J.H.T.M. Koelman

Prediction of poor outcome within the first 3 days of postanoxic coma

Objective: To determine the optimal timing of somatosensory evoked potential (SSEP) recordings and the additional value of clinical and biochemical variables for the prediction of poor outcome in patients who remain comatose after cardiopulmonary resuscitation (CPR). Methods: A prospective cohort study was conducted in 32 intensive care units including adult patients still unconscious 24 hours after CPR. Clinical, neurophysiologic, and biochemical variables were recorded 24, 48, and 72 hours after CPR and related to death or persisting unconsciousness after 1 month. Results: Of 407 included patients, 356 (87%) had a poor outcome. In 301 of 305 patients unconscious at 72 hours, at least one SSEP was recorded, and in 136 (45%), at least one recording showed bilateral absence of N20. All these patients had a poor outcome (95% CI of false positive rate 0 to 3%), irrespective of the timing of SSEP. In the same 305 patients, neuron-specific enolase (NSE) was determined at least once in 231, and all 138 (60%) with a value >33 μg/L at any time had a poor outcome (95% CI of false positive rate 0 to 3%). The test results of SSEP and NSE overlapped only partially. The performance of all clinical tests was inferior to SSEP and NSE testing, with lower prevalences of abnormal test results and wider 95% CI of false positive rates. Conclusion: Poor outcome in postanoxic coma can be reliably predicted with somatosensory evoked potentials and neuron-specific enolase as early as 24 hours after cardiopulmonary resuscitation in a substantial number of patients.

Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with "Lorenzo's oil"

OBJECTIVES X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal fatty acid oxidation, biochemically characterised by the accumulation of saturated very long chain fatty acids (VLCFAs), particularly hexacosanoic acid (C26:0). Dietary treatment with a 4:1 mixture of glyceroltrioleate and glyceroltrierucate (“Lorenzo’s oil”) normalises plasma VLCFA concentrations, but neither ameliorates nor arrests the rapid progression of neurological symptoms in the cerebral variants of X-ALD. The efficacy of “Lorenzo’s oil” in the milder phenotypes of X-ALD was assessed, as this has been much less investigated. METHODS Twenty two patients who were treated with “Lorenzo’s oil” for at least 12 months for a median period of 2.5 (range 1.0–6.0) years were studied. Two had asymptomatic ALD, four the “Addison only” variant, 13 adrenomyeloneuropathy (AMN), and three were symptomatic female carriers. RESULTS The plasma C26:0 concentration normalised or near normalised in 19 patients (86%), in the three others it decreased significantly. Nevertheless, disability as measured with the extended disability status scale score increased mildly (0.5 (95% confidence interval (95% CI) 0.25–1.0)) in the 16 patients with neurological symptoms. Furthermore, one “Addison only” patient and one patient with AMN developed cerebral demyelination, and another “Addison only” patient developed AMN. Adrenocortical insufficiency evolved in one patient with AMN, and hypogonadism in one patient with asymptomatic ALD and two patients with AMN. Nerve conduction, evoked potential studies (SEP, BAEP, VEP), and abnormalities on cerebral MRI did not improve. On the other hand, side effects were often noted—namely, mild increases in liver enzymes (55%), thrombocytopenia (55%), gastrointestinal complaints (14%), and gingivitis (14%). We also found a mild decrease in haemoglobin concentration and leucocyte count. CONCLUSIONS The data suggest that treatment with “Lorenzo’s oil” neither improved neurological or endocrine function nor arrested progression of the disease. Furthermore, the oil often induced adverse effects. Therefore, it is advocated that “Lorenzo’s oil” should not be prescribed routinely to patients with X-ALD who already have neurological deficits.

Botulinum toxin for writer's cramp: a randomised, placebo-controlled trial and 1-year follow-up.

Background: Botulinum toxin type A (BoNT-A) has become the treatment of choice for most types of focal dystonia. Objective: To investigate the efficacy of BoNT-A injections in patients with writer’s cramp in a double-blind, randomised, placebo-controlled trial and to evaluate the follow-up results. Methods: Forty participants were randomised to treatment with either BoNT-A or placebo injections in two sessions. Trial duration was 12 weeks. The primary outcome measure was the patients’ choice to continue with the treatment, despite its possible disadvantages. Secondary outcome measures included several clinical rating scales on the levels of impairment and disability. Assessments were made at baseline and 2 months (secondary outcomes) and 3 months (primary outcome). Duration of follow-up was 1 year. Results: 39 patients completed the trial. Fourteen of 20 patients (70%) receiving BoNT-A reported a beneficial effect and chose to continue treatment, versus 6 of 19 patients (31.6%) in the placebo group (p = 0.03). The changes on most of the clinical rating scales were significantly in favour of BoNT-A. Side effects reported were hand weakness, which was mostly mild and always transient, and pain at the injection site. After 1 year, 20 of 39 patients were still under treatment with a positive effect. Conclusion: Treatment with BoNT-A injections led to a significantly greater improvement compared with placebo, according to patients’ opinion and clinical assessment scales. Weakness in the hand is an important side effect of BoNT-A injections, but despite this disadvantage, most patients preferred to continue treatment. About 50% of our patients were still under treatment after 1 year.

