radiological findings of 9 patients who had progressive idiopathic myelopathy with evidence of spinal cord necrosis. DESIGN AND METHODS: We reviewed personally examined cases of myelopathy that fulfilled the following criteria: (1) regional loss of reflexes, flaccidity, and muscle atrophy; (2) magnetic resonance imaging showing a shrunken or cavitated cord without evidence of arteriovenous malformation; (3) electromyogram showing denervation over several contiguous spinal cord sgements with preservation of sensory potentials in some cases; and (4) the absence of evidence of systemic disease or neoplasm. RESULTS: The illness began in these patients after the age of 40 years, with prominent burning or tingling limb pain, occasionally with radicular features or with less well-defined back, neck, or abdominal pain. Leg or infrequently arm weakness appeared concurrently or soon after the onset of pain. The most distinctive feature was a saltatory progression of symptoms, punctuated by both acute and subacute worsenings approximately every 3 to 9 months, culminating in paraplegia or tetraplegia. The distinguishing clinical findings, together indicative of destruction of gray matter elements of the cord, were limb atrophy, persistent areflexia, and flaccidity. The concentration of cerebrospinal fluid protein was typically elevated between 500 g/L and 1000 g/L, without oligoclonal bands, accompanied infrequently by pleocytosis. Magnetic resonance imaging showed features suggesting cord necrosis, specifically swelling, T2-weighted hyperintensity, and gadolinium enhancement over several spinal cord segments, succeeded months later by atrophy in the same regions. Necrosis of the cord was found in biopsy material from one patient and postmortem pathology in another case, but inflammation and blood vessel abnormalities were absent. Only 2 patients had prolonged visual evoked responses. The disease progressed despite immune-modulating treatments although several patients had brief epochs of limited improvement. CONCLUSIONS: The saltatory course, prolonged visual evoked responses in 2 patients, and a cranial abnormality on magnetic resonance imaging in another, raised the possibility of a link to multiple sclerosis. However, the normal cranial magnetic resonance imaging scans in 6 other patients, uniformly absent oligoclonal bands, and poor response to treatment were atypical for multiple sclerosis. On the basis of shared clinical and laboratory features, idiopathic progressive necrotic myelopathy is indistinguishable from a limited form of Devic disease.

Pain in Guillain-Barré syndrome.

The clinical features of pain were prospectively analyzed in 29 consecutive patients with Guillain-Barré syndrome (GBS). Sixteen (55%) had characteristic pain early in the illness described as similar to the muscular discomfort following exercise ("charley horse"). Pain preceded weakness by one to five days in four patients. The anterior and posterior aspects of the thighs, the buttocks, and the low part of the back were most frequently affected. Pain was frequently worse at night. Specific clinical signs or electrophysiologic abnormalities were not associated with pain, but serum creatine kinase level was elevated in ten of 13 patients with pain and only one of eight without pain. A review of previously reported pathologic material in five patients with GBS failed to disclose a relation between inflammation of dorsal root ganglia and pain. These results suggest that alterations in muscle related to neurogenic changes may cause the typical pain of GBS.

Mechanism of pseudotumor in Guillain-Barré syndrome.

A patient with pseudotumor cerebri and Guillain-Barré syndrome was studied with serial measurements of pressure-volume index, CSF outflow resistance (Ro), and CSF production rate. The results were comparable to findings in previous cases of idiopathic pseudotumor. Although Ro was elevated and progressively diminished as the pseudotumor syndrome improved, the extent of elevation in Ro was inadequate to account for raised CSF pressure. These results suggest an alternative explanation for pseudotumor based on raised effective venous pressures at points of CSF outflow that are passively reflected in raised CSF pressure. A parallel rise in vascular and CSF pressure may also explain why patients with pseudotumor tolerate such high intracranial pressures.

Brain edema after stroke. Clinical syndrome and intracranial pressure.

We studied prospectively the syndrome of brain edema after a large infarction in 12 patients. The major symptom was drowsiness, which began on the first to fourth day after the ictus and which was accompanied by asymmetry in pupillary size of 0.5 to 2.0 mm in eight patients, periodic breathing in seven, and Babinski's sign contralateral to the hemiparesis in five. These accompanying signs appeared several hours after drowsiness in some patients. Seven patients had brain death, one died of sepsis after recovering from brain swelling, and only four survived. In six patients in whom intracranial pressure was continuously measured, levels persistently above 15 mm Hg were associated with eventual brain death (four patients) and levels below 15 mm Hg were associated with survival (two patients).

Blood pressure fluctuations in the dysautonomia of Guillain-Barré syndrome.

A 76-year-old man with severe Guillain-Barré syndrome had extremes of hypotension alternating with hypertension. His blood pressure paralleled both systemic vascular resistance and cardiac output. Heart rate, rather than stroke volume, was the major determinant of cardiac output over a wide range of blood pressures. It was at times invariant for several hours and was unresponsive to carotid massage or respiratory cycles, but slowed slightly with each episode of hypotension. Trend monitoring indicated that hypotension preceded reductions in pulmonary artery diastolic pressure. These findings suggest that hypotension resulted from a vasodepressor response with a vagotomized heart and that hypertension was the result of increased sympathetic activity. Both extremes were caused by parallel changes in vascular resistance and heart rate. Dysfunction of baroreflex buffering may have accounted for the rapid swings in pressure.

