Dean Kilfoyle

Peripheral Neuropathy and Tear Film Dysfunction in Type 1 Diabetes Mellitus

Purpose. To compare tear film metrics in patients with type 1 diabetes mellitus (DM) and healthy controls and investigate the association between peripheral neuropathy and ocular surface quality. Methods. Dry eye symptoms were quantified in 53 patients with type 1 DM and 40 age-matched controls. Ocular examination included tear film lipid layer thickness grading, tear film stability and quantity measurement, and retinal photography. DM individuals additionally underwent a detailed neuropathy assessment. Results. Neither mean age nor dry eye symptom scores differed significantly between the DM and control groups (P = 0.12 and P = 0.33, resp.). Tear lipid thickness (P = 0.02), stability (P < 0.0001), and quantity (P = 0.01) were significantly lower in the DM group. Corneal sensitivity was also reduced in the DM group (P < 0.001) and tear film stability was inversely associated with total neuropathy score (r = −0.29, P = 0.03). Conclusion. The DM group exhibited significantly reduced tear film stability, secretion, and lipid layer quality relative to the age-matched control group. The negative correlation between tear film parameters and total neuropathy score suggests that ocular surface abnormalities occur in parallel with diabetic peripheral neuropathy.

Pulsed methylprednisolone is a safe and effective treatment for diabetic amyotrophy.

There is evidence that diabetic amyotrophy is caused by a microvasculitis of the vasa nervorum. We compared the outcome of patients treated with pulsed methylprednisolone to the published natural history of diabetic amyotrophy and assessed the safety of this treatment in patients with diabetes. We retrospectively reviewed the case records of 10 episodes of diabetic amyotrophy in 9 patients treated with pulsed oral or intravenous methylprednisolone. In 6 episodes there was marked improvement in pain within days of starting treatment. Strength improved more slowly but faster than the natural history of the disease. Treatment started within 2 months of symptom onset was associated with rapid improvement in pain; and very early treatment, started within 4 weeks of symptom onset, resulted in rapid improvement of both strength and pain. Blood glucose increased on treatment days but no patient required lasting changes in diabetic treatment as the result of this therapy and no other serious adverse effects were seen. We conclude that pulsed methylprednisolone appears to be a safe and effective treatment for diabetic amyotrophy.

Recurrent Severe Aseptic Meningitis after Exposure to Lamotrigine in a Patient with Systemic Lupus Erythematosus

To the Editor: In a 16-year-old woman with systemic lupus erythematosus (SLE) and receiving a stable dose of sodium valproate (VPA) for the treatment of idiopathic generalized epilepsy, two episodes of severe aseptic meningitis developed after treatment with lamotrigine (LTG). Both episodes of aseptic meningitis resolved after discontinuation of LTG. Extensive investigations failed to disclose any other cause than a hypersensitivity reaction to LTG. Aseptic meningitis can occur as a rare reaction to several medications, most commonly nonsteroidal antiinflammatory drugs, trimethoprim-sulfamethoxazole, and intravenous immunoglobulin. We present a case of recurrent aseptic meningitis after exposure to LTG. A 16-year-old woman with idiopathic generalized epilepsy with tonic–clonic seizures was first seen with fever and headache after starting LTG, 25 mg, on alternate days in addition to her regular 1 g daily of VPA. She was not taking a nonsteroidal antiinflammatory drug or any other medication. Eighteen months earlier, SLE was suspected on the basis of hemolytic anemia, thrombocytopenia, antinuclear antibody titer >1:2,560 with a speckled staining pattern, and positive anti–double-stranded DNA, anti-Ro, and anti-La antibodies. Anti-Sm and anticardiolipin antibody testing was negative. She met three of the 11 American Rheumatism Association criteria for SLE (1). Her first generalized tonic–clonic seizure occurred at age 8 years. Electroencephalography showed several brief bursts of generalized spike and polyspike-and-wave complexes during hyperventilation and drowsiness consistent with primary generalized epilepsy. She remained seizure free until age 15 years, after which she had frequent generalized tonic–clonic seizures. VPA, 2 g/day was required

Autonomic dysfunction is a major feature of cerebellar ataxia, neuropathy, vestibular areflexia ‘CANVAS’ syndrome

