CSF protein biomarkers for proximal axonal damage improve prognostic accuracy in the acute phase of Guillain-Barré syndrome.

Early predictors of prognosis in Guillain-Barré syndrome (GBS) are needed to identify patients who are likely to make a poor recovery and to guide therapeutic decision-making in the acute phase. Here we investigate whether axonal protein biomarkers released into the cerebrospinal fluid (CSF) following proximal axonal damage improve the early prognostic accuracy in GBS. A prospective multicenter study including 132 patients (38 GBS, 38 neurological controls, 42 headaches, 14 chronic inflammatory demyelinating neuropathy). CSF levels of axonal [neurofilament (NfH) and tau] and glial (S100B and glial fibrillary acidic protein) protein biomarkers were measured on admission. Nerve conduction studies were performed at the time of lumbar puncture and patients were classified according to neurophysiological criteria. Outcome was assessed on the Hughes functional score (F-score). Poor outcome was defined as the inability to walk independently (F-score > or = 3). High NfH levels (>0.73 ng/ml) predicted poor outcome (P = 0.01) with an odds ratio of 7.3 and correlated with the outcome F-score (R = 0.51, P < 0.01), as did hTau levels (R = 0.47, P < 0.01). Patients with poor outcome had significantly higher CSF NfH (median 1.78 ng/ml) when compared to those with good outcome (0.03 ng/ml) or all of the control groups (neurological controls 0.18 ng/ml, headaches 0.06 ng/ml, chronic inflammatory demyelinating neuropathy 0.05 ng/ml). Except for age (P < 0.05) and need for ventilatory support (P < 0.05), none of the other features reliably predicted outcome. Improved prognostic accuracy in the acute phase of GBS seems possible using CSF NfH levels.

CSF neurofilament levels: a potential prognostic marker in Guillain-Barré syndrome.

Long-term morbidity from Guillain-Barré syndrome (GBS) is caused by axonal damage. This prospective study demonstrated that neurofilaments (NfHs), a biomarker for axonal damage, were of prognostic value in GBS. CSF NfH levels correlated with the F score and Medical Research Council summed score and were higher in patients with neurophysiologic evidence of axonal degeneration compared to those without. Pathologically high CSF NfH levels (>0.73 ng/mL) predicted worse motor and functional outcome.

Primary sciatic nerve lymphoma: a case report and review of the literature.

A patient with primary B cell non-Hodgkin's lymphoma of the sciatic nerve is described. He presented with neuropathic symptoms in the left leg, initially diagnosed as tarsal tunnel syndrome. Magnetic resonance imaging (MRI) identified the abnormality in the sciatic nerve. A fascicular biopsy of the sciatic nerve showed a diffuse large B cell non-Hodgkin's lymphoma. The patient was treated with chemotherapy and rituximab (anti-CD20 monoclonal antibody). Four months later he was in remission, and remains so 48 months from presentation. Primary lymphoma of single peripheral nerves may be a unique subtype of extranodal lymphoma, which usually follows an aggressive course and has a variable response to current therapeutic strategies. MRI is useful, alongside electrophysiological studies, in patients with atypical peripheral nerve symptoms.

Chronic inflammatory demyelinating polyradiculoneuropathy: MRI study of brain and spinal cord.

CNS demyelinating lesions have been reported in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). There are no studies of cord atrophy in CIDP. Ten patients with CIDP underwent brain and spinal cord MRI to investigate CNS demyelination and cord atrophy. No CNS demyelination was found, but the mean cervical cord area was significantly smaller in CIDP patients vs control subjects. Spinal cord atrophy may be related to degeneration secondary to axonal loss.

Distal excitability properties of median motor axons.

Excitability properties were recorded from 14 volunteers following stimulation of the recurrent motor branch of the median nerve in the palm. Distal stimulation resulted in significantly lower strength-duration time constant and lower threshold during prolonged hyperpolarization than did wrist stimulation in the same subjects. These differences may be geometric in origin or alternatively may arise from functional changes distally, particularly reduced expression of persistent Na(+) conductances and more hyperpolarization-activated current. Excitability studies using palm stimulation provide information closer to the neuromuscular junction, where membrane properties are preferentially affected in a variety of clinical conditions.

Clinical evaluation of excitability measures in sensory nerve.

