Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subtype of stiff-person syndrome (formerly stiff-man syndrome). It is rare and disabling, and characterised by brainstem symptoms, muscle stiffness, breathing issues... more
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subtype of stiff-person syndrome (formerly stiff-man syndrome). It is rare and disabling, and characterised by brainstem symptoms, muscle stiffness, breathing issues and autonomic dysfunction. We describe a 65-year-old man who presented with odynophagia together with tongue and neck swelling, followed by multiple cranial nerve palsies culminating in bilateral vocal cord paralysis with acute stridor. He subsequently developed progressive generalised hypertonia and painful limb spasms. Serum antiglycine receptor antibody was strongly positive, but antiglutamic acid decarboxylase and other antibodies relating to stiff-person syndrome were negative. We diagnosed PERM and gave intravenous corticosteroids and immunoglobulins without benefit; however, following plasma exchange he has made a sustained improvement.
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Published cases of post-malaria neurological syndrome (PMNS) invariably report clinical and radiological encephalopathy. We report a case of brainstem and spinal cord inflammation without supratentorial involvement following recovery from... more
Published cases of post-malaria neurological syndrome (PMNS) invariably report clinical and radiological encephalopathy. We report a case of brainstem and spinal cord inflammation without supratentorial involvement following recovery from Plasmodium falciparum infection. A 48-year-old woman was diagnosed with P falciparum malaria while on holiday in Sierra Leone, during which she did not take malaria prophylaxis. She responded well to artesunate and amiodaquine. Ten days later, back in the UK, she was admitted to hospital with progressive sensorimotor symptoms in both legs and urinary retention. Neurological examination revealed upbeat nystagmus, minimal neck and shoulder muscle weakness (MRC 4+/5) with hyperreflexia, flaccid paraplegia with retained reflexes, reduced anal tone and a sensory level at T3/4. MRI of the neuraxis showed high signal in the pons, cerebellar peduncles, medulla and most of the spinal cord. The rest of the brain parenchyma was normal. Lumbar puncture was omitted due to brainstem swelling. An extensive infective and autoimmune screen, including aquaporin-4 antibodies, was normal. The patient received 3 days of IV methylprednisolone. Toe movement returned within 36 h and she had minimal paraparesis by 2 weeks. A repeat MRI after 3 weeks showed improvement in signal change with resolution of brainstem swelling. It is argued that the recognised clinical spectrum of PMNS should be expanded to include brainstem and/or spinal cord involvement.
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Amyloidoma is a rare cause for intracranial space-occupying lesions diagnosed on brain imaging. Histology of excised tissue usually reveals the presence of a discrete, λ-light chain secreting plasmacytoma adjacent to an amyloid mass... more
Amyloidoma is a rare cause for intracranial space-occupying lesions diagnosed on brain imaging. Histology of excised tissue usually reveals the presence of a discrete, λ-light chain secreting plasmacytoma adjacent to an amyloid mass comprising aggregated monoclonal immunoglobulin light chains. We described a patient with intracerebral amyloidoma associated with a localised lymphoplasmacytic lymphoma and no systemic paraproteinaemia, tumour or amyloid deposits.
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Mitotic errors during early embryonal cell cleavage result in somatic cells having different genotypes. Such somatic mosaicism, in the presence of a chromosomal or genetic disorder, generally results in a milder disease phenotype, which... more
Mitotic errors during early embryonal cell cleavage result in somatic cells having different genotypes. Such somatic mosaicism, in the presence of a chromosomal or genetic disorder, generally results in a milder disease phenotype, which may go undetected. We describe a case of mosaic tuberous sclerosis (TS) and the circumstances leading to its diagnosis. A 39-year-old man was referred to the adult neurology services for episodes of facial flushing, lip smacking, gustatory hallucinations and clenching movements of his left hand. EEG captured a complex partial seizure with correlating rhythmic θ activity over the right fronto-temporal area. MRI brain in 2004 showed a single high signal area in the right temporal lobe that was deemed artefactual. He was started on levetiracetam and later carbamazepine and was added, with good control. In 2009, his twin children were both diagnosed with tuberous sclerosis caused by a TSC2 exon 9 deletion. Neither the patient nor his wife carried the deletion in blood DNA. To investigate the possibility of somatic mosaicism, both parents underwent renal ultrasound. The patient's ultrasound revealed multiple hyperechoic foci throughout both kidneys typical in appearance of angiomyolipomas. Repeat MRI in 2010 showed disseminated lesions in both hemispheres, suggestive of cortical dysplasia that had emerged in the intervening 6 years. He was diagnosed with mosaic TS, and continues to be regularly reviewed for his epilepsy and renal lesions.