SSEPs and prognosis in postanoxic coma - Only short or also long latency responses?

Background: Short latency somatosensory evoked potential (SSEP) (N20) is a good predictor of poor outcome in postanoxic coma. It has been suggested that the long latency response (N70) may increase the sensitivity of SSEPs for predicting poor outcome. Methods: As part of a prospective cohort study in 407 adult patients unconscious 24 hours after cardiopulmonary resuscitation (CPR), N20 was recorded 24, 48, and 72 hours after CPR, and N70 was recorded at least once in 319 patients. Poor outcome was defined as death or persistent vegetative state 1 month after CPR. Results: Absent N20 had a 0% false positive test rate at all time intervals, with prevalence of poor test result varying from 37 to 48%. Addition of abnormal N70 (absent or delayed > 130 msec) with present N20 as poor test result added 21 to 28% to this prevalence, but at the cost of a false positive test rate of 4 to 15%. Good outcome could not be predicted reliably with either of the tests, as only 28% of patients with normal N20 and N70 had a good outcome. Conclusion: Determination of presence or absence of the N70 in patients with postanoxic coma gives additional information about the likelihood of poor outcome, but it is not precise enough to base treatment decisions solely on its absence.

DYT6 dystonia: Mutation screening, phenotype, and response to deep brain stimulation†

Mutations in THAP1, a gene encoding a nuclear pro‐apoptotic protein, have been associated with DYT6 dystonia. First reports on the phenotype of DYT6 dystonia show an early onset dystonia with predominant cranio‐cervical and laryngeal involvement. Here we assessed the frequency and phenotype of THAP1 mutation carriers in a large Dutch cohort of adult‐onset (≥26 years) dystonia (n = 388) and early‐onset dystonia (n = 67) patients. We describe the phenotype of DYT6 dystonia patients and their response on GPi DBS. Overall, 3 nonsynonymous heterozygous mutations were detected in the early‐onset group (4.5%). Two DYT6 families were identified, showing a heterozygous phenotype. All patients had segmental or generalized dystonia, often associated with profound oromandibular and laryngeal involvement. No nonsynonymous mutations were found in patients with adult‐onset focal dystonia. Rare synonymous variants were identified in conserved regions of THAP1, two in the adult‐onset cervical dystonia group and one in the control group. Four DYT6 dystonia patients were treated with GPi DBS with moderate to good response on motor function but marginal benefit on speech.

Neuropsychological and clinical correlates of antisaccade task performance in schizophrenia.

Objectives: To elucidate pathophysiologic mechanisms involved in abnormal antisaccade task performance in schizophrenia by investigating a possible relationship among antisaccade task performance, neuropsychological test results, and symptomatology in a group of young patients with recent-onset schizophrenia; to compare the effects of olanzapine and risperidone on antisaccades and reflexive saccades. Background: Patients with schizophrenia consistently perform worse than controls on the antisaccade task in which the subject is required to inhibit a reflexive saccade to a suddenly appearing visual target and look in the opposite direction. Methods: In 37 young (mean age 21 years), medicated patients with recent-onset schizophrenia the authors assessed antisaccades, reflexive saccades, neuropsychological test performance, and symptomatology. A subgroup of 18 patients was treated with olanzapine, and 15 patients were treated with risperidone. Reflexive-saccade and antisaccade task results were compared with those obtained in 13 control subjects. Results: The antisaccade error rate was significantly higher in the patients than in the control subjects. In the patients, poor working memory function was related to increased antisaccade error rate. Severity of disorganization symptoms at intake was related to prolonged mean latency of the correct antisaccades. Patients on risperidone had a prolonged mean latency in the reflexive saccade task compared with patients using olanzapine. Conclusions: Abnormal antisaccade task performance is already present in early schizophrenia and may reflect working memory dysfunction. In future studies, medication effects should be considered in interpreting eye movement test results of patients with schizophrenia.

Pretarsal application of botulinum toxin for treatment of blepharospasm.

