Carolyn Gabriel

Ciclosporin A Proof of Concept Study in Patients with Active, Progressive HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis

Introduction Patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) become progressively impaired, with chronic pain, immobility and bladder, bowel and sexual dysfunction. Tested antiretroviral therapies have not been effective and most patients are offered a short course of corticosteroids or interferon-α, physiotherapy and symptomatic management. Pathogenesis studies implicate activated T-lymphocytes and cytokines in tissue damage. We therefore tested the hypothesis that inhibition of T-cell activation with ciclosporin A would be safe and clinically beneficial in patients with early and/or clinically progressing HAM/TSP. Materials and Methods Open label, proof of concept, pilot study of 48 weeks therapy with the calcineurin antagonist, ciclosporin A (CsA), in seven patients with ‘early’ (50% deterioration in timed walk during the preceding three months) HAM/TSP. Primary outcomes were incidence of clinical failure at 48 weeks and time to clinical failure. Results All patients completed 72 weeks study participation and five showed objective evidence of clinical improvement after 3 months treatment with CsA. Two patients exhibited clinical failure over 6.4 person-years of follow-up to week 48. One patient had a >2 point deterioration in IPEC (Insituto de Pesquisa Clinica Evandro Chagas) disability score at weeks 8 and 12, and then stopped treatment. The other stopped treatment at week 4 because of headache and tremor and deterioration in timed walk, which occurred at week 45. Overall pain, mobility, spasticity and bladder function improved by 48 weeks. Two patients recommenced CsA during follow-up due to relapse. Conclusions These data provide initial evidence that treatment with CsA is safe and may partially reverse the clinical deterioration seen in patients with early/progressive HAM/TSP. This trial supports further investigation of this agents safety and effectiveness in larger, randomised controlled studies in carefully selected patients with disease progression.

Anti Ma2-associated myeloradiculopathy: expanding the phenotype of anti-Ma2 associated paraneoplastic syndromes

Anti-Ma2 associated paraneoplastic syndrome usually presents as limbic encephalitis in association with testicular tumours.1 2 Only four patients have been reported with involvement outside the CNS, two of whom also had limbic or brainstem encephalitis.2 3 We report a man with anti-Ma2 associated myeloradiculopathy and previous testicular cancer whose neurological syndrome stabilised and anti-Ma2 titres fell following orchidectomy of a microscopically normal testis. A 46-year-old dentist noticed weakness of pincer movement in the left hand. Six weeks later he developed sequential finger drop of the 4th, 5th and 3rd fingers of the left hand over days. During the subsequent weeks the fingers of his right hand also dropped. He had a prior history of left orchidectomy for stage I testicular seminoma and had been well on surveillance for 5 years. MRI brain, cervical spine and brachial plexii were normal. A diagnosis of multifocal motor neuropathy with conduction block was considered. Neurophysiology of the upper limbs demonstrated reduced motor amplitudes and acute and chronic denervation but no conduction block. Neurophysiology of the lower limbs was normal. He was given a trial of intravenous immunoglobulin without response. Some weeks later he developed an unusual itchy sensation spreading across his back and shoulders. On examination there was head drop with weakness of neck flexion. There was wasting of both forearms and intrinsic hand muscles, with some fasciculations in the biceps and triceps. Tone was normal. There was asymmetric patchy proximal and distal weakness of both arms with finger drop. Reflexes were brisk …

Zoster paresis with Horner's syndrome

Sirs: We describe two cases of shingles with upper limb weakness and ipsilateral Horner’s syndrome. This combination has not been previously described to our knowledge, though can be well understood anatomically. Case 1. A 79 year old man had a three week history of non-pruritic erythematous vesicular rash on the medial left forearm. Shingles was diagnosed after two weeks and oral acyclovir prescribed. He had quiescent polymyalgia rheumatica for which he took 5 mg/day prednisolone and epilepsy that was controlled on sodium valproate. The rash improved but he reported a three day history of difficulty doing up buttons and gripping with the left hand. On examination there was a C7-T1 distribution shingles rash, ipsilateral weakness of finger extension and the small hand muscles and an absent left triceps jerk. One week later, wrist and elbow extension were also weak. Pin-prick sensation was reduced in a C7-T1 distribution. Anisocoria was noted (L < R) and pupillography revealed brisk responses to light bilaterally but redilatation lag on the left, characteristic of a sympathetic deficit. The left pupil responded more than the right to hydroxyamphetamine instillation showing the lesion to be preganglionic. Two weeks later the rash and sensory deficit had improved, the weakness and pupillary change was unchanged but he had developed a partial left ptosis. Three years later the weakness and Horner’s syndrome persist. Case 2. A 79 year old woman developed a tender blistering rash on the medial surface of her left arm. Shingles was diagnosed and treated with oral famcyclovir. Two weeks later she noted difficulty extending the medial three fingers of her left hand. Four weeks following this, she developed pain in the medial three fingertips spreading over days to the elbow. She had asthma and took 2 mg/day prednisolone. On examination there was a healed shingles rash in the C8-T1 territory of her left arm. She had a left Horner’s syndrome. There was ipsilateral weakness of finger extension and the small hand muscles. The left triceps reflex was reduced. Pin-prick sensation was reduced in a C8 distribution. Ten months later, the pain had resolved but the weakness and Horner’s syndrome persisted. Arm weakness and Horner’s syndrome are rare manifestations of herpes zoster and to our knowledge the combination has not been previously described. Segmental limb weakness (zoster paresis) is a focal, asymmetric weakness in a limb affected by cutaneous zoster [1]. After chickenpox the DNA of varicella-zoster virus becomes latent in ganglia [2]. The biologic mechanisms underlying the transition to active replication are not understood [3] although, as with our patients, concurrent immunosuppression is common. Reactivation causes inflammation and neuronal loss in affected ganglia, and may spread to adjacent nerve roots and sometimes to the cord [4, 5]. Paresis occurs in 3–5 % of patients with cutaneous zoster, especially with proximal limb weakness [6]. The interval between rash and weakness averages two weeks, as in our cases, although may extend to five weeks. Functional motor recovery occurs in 75 % by 1–2 years. Horner’s syndrome is described in association with ophthalmic [7] or thoracic [8, 9] zoster, but is rare. The oculosympathetic pathway from the hypothalamus descends through the brainstem, synapsing in the intermediolateral cells of the spinal cord at the C8-T2 level. Preganglionic fibres exit the cord via the ventral roots forming the paravertebral chain and proceed through the stellate ganglion to synapse in the superior cervical ganglion. Thus inflammation associated with reactivated herpes virus causes a preganglionic sympathetic lesion. The combination of paresis affecting C7-T1 innervated muscles with Horner’s syndrome is likely to result from inflammation induced by viral activation spreading from dorsal root ganglion to cord or ventral roots, affecting the sympathetic oculosympathetic fibres as it does so.