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We report a case of paraneoplastic limbic encephalitis presenting with purely olfactory symptoms. For 7 weeks, a 76-year-old man experienced distorted impressions of the odour of most foods and liquids and hallucinatory olfactory... more
We report a case of paraneoplastic limbic encephalitis presenting with purely olfactory symptoms. For 7 weeks, a 76-year-old man experienced distorted impressions of the odour of most foods and liquids and hallucinatory olfactory perceptions without objective stimuli. The perceived odour was metallic and foul, causing loss of appetite and weight, nausea and repeated retching. No dental or ENT cause for his symptoms was found. MRI of the brain and sinuses was normal. EEG showed no focal or paroxysmal activity. CSF protein was elevated (1.17 g) and isoelectric focusing revealed oligoclonal bands (3+) in the CSF only. A paraneoplastic antibody screen was positive for anti-Hu and weakly positive for anti-amphiphysin. CT TAP revealed malignant-appearing mediastinal lymphadenopathy but no pulmonary abnormality. The patient underwent endoscopic biopsy of the enlarged subcarinal lymph nodes. Histology confirmed metastatic small cell lung carcinoma (SCLC). Clinically, he was initially intact but later developed diplopia and bilateral horizontal nystagmus on lateral gaze. His gait became ataxic, veering towards the left, and he developed asymmetrical leg weakness, L>R. Repeat MRI brain and spine showed no metastatic deposits to explain his symptoms. Olfactory abnormalities may be associated with limbic encephalitis but have never been reported as an isolated presenting symptom. Occult malignancy should be considered in new onset olfactory symptoms in the absence of other causes.
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Tremor is defined as an involuntary, oscillatory, rhythmic movement of a body part produced by the alternating contractions of antagonistic pairs or muscles. It is the most common movement abnormality encountered and investigated in both... more
Tremor is defined as an involuntary, oscillatory, rhythmic movement of a body part produced by the alternating contractions of antagonistic pairs or muscles. It is the most common movement abnormality encountered and investigated in both primary care and neurology practice. Tremor is not a diagnosis in itself; rather it is symptomatic of an underlying disorder that should be identified and when possible treated. The diagnostic process ought to include a detailed medical history, a careful assessment of the characteristics of the tremor and a search for other neurological or physical signs. This process may present challenges, particularly in describing tremor phenomenology and linking it to the likely diagnosis. This article outlines briefly the main points to explore when evaluating a patient’s tremor history, the key characteristics of tremor that should be examined for and the correct nomenclature for their description, followed by an overview of the common types of tremor encoun...
Background Alemtuzumab, a CD52 - specific monoclonal antibody depletes T and B cell population to reduce relapse in multiple sclerosis. Neutrophils also express low levels of CD52 and can be depleted transiently by alemtuzumab, increasing... more
Background Alemtuzumab, a CD52 - specific monoclonal antibody depletes T and B cell population to reduce relapse in multiple sclerosis. Neutrophils also express low levels of CD52 and can be depleted transiently by alemtuzumab, increasing the risk of infection in the post-alemtuzumab treatment period. Aim In this study in the Greater Manchester Neuroscience Centre (GMNC) we investigated at risk population for alemtuzumab induced neutropaenia. The outcome of these patients is also discussed. Method Retrospective study of patients who developed neutropaenia following treatment with alemtuzumab at the GMNC. Data of patient demographics, grade of neutropeania, symptoms while neutropaenic and management were evaluated. Results Of the 131 patient (86 F: 45 M) treated with alemtuzumab (1.9 F: 1 M ratio), 18 patient (13.7%) developed neutropaenia (17 F Vs 1 M, 19.8% F Vs 2.2% M). Moderate to severe (grade 2–4) neutropaenia was only observed in females. Average duration to develop neutropaen...