The response to botulinum toxin type A was compared after two injection techniques in 45 patients with blepharospasm. Initially, patients were treated according to a triple injection technique; two injections into the upper eyelid and one injection into the lower eyelid. Subsequently, without altering the dose, the same patient group received two further injections into the pretarsal portion of the orbicularis oculi muscle of the upper lid. Triple injections were given in 227 treatments, of which 81% were successful. Mean duration of benefit was 8.5 weeks. Additional pretarsal injections were given in 183 treatment sessions. The number of successful treatments significantly increased, to 95% (P < 0.001), and the mean duration of benefit increased to 12.5 weeks (P < 0.001). Ptosis occurred significantly less often after pretarsal injections (P < 0.01). Patients with combined blepharospasm and involuntary levator palpebrae inhibition responded better to the pretarsal injection technique.

Peripheral nerve abnormalities in adrenomyeloneuropathy: A clinical and electrodiagnostic study

Article abstract-Adrenomyeloneuropathy (AMN) is one of the two most frequent phenotypes of X-linked adrenoleukodystrophy. Whether the polyneuropathy in AMN results from primary demyelination or axonal degeneration is uncertain. We examined 23 patients (18 men with AMN and five female carriers with AMN symptomatology), performed electroneurography and EMG, and compared our results with standardized electrodiagnostic criteria for primary demyelination. Both clinically and electrodiagnostically, the lower extremities were most frequently and most severely affected. A longer duration of symptoms was related to more severe pyramidal dysfunction (p < 0.004) and spasticity (p < 0.04), and to a more severe impairment of vibration sense (p < 0.05). There were no correlations between the different electrophysiologic studies and the duration of neurologic symptoms. Only two AMN patients (9%) fulfilled the electrodiagnostic criteria for primary demyelination. However, both had abnormally low compound muscle action potentials, which may have been a reflection of primary axonal degeneration. Six other patients (26%) partially fulfilled the criteria for primary demyelination, of whom five also manifested low compound muscle action potentials. In 15 patients (65%), we found polyneuropathy with predominantly axonal, sensorimotor features. We conclude that the neuropathy in AMN patients is due to primary axonal degeneration. NEUROLOGY 1996;46: 112-118

Interobserver variation in the interpretation of SSEPs in anoxic–ischaemic coma

OBJECTIVE To study interobserver variation in the interpretation of median nerve SSEPs in patients with anoxic-ischaemic coma. METHODS SSEPs of 56 consecutive patients with anoxic-ischaemic coma were interpreted independently by 5 experienced clinical neurophysiologists using guidelines derived from a pilot study. Interobserver agreement was expressed as kappa coefficients. RESULTS Kappa ranged from 0.20 to 0.65 (mean 0.52, SD 0.14). Disagreement was related with noise level and failure to adhere strictly to the guidelines in 15 cases. The presence or absence of N13 and cortical peaks caused disagreement in 5 cases each. For recordings with a noise level of 0.25 microV or more, mean kappa was 0.34; for recordings with a noise level below 0.25 microV mean kappa was 0.74. CONCLUSIONS Interobserver agreement for SSEPs in anoxic-ischaemic coma was only moderate. Since the noise level strongly influenced interobserver variation, utmost attention should be given to its reduction. If an artefact level over 0.25 microV remains, absence of N20 cannot be judged with sufficient certainty and the SSEP should be repeated at a later stage. SIGNIFICANCE Because of its moderate interobserver agreement, great care has to be given to accurate recording and interpretation of SSEPs before using the recordings for non-treatment decisions.

Phenotype of Charcot–Marie–Tooth disease Type 2

Objective: To investigate the clinical and electrophysiologic phenotype of Charcot–Marie–Tooth disease (CMT) Type 2 in a large number of affected families. Methods: We excluded CMT Type 1, hereditary neuropathy with liability to pressure palsies, and CMT due to Cx32 gene mutations by DNA analysis. We performed genetic analysis of the presently known CMT Type 2 genes. Results: Sixty-one persons from 18 families were affected. Ninety percent of patients were able to walk with or without the help of aids. Proximal leg muscle weakness was present in 13%. Asymmetrical features were present in 15%. Normal or brisk knee reflexes were present in 36%. Extensor plantar responses without associated spasticity occurred in 10 patients from eight families. Only three causative mutations were identified in the MFN2, BSCL2, and RAB7 genes. No mutations were found in the NEFL, HSPB1, HSPB8, GARS, DNM2, and GDAP1 genes. Conclusions: At group level, the clinical phenotype of Charcot–Marie–Tooth disease (CMT) Type 2 is uniform, with symmetric, distal weakness, atrophy and sensory disturbances, more pronounced in the legs than in the arms, notwithstanding the genetic heterogeneity. Brisk reflexes, extensor plantar responses, and asymmetrical muscle involvement can be considered part of the CMT Type 2 phenotype. The causative gene mutation was found in only 17% of the families we studied.