Thomas H. Brannagan

Complications of intravenous immune globulin treatment in neurologic disease

Intravenous immune globulin (IVIg) is advocated as a safe treatment for immune-mediated neurologic disease. We reviewed the medical records of 88 patients who were given IVIg for a neurologic illness. Major complications in four patients (4.5%) included congestive heart failure in a patient with polymyositis, hypotension after a recent myocardial infarction, deep venous thrombosis in a bed-bound patient, and acute renal failure with diabetic nephropathy. Other adverse effects included vasomotor symptoms 26, headache 23, rash 5, leukopenia 4, fever 3, neutropenia 1, proteinuria (1.9 g/day) 1, viral syndrome 1, dyspnea 1, and pruritis 1. Fifty-two patients (59%) had some adverse effect of IVIg infusion, most commonly vasomotor symptoms, headaches, fever, or shortness of breath in 40 (45%), which improved with reduced infusion rate or symptomatic medications. Five (6%) had asymptomatic laboratory abnormalities and seven (8%) had other minor adverse effects. Adverse effects led to discontinuation of therapy in 16% and permanent termination of therapy in 10% of patients. There was no mortality or long-term morbidity. Although adverse effects were frequent, serious complications were rare except in patients with heart disease, renal insufficiency, and bed-bound state. NEUROLOGY 1996;47: 674-677

Non-length dependent small fibre neuropathy/ganglionopathy

Objective: To describe the clinical and laboratory features of a painful non-length dependent, small fibre ganglionopathy (SFG). Background: The syndrome of generalised SFG with early involvement of the face, trunk or proximal limbs is not well recognised and contrasts with the burning feet syndrome of small fibre neuropathy (SFN) and classical large fibre features of sensory ganglionopathy. Methods: Retrospective case review including skin biopsies from four neuromuscular centres. Patients with pre-existing diseases associated with ganglionopathies were excluded. Results: 12 men and 11 women, with an average age of 50 years, were studied. Neuropathic pain developed over days in eight and over months in the other patients. The face (n = 12), scalp (n = 10), tongue (n = 6), trunk (n = 15) and acral extremities (n = 21) were involved. Symptoms began in the hands or face before the legs in 10. The pain was characterised as burning (n = 22), prickling (n = 13), shooting (n = 13) or allodynic (n = 11). There was loss of pinprick sensation in affected regions in 19, with minimal or no loss of large fibre sensibility. Laboratory findings included abnormal glucose metabolism in six patients, Sjögren syndrome in three and monoclonal gammopathy, sprue and hepatitis C infection in one each, with the remainder idiopathic. Sensory nerve action potentials were normal in 12 and were reduced in the hands but normal in the legs in six. Skin biopsy in 14 of 17 showed reduced nerve fibre density in the thigh equal to or more prominent than in the calf. Two of seven patients improved with immune therapies, 13 symptomatically with analgesic medications and the remainder had little improvement. Ten considered the pain disabling at the last follow-up (mean 2 years). Conclusion: The pattern of symmetric, non-length dependent neuropathic pain with face and trunk involvement suggests a selective disorder of the dorsal ganglia cells subserving small nerve fibres. It can be distinguished from distal SFN. A potential metabolic or immune process was detected in half of the cases and the disorder was often refractory to treatment.

HIV-associated Guillain–Barré syndrome

Human immunodeficiency virus-associated Guillain-Barré syndrome (HIV-GBS) has been reported since 1985. Based on previous reports, this neuropathy typically occurs early in HIV infection, even at seroconversion, prior to developing acquired immunodeficiency syndrome (AIDS). Patients with GBS and CD4 counts of <50 have been proposed to have cytomegalovirus (CMV) infection and empiric gancyclovir is recommended. We reviewed medical records of 10 patients with HIV-GBS at five hospitals from 1986 to 1999. The mean CD4 count was 367/mm(3) (range 55-800). GBS was the first symptom of HIV infection in three patients. Four patients had AIDS with CD4 counts ranging from 55 to 190. CSF white blood cell (WBC) was 0 wbc/mm(3) in four patients, 2-10 wbc/mm(3) in three and 11-17 wbc/mm(3) in two. Three had recurrent weakness from 9 weeks to 4 years after the onset of symptoms, which persisted. HIV-GBS occurs in early and late stages of HIV infection, and may follow the onset of AIDS. No patients were seen with severe immunosuppression (CD4<50). A mild cerebrospinal fluid (CSF) pleocytosis in GBS suggests HIV infection, but is frequently absent. Compared to HIV-negative people, HIV-GBS may be associated with more frequent recurrent episodes or the development of CIDP.