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Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subtype of stiff-person syndrome (formerly stiff-man syndrome). It is rare and disabling, and characterised by brainstem symptoms, muscle stiffness, breathing issues... more
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subtype of stiff-person syndrome (formerly stiff-man syndrome). It is rare and disabling, and characterised by brainstem symptoms, muscle stiffness, breathing issues and autonomic dysfunction. We describe a 65-year-old man who presented with odynophagia together with tongue and neck swelling, followed by multiple cranial nerve palsies culminating in bilateral vocal cord paralysis with acute stridor. He subsequently developed progressive generalised hypertonia and painful limb spasms. Serum antiglycine receptor antibody was strongly positive, but antiglutamic acid decarboxylase and other antibodies relating to stiff-person syndrome were negative. We diagnosed PERM and gave intravenous corticosteroids and immunoglobulins without benefit; however, following plasma exchange he has made a sustained improvement.
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subtype of stiff-person syndrome (formerly stiff-man syndrome). It is rare and disabling, and characterised by brainstem symptoms, muscle stiffness, breathing issues... more
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subtype of stiff-person syndrome (formerly stiff-man syndrome). It is rare and disabling, and characterised by brainstem symptoms, muscle stiffness, breathing issues and autonomic dysfunction. We describe a 65-year-old man who presented with odynophagia together with tongue and neck swelling, followed by multiple cranial nerve palsies culminating in bilateral vocal cord paralysis with acute stridor. He subsequently developed progressive generalised hypertonia and painful limb spasms. Serum antiglycine receptor antibody was strongly positive, but antiglutamic acid decarboxylase and other antibodies relating to stiff-person syndrome were negative. We diagnosed PERM and gave intravenous corticosteroids and immunoglobulins without benefit; however, following plasma exchange he has made a sustained improvement.
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In 2014, teriflunomide and dimethyl fumarate were approved by NHS regulators as first-line oral treatments for multiple sclerosis in England. We audited the safety, tolerability and treatment retention rates of the first line oral DMTs in... more
In 2014, teriflunomide and dimethyl fumarate were approved by NHS regulators as first-line oral treatments for multiple sclerosis in England. We audited the safety, tolerability and treatment retention rates of the first line oral DMTs in Greater Manchester. Case notes of MS patients treated with first line oral DMTs were analysed for drug discontinuation reason, blood monitoring compliance and drug related side effects within the first 12 months of treatment. Of 39 patients, treated with teriflunomide, 89% were still on treatment at 12 months and reported very few side effects. 5% withdrew from treatment due to non-adherence with blood test monitoring, 3% due to lack of efficacy and 3% due to side effects. 273 patients treated with dimethyl fumarate, had a retention rate of 75% after 12 months. 12% discontinued treatment due to gastrointestinal side effects and 3% due to fatigue, headache and depression. Occasionally patients reported appetite/weight changes and altered hair appear...
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Amyotrophic lateral sclerosis (ALS) is frequently caused by mutations in the SOD1 gene. Here, we report the first SOD1 variant in Malta, an archipelago of three inhabited islands in southern Europe. We describe a patient with a sporadic... more
Amyotrophic lateral sclerosis (ALS) is frequently caused by mutations in the SOD1 gene. Here, we report the first SOD1 variant in Malta, an archipelago of three inhabited islands in southern Europe. We describe a patient with a sporadic form of ALS living on the island of Gozo in which the heterozygous SOD1 c.272A>C; p.(Asp91Ala) variant was detected. The patient had a late onset (79 years), sensory impairments and rapid disease progression culminating in respiratory failure. ALS has not yet developed in any of the three additional family members in which the D91A variant was identified. None of the healthy controls from the Maltese population were found to carry this variant. This report underscores the high prevalence of the D91A variant in Europe, despite the presence of a North-South gradient in its frequency, and confirms that this variant can be associated with dominant cases in Mediterranean countries.