Treatment of patients with HTLV-1-associated myelopathy with methotrexate

The lifetime risk of developing HTLV-1 associated myelopathy (HAM) is 0.25-3%. The main pathological feature is an immune-mediated response leading to chronic inflammation of the spinal cord. The optimal long term treatment has yet to be determined although clinical improvement with ciclosporin has been shown in a pilot study. Methotrexate, commonly used for autoimmune diseases, was introduced for the treatment of HAM at the National Centre for Human Retrovirology, London, UK as an alternative to ciclosporin.

Case 37: Neutropenia and macrocytosis in a middle-aged man

A myelodysplastic syndrome (MDS) was suspected in a middle-aged man who presented with neutropenia and macrocytosis. The correct non-neoplastic diagnosis was not made for 5 years. It is of crucial importance to exclude treatable causes of cytopenia and dysplasia when MDS is suspected.

A proof of concept study of Infliximab for the treatment of HTLV-1-associated myelopathy

Background Disease modifying treatment options for patients with HAM are limited. Most studies have included all patients regardless of duration, disability or disease activity. The Medical Research Council UK funded a series of proof of concept studies for patients with early (50% deterioration during preceding 3 months). The results of the first study of ciclosporin have been published. The second study, of the anti-TNF monoclonal antibody Infliximab, is presented.

Copper deficiency myeloneuropathy in a patient with haemachromatosis: a case report

A 64-year-old British Caucasian man presented with red skin wheals and breathlessness and then developed a progressive neurological syndrome. Investigation revealed hereditary haemachromatosis, porphyria, and a myelodysplastic syndrome. No unifying diagnosis was made, and his neurological symptoms remained unexplained, until further studies revealed an underlying copper deficiency.

ULTRASOUND-GUIDED LUMBAR PUNCTURE AS A DIAGNOSTIC AID TO IMPROVE PATIENT SAFETY AND SATISFACTION: DESIRABLE OR NECESSARY?

Background There is some evidence that using ultrasound (USS)-guidance reduces the number of lumbar puncture (LP) failures and improves the ease of the procedure in obese patients. We have begun to use this on our unit in unselected non-emergency patients and tested if it is associated with a reduced risk of complications and number of attempts required. Method The study was designed as a mixed retrospective-prospective case-control design over a 6-month period. Retrospective data was collected from 28 patients that had a non-USS-guided LP. Prospective data was collected on 23 patients that underwent an USS-guided LP. Difficulty factors (DFs) such as scoliosis, obesity, previous spinal surgery or general immobility were recorded. Results The mean attempt rate in patients without DFs was 1.6 with an unguided LP compared to 1.0 with USS-guided LP (p=0.02). In patients with DFs, this was 3.60 vs 1.67 (p=0.006). The back pain rate in patients without DFs was 13.3% without USS vs 0% with USS (n.s.). In patients with DFs this was 53.8% without USS and 8.3% with USS (p=0.017). A logistic regression analysis confirmed that US-guided LP was a good predictor. 14% of unguided LPs produced CSF samples which were blood contaminated. Discussion This study demonstrates that USS-guided LPs are associated with reduced number of attempts, reduced complication rate and reduced blood contamination particularly in those with difficulty factors. USS-guided LP would aid clinicians in ensuring patient safety, reduction of post-procedure complications and better practice.

PONM16 Unusual surgery for progressive finger-drop

We present the case of a 46-year-old dentist who noticed weakness of pincer movement of the left hand whilst at work. Six weeks later, he developed progressive finger-drop affecting the left hand over days and then the right hand over weeks. Over this period, he reported altered sensation spreading across his shoulders and back. Five years previously, he had been treated successfully for seminoma with orchidectomy alone and had normal follow-up assessments. Abnormal examination findings were restricted to his upper limbs with bilateral wasting of shoulder-girdle, arm and forearm muscles more marked distally, some fasciculations, but preserved reflexes and marked bilateral finger-drop. General physical examination was normal. EMG suggested a severe motor neuropathy or neuronopathy affecting the cervical regions. Detailed brain and spine neuroimaging was normal. PET scanning and testicular ultrasound were normal. Oligoclonal bands were positive in the CSF only. Extensive blood tests for infection and inflammation were normal. He was initially managed for inflammatory motor neuropathy until the result of one blood test which led to an unusual surgical procedure being sought for his further management. This case represents a unique presentation of a rare neurological syndrome and illustrates the expanding clinical spectrum associated with this syndrome.

Neuromuscular disease. Evidence and analysis in clinical neurology

Michael Benatar, New Jersey: Humana Press Inc, 2006, US