Mechanisms underlying celiac disease and its neurologic manifestations

Abstract.The extra-intestinal manifestations of celiac disease (CD), including ataxia and peripheral neuropathy, are increasingly being recognized as the presenting symptoms of this autoimmune disease. Although there is a greater understanding of the pathogenesis of the intestinal lesions in CD the mechanisms behind the neurologic manifestations of CD have not been elucidated. In this article, the authors review the cellular and molecular mechanisms behind the histopathologic changes in the intestine, discuss the presentation and characteristics of neurologic manifestations of CD, review the data on the mechanisms behind these manifestations, and discuss the diagnosis and treatment of CD. Molecular mimicry and intermolecular help may play a role in the development of neurologic complications.

High-dose cyclophosphamide results in long-term disease remission with restoration of a normal quality of life in patients with severe refractory chronic inflammatory demyelinating polyneuropathy

Abstract  We previously reported the improvement of clinical parameters in severe, refractory chronic inflammatory demyelinating polyneuropathy (CIDP) following high‐dose cyclophosphamide therapy. Here, we examine effects of this therapy on quality of life, report long‐term clinical follow‐up, and include new data on a fifth patient. Patients completed The Medical Outcomes Short Form 36 to assess quality of life impact. Pretherapy and post‐therapy scores were compared with the Wilcoxon Signed Ranks Test. Patients post‐therapy scores were compared with the normal United States population. Functional status was assessed with the Modified Rankin score. Strength was assessed using a summated MRC strength. Nerve conduction studies were conducted using standard techniques with supramaximal stimulation. The median follow‐up for the five patients is 2.9 (range: 1.6–4.8) years. The first four patients remain off all immunomodulatory medications. In six of the eight quality of life scales measured, patients enjoyed clinically significant improvement. Their overall strength increased by a median change of 10 (range: −1 to 20); their overall Modified Rankin score increased by a median of 3 (range: 0–4), and their summated compound motor action potential amplitudes increased by a mean of 3.69 mV (range: 0.156–7.83). Patient 5 has had stabilization of motor strength. High‐dose cyclophosphamide can markedly improve functionality and quality of life for patients with severe refractory CIDP.

Current treatments of chronic immune-mediated demyelinating polyneuropathies

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), and anti–myelin‐associated glycoprotein (anti‐MAG) neuropathy are three demyelinating acquired neuropathies, with distinct responses to immunotherapy. In placebo‐controlled, double‐blind, randomized trials, intravenous immunoglobulin (IVIg) has been effective for CIDP and MMN, and plasmapheresis has been effective for CIDP. Corticosteroids have been beneficial in controlled trials for CIDP. Other agents, including cyclophosphamide, rituximab, azathioprine, cyclosporine, interferons, fludarabine, mycophenolate mofetil, and etanercept, have been reported to benefit some patients with inflammatory demyelinating neuropathies in case series and case reports. This review examines the use and toxicity associated with these immunotherapy medications in treating patients with chronic immune‐mediated demyelinating neuropathies. Muscle Nerve, 2009