A recently described method for recording multiple excitability parameters of human motor nerves has been adapted to the study of sensory nerves. The protocol measures stimulus-response behavior using two stimulus durations (from which the distribution of strength-duration time constants is estimated), threshold electrotonus to 100 ms polarizing currents, a current-threshold relationship (indicating inward and outward rectification), and the recovery of excitability following supramaximal activation. The method was tested on 50 healthy volunteers, stimulating the median nerve at the wrist and recording the antidromic compound sensory nerve action potential (SNAP) from digit 2. The excitability measurements were similar, where comparisons were possible, with published sensory nerve data, and confirmed differences from motor nerves, particularly in strength-duration behavior and recovery cycle, likely to reflect functional differences between sensory and motor nerves. Although slower than for motor nerves, the sensory nerve recordings were sufficiently quick (16 to 18 min) to allow them to be included in routine clinical studies. We propose that this method, which provides quite different and complementary information about nerve function to conventional conduction studies, provides a useful new approach for exploring the pathophysiology of sensory neuropathies.

Transcarpal motor conduction velocity in carpal tunnel syndrome.

Transcarpal motor conduction to abductor pollicis brevis (APB) was evaluated in 43 patients (70 hands) with suspected carpal tunnel syndrome (CTS). Transcarpal motor conduction was abnormal in 80% of hands compared with 11.5% with prolongated distal motor latency from wrist stimulation. Transcarpal motor conduction was comparable in sensitivity with transcarpal sensory conduction and 2nd lumbrical-interosseous latency difference. Transcarpal motor conduction is a sensitive test for diagnosis of CTS. Sensory fibers were no more susceptible than motor fibers to compression in the carpal tunnel, and fibers to APB were as susceptible as those to the 2nd lumbrical muscle.

Salbutamol treatment in a patient with hyperkalaemic periodic paralysis due to a mutation in the skeletal muscle sodium channel gene (SCN4A).

A 35 year old woman with clinical features of hyperkalaemic periodic paralysis confirmed on provocative exercise testing was investigated. DNA sequence analysis of the gene for the alpha-subunit of the skeletal muscle voltage gated sodium channel (SCN4A) on chromosome 17q23 identified a point mutation at nucleotide position 2188. This results in a threonine to methionine substitution at amino acid position 704. The patient was intolerant of diuretic medication but showed a striking clinical and electrophysiological improvement with salbutamol therapy. Treatment with beta-adrenergic agents should be considered in patients with hyperkalaemic periodic paralysis who are intolerant of, or resistant to, diuretic medications.

The sympathetic skin response in peripheral autonomic failure--evaluation in pure failure, pure cholinergic dysautonomia and dopamine-beta-hydroxylase deficiency.

The sympathetic skin response (SSR) detects changes in the electrical potential in the skin in response to physiological and electrical stimuli and, therefore, may indicate the integrity of sympathetic cholinergic neural pathways to sweat glands. This has been evaluated in 21 patients with three forms of peripheral autonomic failure. Of these, 15 had pure autonomic failure (PAF) without additional neurological features; investigations indicated both sympathetic and parasympathetic failure. Four patients had pure cholinergic dysautonomia (PCD), with clinical and laboratory features indicating only cholinergic failure. Two siblings had dopamine-beta-hydroxylase (DBH) deficiency with only sympathetic adrenergic failure. None was on drugs affecting cholinergic function. Ten normal individuals were aged-matched with PAF patients and studied as controls. The SSR was recorded from the palmar hand and plantar foot surfaces, using previously described techniques, in response to physiological (auditory, cough and inspiratory gasp) and electrical stimuli. Nerve conduction studies excluded an associated motor or sensory neuropathy. The SSR was present in all normal individuals, and in both patients with DBH deficiency who had preserved cholinergic and sudomotor function, It was absent in all 15 PAF and all four PCD patients with impaired cholinergic function. Therefore, we conclude that the SSR reflected sympathetic cholinergic function in these three different groups with peripheral autonomic failure.

An open-labelled clinical and electrophysiological study of 3,4 diaminopyridine in the treatment of fatigue in multiple sclerosis.