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative ganglionopathy. Prompted by the presence of symptomatic postural hypotension in two patients with CANVAS, we hypothesized that autonomic dysfunction may be an associated feature of the syndrome. We assessed symptoms of autonomic dysfunction and performed autonomic nervous system testing among 26 patients from New Zealand. After excluding three patients with diabetes mellitus, 83% had evidence of autonomic dysfunction; all patients had at least one autonomic symptom and 91% had more than two symptoms. We also found a higher rate of downbeat nystagmus (65%) than previously described in CANVAS. We confirmed that sensory findings on nerve conduction tests were consistent with a sensory ganglionopathy and describe two patients with loss of trigeminal sensation consistent with previous pathological descriptions of trigeminal sensory ganglionopathy. Our results suggest that autonomic dysfunction is a major feature of CANVAS. This has implications for the management of patients with CANVAS as the autonomic symptoms may be amenable to treatment. The findings also provide an important differential diagnosis from multiple system atrophy for patients who present with ataxia and autonomic failure.

Phase I drug-interaction study of effects of calcium and magnesium infusions on oxaliplatin pharmacokinetics and acute neurotoxicity in colorectal cancer patients

BackgroundCalcium and magnesium (Ca/Mg) infusions have been suggested as an effective intervention for preventing oxaliplatin-induced neurotoxicity, but the effects of Ca/Mg infusions on oxaliplatin pharmacokinetics, motor nerve hyperexcitability and acute neurotoxicity symptoms are unclear.MethodsIn this double blind crossover study, colorectal cancer patients undergoing oxaliplatin-based chemotherapy were randomised to receive Ca/Mg (1g Ca Gluconate plus 1g MgSO4) on cycle 1 and placebo (vehicle alone) on cycle 2, or to receive the same treatments in the opposite sequence. Study endpoints included plasma pharmacokinetics of intact oxaliplatin and free platinum; electromyography (EMG) detection of abnormal spontaneous high-frequency motor unit action potential discharges; and patient-reported acute neurotoxicity symptoms and their preferred study treatment for reducing these symptoms.ResultsNineteen of 20 enrolled patients completed the study. Plasma pharmacokinetics of intact oxaliplatin and free platinum were similar when oxaliplatin was given with Ca/Mg or placebo (ratio of geometric means of AUC0-t with Ca/Mg or placebo: intact oxaliplatin, 0.95 (90% CI, 0.90 – 1.01); free platinum, 0.99 (90% CI, 0.94 – 1.05)). EMG motor nerve hyperexcitability scores were similar with Ca/Mg and placebo (mean difference in EMG score between Ca/Mg and placebo: -0.3 (95% CI, -2.2 – 1.6)). Patient-reported acute neurotoxicity symptoms were similar in frequency with Ca/Mg and placebo. For reducing neurotoxic symptoms, fewer patients preferred Ca/Mg than placebo or neither treatment (26% versus 74%; P<0.01).ConclusionsCa/Mg infusions do not alter the clinical pharmacokinetics of oxaliplatin and do not seem to reduce its acute neurotoxicity.Trial registrationTrial registration identifier ACTRN12611000738921

Facial onset sensorimotor neuronopathy syndrome: a case series.

Objective: Facial onset sensorimotor neuronopathy (FOSMN) is a recently described neurological syndrome characterized by slow onset of facial sensory abnormalities and subsequent development of motor deficits. Except for 1 patient, FOSMN has so far been identified only in men. Methods: We describe a case series of 3 women with FOSMN. We report their clinical, laboratory, and neurophysiological findings. Results: The age of onset ranged from 39 to 72 years (mean, 60 years) with presentation 4–7 years after symptom onset. The first symptom was slowly progressive facial numbness, which was followed years later by dysphagia and impaired corneal reflexes. Dysarthria occurred in 2 patients, and mild arm weakness was noted in 2. Muscle stretch reflexes were increased in 1 patient, and in another case, arm sensation was reduced. Laboratory studies were unremarkable, and magnetic resonance imaging of the brain in 3 patients and of the cervical spine in 2 patients was normal. Nerve conduction studies showed reduced leg compound muscle action potential amplitudes in 1 patient and asymmetrically reduced arm sensory nerve action potentials in another case. In 2 patients, electromyography showed widespread active denervation in arm muscles in conjunction with the involvement of leg muscles in 1 case and the tongue in the other patient. We identified chronic neurogenic motor unit action potentials in the genioglossus muscle of all 3 cases while facial EMG performed in case 3 showed similar findings. Blink reflexes were abnormal in all patients. We treated 1 patient with high-dose intravenous methylprednisolone followed by intravenous immunoglobulin without any improvement, and she required percutaneous endoscopic gastrostomy (PEG) tube placement. Conclusions: This is the first case series describing 3 women with the FOSMN syndrome. We expand phenotype of FOSMN to include upper motor neuron signs and normal arm sensory nerve action potentials.