Acute relapsing Guillain-Barré syndrome after long asymptomatic intervals.

Five patients who recovered from an initial episode of Guillain-Barré syndrome had acute relapses 4, 10, 15, 17, and 36 years later, respectively. Two patients had multiple subsequent relapses. The antecedent illnesses, distribution of weakness, and clinical courses of each relapse were similar for each patient, except that relapses in three patients were briefer than the initial episode. One patient had asymptomatic sarcoidosis. Pharyngeal, oculomotor, and diaphragmatic weakness requiring a ventilator were common. Complete recovery or mild residual deficits, return of reflexes, normal cerebrospinal fluid protein at the onset of recurrent episodes, and normal or virtually normal nerve conduction velocities at various times distinguished these patients from those with more typical chronic relapsing inflammatory polyneuropathy.

Nonpoliovirus poliomyelitis simulating Guillain-Barré syndrome.

BACKGROUND: Paralytic poliomyelitis due to the wild-type poliovirus has been eradicated in the United States because of effective immunization programs. In the postvaccination era, most cases are caused by other RNA viruses, such as coxsackievirus or echovirus. The condition usually begins with a fever and upper respiratory tract or gastrointestinal tract symptoms that progress to a "paralytic" phase characterized by limb weakness, areflexia, and, occasionally, respiratory failure that superficially resemble Guillain-Barré syndrome. OBJECTIVE: To describe 2 patients with nonpoliovirus poliomyelitis and highlight the findings on magnetic resonance imaging of the spinal cord to distinguish these cases from variants of Guillain-Barré syndrome. DESIGN AND SETTING: Case series from an academic medical center. PATIENTS: Following a viral illness, the patients, aged 35 and 50 years, had painless, progressive, asymmetrical weakness in the arms followed by respiratory failure in one patient, and generalized limb weakness in the other patient, reaching a nadir in 1 week. Both patients had fevers but no signs of meningitis at onset. Tendon reflexes were absent or reduced in affected regions. The cerebrospinal fluid findings were as follows: mononuclear leukocyte counts of 100 000 cells/mm(3) and 700 000 cells/mm(3), respectively, and the protein level was above 10 g/dL in both patients. Compound muscle action potential amplitudes were reduced in some nerves with active denervation in clinically affected muscles, and F-responses were absent but there were no other demyelinating features. Magnetic resonance imaging showed discrete T2-weighted signal changes of the ventral horns of the spinal cord, and one had elevated coxsackievirus titers in the serum. There was little recovery and significant atrophy in weak muscles after 3 years. CONCLUSIONS: The poliomyelitis syndrome still occurs in adults in developed countries. It has superficial similarities to a motor axonal variant of Guillain-Barré syndrome but can be distinguished by clinical, cerebrospinal fluid, and, perhaps specifically, magnetic resonance imaging characteristics.

Mild Guillain-Barré syndrome.

BACKGROUND: The unpredictability of the early course of Guillain-Barré syndrome (GBS) makes it difficult to determine which patients' conditions will worsen under observation. Most large randomized treatment trials for GBS have used an inability to walk as the enrollment criterion. Consequently, little is known about the treatment of those patients with milder degrees of affection. OBJECTIVES: To determine the approximate frequency of mild GBS with the persistent ability to walk and to see if there were features that predicted that the illness would remain mild. SETTING: A registry of patients with GBS seen on the wards and in the neurology clinic from January 1,1992, to May 1, 2000, in a 400-bed community teaching hospital. PATIENTS: Twelve (4.7%) of 254 patients in our case series were able to walk throughout their illness. Eight had been treated with plasmapheresis or intravenous immunoglobulin; the others were observed without treatment. RESULTS: There was no age, sex, or seasonal preponderance in comparison with large case series that included cases of all severities. Nine of 12 patients had a preceding respiratory tract infection, 10 had paresthesias, 7 had prominent pain, and 9 had ataxia. Seven of 10 patients who were examined had normal cerebrospinal fluid protein levels. It took 8 days, on average, to reach the maximal degree of weakness. One additional treated patient, excluded from our case series, had mild weakness for the first 3 weeks and subsequently worsened with a relapsing course more typical of chronic inflammatory demyelinating polyneuropathy. Eleven patients demonstrated proximal, intermediate, or distal conduction block, and only 3 had a mild degree of denervation. There were no distinguishing clinical or electrophysiologic features between treated and untreated patients with mild GBS and, except for the mild degree of affection and the absence of substantial electromyographic changes of axonal disruption, there were no important differences between these mild cases as a group and patients who developed more severe GBS. CONCLUSIONS: Cases of mild GBS reach a clinical nadir in a similar time to those with more severe disease. Treatment may be unnecessary in patients who are able to walk during the second week of illness, but observation until approximately the eighth day seems appropriate to be certain that the illness does not progress. In all likelihood there are mild cases of GBS that never come to the attention of a neurologist.