We studied the electrophysiological parameters of motor performance in eight patients with multiple sclerosis and troublesome fatigue, before and after treatment with 3,4-diaminopyridine. Symptomatic fatigue was evaluated by the Krupp Fatigue Severity Score and motor performance of adductor pollicis by transcranial magnetic stimulation, rapid voluntary movements and a fatiguing exercise test of a sustained 45-s isometric contraction. The motor tests revealed baseline abnormal motor function and substantial central fatigue. After a 3-week course of 3,4-diaminopyridine (25-60 mg/day), six out of the eight patients reported substantial improvement in fatigue and the group showed slightly less fatigue on the exercise test. Other electrophysiological tests of motor function were unchanged. The findings suggest that 3,4-diaminopyridine may play a role in the symptomatic treatment of fatigue in multiple sclerosis. However, the mechanism behind such a benefit in fatigue remains unclear and the discrepancy between subjective and more objective responses underlines the probable multifactorial nature of the pathogenesis of this symptom in multiple sclerosis.

Latent cochlear damage in personal stereo users: a study based on click-evoked otoacoustic emissions.

OBJECTIVE: To assess the effects of use of personal stereo systems (PS) on hearing by means of the objective measure of transient-evoked otoacoustic emissions. PARTICIPANTS AND SETTING: People aged between 10 and 59 years who had otoacoustic emissions recorded by the National Acoustic Laboratories between 1989 and 1997 were eligible for inclusion. Recordings from participants with hereditary disorders or any form of aural disease (e.g., otitis media, otosclerosis, fluctuant hearing loss, Meniere's syndrome, or exposure to ototoxic substances) were excluded. METHODS: Transient-evoked otoacoustic emission (TEOAE) records were obtained with a standard 260 repetitions of an 80 dB train of clicks used for recording outer hair cell activity. The measure of otoacoustic emission strength was the Otodynamics ILO88 variable Waverepro%. For each participant, all the key factors relating to their hearing history were assessed from patient referral information or from demographic information obtained in writing at the time of recording either in the form of a detailed questionnaire or verbal assessment. Otoacoustic emission data were analysed according to age, industrial noise exposure and personal stereo use. RESULTS: Usable otoacoustic emission records were obtained from 1724 people (1066 males and 658 females). Otoacoustic emission strength declined with age, and was significantly lower in males than females, lower in people exposed to industrial noise than those not exposed, and significantly lower in users of personal stereo systems than non-users. People with both kinds of noise exposure had values which were significantly lower again, indicating an additive effect. CONCLUSIONS: As only 39 people with PS exposure admitted any hearing problems, decline in otoacoustic emission strength forewarns premature hearing loss in personal stereo users.

An electrophysiological study of the mechanism of fatigue in multiple sclerosis.

Fatigue is a common and disabling symptom in multiple sclerosis but is poorly understood. We investigated 'physiological' fatigue in 21 patients with multiple sclerosis who complained of disabling fatigue by measuring the decline in strength during a 45 s maximal contraction of the adductor pollicis muscle. The results were compared with those from a control group of 19 healthy subjects. The strength of control subjects declined by approximately 20% during the contraction; twitch interpolation showed central drive remained almost maximal throughout, and therefore that the fatigue was peripheral in origin. Patients had normal baseline strength, but developed greater fatigue (approximately 45%), which was central in origin. In both cases, the decline in strength followed a roughly linear time course suggesting that the patients, like the normals, were trying to maintain a maximum voluntary effort. Evidence for frequency-dependent conduction block (FDCB) in the patients' central motor pathways was sought by measuring the EMG responses to single and paired transcranial magnetic stimuli. Fatigue had no effect on the latency or size of EMG responses to transcranial magnetic stimulation, suggesting that FDCB was unlikely to have occurred. This was supported by measurements of the maximum speed of voluntary muscle contraction; although the patients showed relatively slow speeds before exercise, the decline in speed after fatigue was no greater than in normal subjects. We conclude that excessive 'physiological' fatigue contributes to the symptom of fatigue in multiple sclerosis and is central in origin. However, since the degree of exercise-induced fatigue did not correlate with the baseline complaint of fatigue, other factors must also be operating to produce the full range of clinical symptoms. We found no conclusive evidence that central fatigue is related to increased dysfunction in the primary central motor pathways and no evidence that FDCB is the pathophysiological mechanism. We postulate that central fatigue in multiple sclerosis is due to impaired drive to the primary motor cortex and several lines of evidence strongly suggest that this is not due to a lack of motivation.

Lumbrical-interosseous latency comparison in the diagnosis of carpal tunnel syndrome.