Incidence of Transient Ischemic Attack in Auckland, New Zealand, in 2011 to 2012

Background and Purpose— There have been few recent population-based studies reporting the incidence (first ever) and attack rates (incident and recurrent) of transient ischemic attack (TIA). Methods— The fourth Auckland Regional Community Stroke study (ARCOS IV) used multiple overlapping case ascertainment methods to identify all hospitalized and nonhospitalized cases of TIA that occurred in people ≥16 years of age usually resident in Auckland (population ≥16 years of age is 1.12 million), during the 12 months from March 1, 2011. All first-ever and recurrent new TIAs (any new TIA 28 days after the index event) during the study period were recorded. Results— There were 785 people with TIA (402 [51.2%] women, mean [SD] age 71.5 [13.8] years); 614 (78%) of European origin, 84 (11%) Māori/Pacific, and 75 (10%) Asian/Other. The annual incidence of TIA was 40 (95% confidence interval, 36–43), and attack rate was 63 (95% confidence interval, 59–68), per 100 000 people, age standardized to the World Health Organization world population. Approximately two thirds of people were known to be hypertensive or were being treated with blood pressure–lowering agents, half were taking antiplatelet agents and just under half were taking lipid-lowering therapy before the index TIA. Two hundred ten (27%) people were known to have atrial fibrillation at the time of the TIA, of whom only 61 (29%) were taking anticoagulant therapy, suggesting a failure to identify or treat atrial fibrillation. Conclusions— This study describes the burden of TIA in an era of aggressive primary and secondary vascular risk factor management. Education programs for medical practitioners and patients around the identification and management of atrial fibrillation are required.

A unique case of neural amyloidoma diagnosed by mass spectrometry of formalin-fixed tissue using a novel preparative technique

We report here a unique amyloidoma of the radial nerve which could not be subtyped by available techniques, including immunohistochemistry and standard clinical and laboratory evaluation. In order to identify the amyloid monomer, we developed a novel preparative procedure designed to optimize conditions for liquid chromatography tandem mass spectrometry analysis of formalin-fixed/paraffin-embedded (FFPE) tissue. Subsequent mass spectrometric analysis clearly identified kappa light chain as the monomer, with no evidence of lambda light chain. Manual interpretation of the matched spectra revealed no evidence of polyclonality. This study also enabled detailed characterisation of twelve likely amyloid matrix components. Finally, our analysis revealed extensive hydroxylation of collagen type I but, unexpectedly, an almost complete lack of hydroxylated residues in the normally heavily-hydroxylated collagen type VI chains, pointing to structural/functional alterations of collagen VI in this matrix that could have contributed to the pathogenesis of this very unusual tumour. Given the high quality of the data here acquired using a standard quadrupole-time of flight tandem mass spectrometer of modest performance, the robust and straightforward preparative method described constitutes a competitive alternative to more involved approaches using state-of-the-art equipment.

Peripheral nerve ultrasound in Friedreich ataxia: Nerve Ultrasound in Friedreich Ataxia

Sensory impairment in Friedreich ataxia (FRDA) is generally accepted as being due to a ganglionopathy. The degree of contribution from axonal pathology remains a matter of debate. Nerve ultrasound may be able to differentiate these processes.

S69. Peripheral nerve ultrasound in Friedreich’s ataxia

Introduction Sensory impairment in Friedreich’s ataxia (FRDA) is generally accepted as being due to a ganglionopathy. The degree of contribution from axonal pathology remains a matter of debate. Nerve ultrasound may be able to differentiate these processes. Methods The ultrasound cross-sectional area of median, ulnar, tibial and sural nerves of 8 patients with FRDA was compared with 8 age- and gender-matched healthy controls and with reference values in our population. Results The nerves of the patients with FRDA were significantly larger than healthy controls’ at all upper limb sites ( p 0.05 ) but not significantly different in the lower limbs. Conclusion Our findings add further weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are likely to also play a role.