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Functional outcome after subarachnoid haemorrhage has traditionally been assessed using scales developed for other neurological conditions. The modified Rankin score and Glasgow Outcome Scale are most commonly used. Employment of these... more
Functional outcome after subarachnoid haemorrhage has traditionally been assessed using scales developed for other neurological conditions. The modified Rankin score and Glasgow Outcome Scale are most commonly used. Employment of these scales in subarachnoid haemorrhage is hampered by well recognized limitations. We set out to develop and validate a new condition-specific subarachnoid haemorrhage outcome tool (SAHOT). Items addressing diverse aspects of the impact of subarachnoid haemorrhage were collected during focus groups involving patients, next-of-kin and multidisciplinary professionals involved in subarachnoid haemorrhage management. After a series of iterative revisions, the resultant questionnaire was applied to patients and their next-of-kin at 1, 3 and 6 months post-subarachnoid haemorrhage. Rasch methodology was used to finalize the structure of the questionnaire and explore the extent to which SAHOT scores met Rasch-based criteria of successful measurement. The SAHOT wa...
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Sarcoidosis is an idiopathic multisystem granulomatous disorder of unknown cause. Nervous system involvement (central and/or peripheral) is uncommon, developing in 5%-10%. The presenting symptoms are variable, reflecting the level of... more
Sarcoidosis is an idiopathic multisystem granulomatous disorder of unknown cause. Nervous system involvement (central and/or peripheral) is uncommon, developing in 5%-10%. The presenting symptoms are variable, reflecting the level of involvement, and frequently fluctuate and progress. Diagnosing neurosarcoidosis in people with previously confirmed systemic disease may be relatively straightforward, but diagnosing primary neurosarcoidosis is challenging. Managing neurosarcoidosis is primarily consensus based; corticosteroid is its mainstay, alongside corticosteroid-sparing agents and emerging novel therapies. We describe a 39-year-old woman who presented with cranial neuropathy. Serial imaging, cerebrospinal fluid sampling and tissue biopsy gave a diagnosis of probable neurosarcoidosis. Her clinical course was complicated by intracerebral haemorrhage following intravenous corticosteroids for neurological relapse. This is a very rare complication of neurosarcoidosis; we discuss its po...
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There is a shortfall of suitably powered studies to provide evidence for safe prescribing of AEDs to people with Intellectual Disability (ID). We report clinically useful information on differences in response to Perampanel (PER)... more
There is a shortfall of suitably powered studies to provide evidence for safe prescribing of AEDs to people with Intellectual Disability (ID). We report clinically useful information on differences in response to Perampanel (PER) adjunctive treatment for refractory epilepsy between ID sub-groups and general population from the UK Ep-ID Research Register. Pooled retrospective case notes data of consented people with epilepsy (PWE) prescribed PER from 6 UK centres was classified as per WHO guidance into groups of moderate -profound ID, mild ID and General population. Demographics, concomitant AEDs, starting and maximum dosage, exposure length, adverse effects, dropout rates, seizure type and frequency were collected. Group differences were reported as odds ratios estimated from univariable logistic regression models. Of the 144 PWE (General population 71, Mild ID 48, Moderate to profound ID 48) examined the association between withdrawal and ID type was marginally statistically signif...