We examined 66 hands referred with suspected carpal tunnel syndrome (CTS) using the second lumbrical-interosseous distal motor latency difference (2LI-DML) as well as standard tests: Forty-nine cases of CTS were diagnosed by the standard tests, 48 of whom had an abnormal median-ulnar palmar velocity comparison and 48 an abnormal 2LI-DML. The results of these 2 tests were closely correlated. The 2LI-DML supported the diagnosis of CTS in all cases except one, where the result was borderline. In one suspected case the 2LI-DML was the only abnormality. In 9 severe cases no median palmar responses could be obtained but an abnormal 2LI-DML was found. We conclude that the 2LI-DML is as sensitive as the palmar comparison and thus will support the diagnosis of CTS made by standard tests by providing an additional abnormality but that its routine use is unlikely to increase the diagnostic yield. Its value therefore may be in mild cases where the median-ulnar palmar comparison is normal or equivocal and in severe cases where standard test responses are unobtainable. It has also proved useful as a quick and simple screening test for CTS on the asymptomatic side.

Electrodiagnosis.

Attempts to increase the diagnostic yield and reproducibility of electrophysiological investigation of peripheral nerve disorders have led to the development of new techniques, such as measurement of nerve refractoriness, as well as the re-evaluation, refinement and modification of more conventional nerve conduction tests. Other studies have characterized the clinical and electrophysiological features of the subtypes of polyneuropathies associated with monoclonal gammopathies and have documented their natural history, providing important diagnostic and prognostic information. Techniques originating in basic neuroscience that study the excitability of neurons and nerve membranes have been applied to clinical conditions, such as motor neuron disease and cramps, and have provided considerable insight into their pathogenesis.

Pain and remote weakness in limbs injected with botulinum toxin A for writer's cramp.

We describe two cases of a syndrome resembling neuralgic amyotrophy that occurred in limbs injected with botulinum toxin for writer's cramp. In both cases, one of the injections was followed by pain and the next, 7-10 weeks later, by weakness. We believe that unexplained pain in the shoulder region after an injection of botulinum toxin contraindicates a second injection.

Management and outcome of severe Guillain-Barré syndrome.

Seventy-nine patients with Guillain-Barré syndrome admitted to a neurological intensive therapy unit (ITU) between 1985 and 1992 were studied retrospectively. The mean age was 49.8 years (range 16-86) and the time between the first neurological symptom and admission to ITU was 10.2 days (0-62). Admission was precipitated by a combination of respiratory failure requiring ventilatory support (73.4%), bulbar weakness (57.0%), autonomic features (11.4%) and general medical factors (10.1%). Specific treatments included plasma exchange (65.8%), intravenous immunoglobulin (13.9%) and methylprednisolone/placebo (12.7%). Significant complications included lower respiratory tract infections (45.6%), hyponatraemia (25.3%), dysautonomia (19.0%), urinary tract infection (12.7%) and cognitive disturbances (8.9%). Four patients (5.1%) died during the acute illness. Duration of nadir correlated with duration of ventilation, duration of ITU stay and outcomes at 3 months, 6 months and 1 year. However, time to nadir, an indicator of rapidity of deterioration, did not correlate with any outcome. The low mortality in this series of acutely ill and severely disabled patients suggests that specialized intensive therapy units continue to have an important role in the management of acutely ill patients with Guillain-Barré syndrome.

Body sway and vibration perception thresholds in normal aging and in patients with polyneuropathy.

Body sway and vibration perception in the lower limbs were measured in 32 normal subjects and 25 patients with peripheral neuropathies; nerve conduction studies were also performed in the patients with neuropathies. Body sway was measured by means of force-plate posturography, and three methods were used to assess vibration perception: a neurothesiometer, a semiquantitative tuning fork, and the bone vibrator of a conventional audiometer. Body sway and vibration perception were increased in the patients with peripheral neuropathies and there was significant correlation between these measures.d These findings, together with the lack of correlation between sway and muscle strength, indicate that the main source of unsteadiness in these patients is the loss of proprioceptive information. Vibration perception and body sway did not correlate with the electrophysiological variables, indicating that these measures assess different aspects of peripheral nerve function. In all subjects there was close correlation between vibration perception as assessed by the neurothesiometer and the audiometer could be used to screen proprioceptive function in patients with balance disorders. In normal subjects age correlated with vibration perception (measured with the neurothesiometer and audiometer) and also with body sway standing on foam. This suggests that the increased body sway in elderly people may partly be due to redue proprioception in the lower limbs.