Cerebellar ataxia and coeliac disease

A 37-year-old woman presented in July, 2002, with a 12-year history of progressive dysarthria and ataxia. Her symptoms became noticeably worse during pregnancy in 1999 and 2001. She had also been anaemic for the past 7 years, and coeliac disease had been diagnosed in 1997. At that time, she had high serum concentrations of IgG and IgA antibodies to gliadin, an endomysial titre of 1:32, and duodenal atrophy on endoscopy; a duodenal biopsy showed subtotal villous atrophy. Neurological tests were done at the same time; median somatosensory evoked potentials showed a delay between the lower brainstem and cortex. She underwent tests for spinocerebellar ataxia, 1–3 brainstem auditory and visual evoked potentials, and cerebral MRI, none of which showed any abnormalites. Cervical spine MRI showed mild degenerative changes. For 5 years, she had followed a strict gluten-free diet, but on examination in 2002 she had severe dysarthria, left finger-to-nose dysmetria, poor right rapid-alternating and fine-finger movements, diminished pedal pin-perception, ankle areflexia, and a severely ataxic, wide-based gait. A modified (without Archimedes Spiral) International Cooperative Ataxia Rating scale (ICARS) score was 31/96. 4 We did many serological tests for autoimmune disease including IgG and IgA antibodies to gliadin, purkinje cells, and voltage-gated calcium channels. The only abnormal results were increased IgA antibodies to transglutaminase, and glutamic acid decarboxylase (GAD). Cerebral MRI showed superior vermis atrophy, whereas lumbosacral MRI was normal. Sensory nerve conduction amplitudes were low. H reflexes were absent. Electromyography showed prolonged durations of motor unit potentials distally. We did not do a nerve biopsy, and we do not have the facilities to do indirect immunohistochemistry or immunofluoresence. We treated her with intravenous immunoglobulin (IVIg) 2 g/kg initially, and 0.5 g/kg 2 weeks later. Within a month, she reported substantial improvements in her speech and gait. She was able to safely hold her children. Acquaintances noted that the audible slap of her walk CASE REPORT disappeared. Squatting, walking, stair-climbing, tandem gait, and standing on one leg all became much easier, and she no longer spilt cups of liquid. On examinaton, we found that all the neurological signs had improved; she still had slight dysarthria and left finger-nose dysmetria, an unsteady gait with a widened base and very slight slapping, and impaired tandem walking, and we calcuated a modified ICARS score of 3/96. She developed a slight rash, so we stopped IVIg and gave her a single dose of methylprednisolone. However, 5 …

Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibres on skin biopsy

Clinical, laboratory and electrodiagnostic (EDX) characteristics of 62 patients with sensory neuropathy with abnormal skin biopsies were reviewed. Reduced epidermal nerve fibre density (ENFD) was seen in 71% and morphological changes with normal ENFD were seen in 29% of the patients. Patients with small fibre sensory neuropathy may have associated large fibre loss undetected by routine EDX. Identified associations included abnormal glucose metabolism, Lyme vaccination, monoclonal gammopathy, vitamin B12 deficiency, coeliac disease, and diseases of the connective tissue, inflammatory bowel and thyroid. Sensory neuropathy remained undetermined in 50% of the patients.

Multiple system atrophy and amyotrophic lateral sclerosis in a family with hexanucleotide repeat expansions in C9orf72.

IMPORTANCE Here we report a family with coexistence of multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS) with hexanucleotide repeat expansions in C9orf72. OBSERVATIONS A 65-year-old woman had a 2-year history of ataxia with autonomic dysfunction but without motor neuron signs. She was diagnosed as having MSA based on her clinical history and the hot cross bun sign on brain magnetic resonance imaging. Her 62-year-old brother had progressive weakness, fasciculations, hyperreflexia, and active denervation on electromyography without cerebellar ataxia. He was diagnosed as having ALS. Both patients had a greater than 1000/2 hexanucleotide expansion in C9orf72. CONCLUSIONS AND RELEVANCE Patients with hexanucleotide repeat expansions in C9orf72 can present with MSA as well as ALS or frontotemporal dementia. We report this family with coexisting MSA and ALS, highlighting the phenotypic variability in neurologic presentations with hexanucleotide repeat expansions in C9orf72.

Experience with the Awaji Island modifications to the ALS diagnostic criteria

Amyotrophic lateral sclerosis (ALS) remains a clinical diagnosis without validated biomarkers. To increase diagnostic sensitivity, an expert group modified the Airlie House diagnostic criteria and formulated new recommendations at a meeting on Awaji Island. Our retrospective analysis of patients referred over a 6‐month period to the electromyography (EMG) laboratory for suspected motor neuron disease (MND) showed a higher agreement of the Awaji modifications than the Airlie House criteria with the clinical diagnosis of ALS. Muscle Nerve, 2010