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ABSTRACT
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We report the case of a 46 year old woman referred to our Headache Clinic with a 12 month history of severe episodic headache. The headache was left-sided, pressure-like and reliably triggered by outbursts of laughter. Episodes lasted... more
We report the case of a 46 year old woman referred to our Headache Clinic with a 12 month history of severe episodic headache. The headache was left-sided, pressure-like and reliably triggered by outbursts of laughter. Episodes lasted most of the day and were associated with kaleidoscopic visual disturbances, photophobia and nausea. The headache was not triggered by coughing, sneezing, bending forward or neck movement, and could be prevented if she avoided laughing. Her past medical history was significant for asthma and she was on no medication. Neuro-logical examination was normal. MRI of the head and neck did not show any abnormality in the cranio-cervical junction, venous sinuses, cerebral aneurysm or space-occupying lesion. She was interested in herbal remedies and eventually did well on Feverfew and Co-enzyme Q10. Published cases of headache triggered by laughter have generally been associated with type 1 Chiari malformation. Laughter-induced headache may also occur as a prima...
Background: CAMS concluded that cannabinoids do not reduce muscle spasticity in pwMS, contradicting substantial anecdotal clinical evidence and animal studies. Aim: To explore whether measurement limitations in the Ashworth scale, CAMS’... more
Background: CAMS concluded that cannabinoids do not reduce muscle spasticity in pwMS, contradicting substantial anecdotal clinical evidence and animal studies. Aim: To explore whether measurement limitations in the Ashworth scale, CAMS’ primary outcome measure, influenced the study’s interpretations. Methods: We reanalysed the CAMS Ashworth data (n=667) where ten limb muscles were scored bilaterally and summed into a total spasticity score. We used Rasch analysis to test the extent to which summed Ashworth scales satisfied psychometric requirements for measurement. Results: Ashworth total body spasticity scores did not satisfy requirements for measurement. Raters could not reliably distinguish between the six response categories in 17 of 20 muscles examined. Scores for many individual muscles had substantial floor effects indicating a very limited ability to detect clinical change in spasticity. There was evidence that combining upper and lower limb muscles compromises measurement p...
Background: Rating scales are used increasingly as outcome measures. They are assumed to deliver scientifically rigorous and clinically meaningful measurement. This abstract discusses the extent to which this assumption is valid. The... more
Background: Rating scales are used increasingly as outcome measures. They are assumed to deliver scientifically rigorous and clinically meaningful measurement. This abstract discusses the extent to which this assumption is valid. The Issue: Measurement is defined as the quantitative comparison between any magnitude and a standard unit, expressed as a numerical ratio. For instance, a 10 metre length is ten times the unit (1 metre). In contrast, rating scales assign numbers to rank-ordered clinically distinct magnitudes of unknown interval size. For example, the Rankin scale assigns sequential integers to descriptions of increasing disability. As such, raw rating scale scores do not meet the definition of measurement. The Solution: Rating scale data may only be treated as measurements when investigators apply a legitimate method for constructing, from raw scores, estimates that satisfy the definition of measurements. Rasch measurement theory is currently the only vehicle allowing us t...
Background: The Medical Research Council (MRC) Grading System is a six-category rating scale used for measuring individual muscle strength. It is often assumed that scores for individual muscles can be summed to generate total scores that... more
Background: The Medical Research Council (MRC) Grading System is a six-category rating scale used for measuring individual muscle strength. It is often assumed that scores for individual muscles can be summed to generate total scores that measure total body strength. Objectives: We tested this assumption during the construction of a clinician-reported scale for measuring muscle strength in multiple sclerosis (MS). Methods: Thirty nine muscles were graded in 100 people with MS. We used Rasch analysis to test the extent to which summed MRC scores satisfied psychometric requirements for measurement. Results: Data satisfied measurement requirements articulated by the Rasch model, indicating equal-interval measurements of strength can be constructed using aggregate muscle grades. However, for many muscles lower MRC grades (0—3) were not endorsed, and the ability to discriminate among stronger people was limited. Conclusions: Combining individual muscle strength scores into a total body s...
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Epilepsy-related death, particularly sudden unexpected death in epilepsy (SUDEP), is underestimated by healthcare professionals. One argument that physicians use to justify the failure to discuss SUDEP with patients and their families is... more
Epilepsy-related death, particularly sudden unexpected death in epilepsy (SUDEP), is underestimated by healthcare professionals. One argument that physicians use to justify the failure to discuss SUDEP with patients and their families is that there is a lack of evidence for any protective interventions. However, there is growing evidence of potentially modifiable risk factors for SUDEP; although large-scale trials of interventions are still lacking. We determined the main risk factors associated with SUDEP in a comprehensive community sample of epilepsy deaths in Cornwall UK from 2004 to 2012. We systemically inspected 93 cases of all epilepsy and epilepsy associated deaths which occurred in Cornwall between 2004 and 2012 made available to us by the HM Cornwall coroner. These are the deaths where epilepsy was a primary or a secondary cause. 48 cases met the criteria for SUDEP and we elicited associated relevant risk factors. Many findings from our study are comparable to what has be...
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To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS). We analyzed prospective clinical and serologic data from 248 patients with MS... more
To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS). We analyzed prospective clinical and serologic data from 248 patients with MS treated with alemtuzumab, with median follow-up of 34.3 months (range 6.7-107.3). Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of hematologic, renal, and dermatologic AID were also observed as was asymptomatic development of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent 12-18 months after first treatment. No new cases of AID were identified 60 months or more after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of dosage. While established risk factors for AID including sex and age had no impact on AID frequency, both family history (odds ratio = 7.31, 95% confidence interval 3.02-17.68) of AID and a personal smoking history (odds ratio = 3.05, 95% confidence interval 1.50-6.19) were predictive of AID expression. Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent between 12 and 18 months following first dose and evident for up to 5 years. Individual risk is modified by smoking and family history, which should be incorporated within the counseling process prior to treatment. This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors.
Research Interests: Cognitive Science, Neurology, Multiple sclerosis, Adolescent, Counseling, and 15 moreProspective studies, Humans, Autoimmune diseases, Female, Male, Monoclonal Antibodies, Clinical Sciences, Aged, Middle Aged, Adult, Antineoplastic Agents, Neurosciences, Autoantibodies, Cohort Studies, and Methylprednisolone
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Alemtuzumab is a anti-CD52 humanised monoclonal antibody shown to be an effective treatment for relapsing multiple sclerosis (MS) in phase II studies but exhibits a unique adverse event profile. In limited follow-up studies development of... more
Alemtuzumab is a anti-CD52 humanised monoclonal antibody shown to be an effective treatment for relapsing multiple sclerosis (MS) in phase II studies but exhibits a unique adverse event profile. In limited follow-up studies development of autoimmune disease has been observed 20–30% of patients. Currently, the exact range and temporal evolution of autoimmune disease following treatment remains unclear but will have
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ABSTRACT Background We previously described the construction of a measure for global strength in MS. However, loss of strength is common to many diseases. Thus, a generic strength measure may prove widely applicable and allow... more
ABSTRACT Background We previously described the construction of a measure for global strength in MS. However, loss of strength is common to many diseases. Thus, a generic strength measure may prove widely applicable and allow inter-disease comparison. Aim To determine whether measurement performance of the MS-derived strength scale remained stable in people with CIDP. Method MRC strength data from the RMC study (n=238) were amalgamated with those from our previously described MS sample (n=371). Items included were the eight pairs of muscles (four upper limb; four lower limb) consistent across both studies. Rasch analysis was used to determine the extent to which the 16-item scale met expected criteria for measurement. Results Analysis indicated muscles mapped a measurable range of global strength. However, 9/16 muscles had statistically significant differential item functioning (DIF). In these muscles, mean scores in groups of equally strong people varied between diseases by up to 2.8 MRC grades. Analysing disease-specific data separately suggested muscle locations on the "strength ruler" changed in hierarchy depending on the disease measured. Conclusion Summed strength scores should not be compared across diseases. Rather, scores for different diseases should be analysed in the context of their own muscle hierarchies using a vehicle such as Rasch analysis. However, this study does identify a group of nondiscriminatory muscles on which a generic strength scale may be constructed.