Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial.

BACKGROUND AND PURPOSE: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study. METHODS: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed. RESULTS: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure. CONCLUSION: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.

Effect of intravenous immunoglobulin on cerebellar ataxia and neuropathic pain associated with celiac disease.

BACKGROUND: Cerebellar syndrome and small fiber neuropathy may complicate celiac disease (CD) and may be resistant to a strict gluten-free diet. METHODS: Case series. RESULTS: We report three patients with biopsy-proven CD who developed cerebellar ataxia and neuropathic pain despite strict adherence to a gluten-free diet. A small fiber neuropathy was suggested by skin biopsy findings in two patients. All patients' symptoms, including small fiber neuropathy symptoms, responded to treatment with intravenous immunoglobulin (IVIG). Discontinuation of IVIG in two patients resulted in worsened ataxia that reversed after resumption of IVIG. CONCLUSION: Intravenous immunoglobulin may be effective in treating cerebellar ataxia and small fiber neuropathy associated with CD, suggesting an immune pathogenesis. Further prospective, controlled studies are necessary to determine the long-term response to IVIG or other immunomodulation therapy.

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.

Anti-MAG/SGPG associated neuropathy does not commonly cause distal nerve temporal dispersion.

Patients with anti-myelin associated glycoprotein (anti-MAG) neuropathy have uniform slowing without temporal dispersion, but do usually have disproportionately distal slowing. We evaluated distal compound muscle action potential (CMAP) dispersion in 29 patients with anti-MAG/sulphated glucuronyl paragloboside (SGPG) neuropathy (titres > or = 12,800). Among 138 motor responses, 15% (tibial), 7.3% (peroneal), 10.7% (median) and 13.8% (ulnar) had distal CMAP duration > 9 ms. Disproportionate distal slowing with normal distal CMAP duration in the arms may be useful to differentiate chronic inflammatory demyelinating polyneuropathy from anti-MAG/SGPG associated neuropathy.

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.

Multifocal axonal polyneuropathy in celiac disease.

The authors report six patients with multifocal axonal polyneuropathy and the subsequent diagnosis of celiac disease (CD). Five patients did not improve or had only modest improvement following dietary intervention or immune therapies; one patient with marked weakness and mild electrodiagnostic findings had complete resolution of the neuropathy following immunomodulatory therapy. CD may be a cause of multifocal axonal polyneuropathy.

Correlation of clinical and demyelinating features in patients with neuropathy of otherwise unknown etiology.

PURPOSE: To correlate the electrodiagnostic and clinical features of patients with demyelinating abnormalities and neuropathy of otherwise unknown etiology. METHODS: We examined the records of patient with demyelinating abnormalities and no other cause for neuropathy that were evaluated in our electrophysiology laboratory over the course of a year, to correlate the clinical and electrodiagnostic features. RESULTS: Eight percent of all patients had one or more demyelinating abnormalities. Demyelinating features were significantly more numerous in generalized or asymmetric neuropathy than in distal polyneuropathy. The peroneal nerve was the most commonly affected in all phenotypes, and none of the patients with distal neuropathy had F-wave prolongation in the demyelinating range. CONCLUSIONS: The number and type of demyelinating abnormalities in patients with polyneuropathy vary with the clinical phenotype. The clinical presentation should be considered in developing or evaluating electrodiagnostic criteria for demyelinating neuropathies.

Mechanisms underlying celiac disease and its neurologic manifestations.

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.

Peripheral neuropathy in patients with inflammatory bowel disease.

Peripheral neuropathy (PN) in inflammatory bowel disease (IBD) patients has been reported as individual cases or small series; however, its clinical and electrodiagnostic features have not been well characterized. We conducted a retrospective review of patients with PN and either Crohn's disease (CD) or ulcerative colitis (UC). Eighteen patients with CD and 15 patients with UC were identified after other PN causes were excluded. Male predominance and mean age of PN presentation in the fifties was seen in both groups. Demyelinating neuropathy (CIDP or MMN) occurred in close to 30% of the patients, in a higher percentage of women, than in the non-demyelinating patients. One-third of CD and UC patients had small-fibre or large-fibre sensory axonal PN, while approximately 40% of the CD and UC patients had large-fibre axonal sensorimotor PN. PN symptoms began earlier in the course of CD than in UC (P < 0.05). Patients with large-fibre axonal PN were older than patients with small-fibre sensory axonal PN (P < 0.05). Close to 60% of each group received immunotherapy with different agents. Half of those treated with CD and 40% with UC had demyelinating PN. Most of the patients who completed immunotherapy in both groups improved; all the patients with demyelinating neuropathy had either moderate or major improvement. The PN syndromes in IBD patients are diverse. Demyelinating forms may occur at any time, but early in the IBD course, pure sensory neuropathy is more common. Response to immunotherapy may occur in both demyelinating and axonal neuropathies.

Celiac neuropathy.

BACKGROUND: Celiac disease (CD) is a chronic inflammatory enteropathy resulting from sensitivity to ingested gluten. Neurologic complications are estimated to occur in 10% of affected patients, with ataxia and peripheral neuropathy being the most common problems. The incidence and clinical presentation of patients with CD-associated peripheral neuropathy have not previously been investigated. OBJECTIVE: To determine the incidence of CD in patients with neuropathy and to characterize the clinical presentation. METHODS: The records of 20 patients with neuropathy and biopsy-confirmed CD were reviewed. RESULTS: Six of the 20 patients had neuropathic symptoms alone without gastrointestinal involvement, and neuropathic symptoms preceded other CD symptoms in another 3 patients. All patients had burning, tingling, and numbness in their hands and feet, with distal sensory loss, and nine had diffuse paresthesias involving the face, trunk, or lumbosacral region. Only two had weakness. Results of electrophysiologic studies were normal or mildly abnormal in 18 (90%) of the patients. Sural nerve biopsies, obtained from three patients, revealed mild to severe axonopathy. Using the agglutination assay, 13 (65%) of the patients were positive for ganglioside antibodies. Excluding patients who were referred with the diagnosis of celiac neuropathy, CD was seen in approximately 2.5% of all neuropathy patients and in 8% of patients with neuropathy and normal electrophysiologic studies seen at our center. CONCLUSION: CD is commonly associated with sensory neuropathy and should be considered even in the absence of gastrointestinal symptoms.

High-dose cyclophosphamide without stem-cell rescue for refractory CIDP.

Four patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who were refractory to conventional treatment were treated with high-dose cyclophosphamide (200 mg/kg over 4 days). All improved in functional status and muscle strength. Nerve conduction studies improved in three of four. Other immunomodulatory medications have been discontinued. High-dose cyclophosphamide can be given safely to patients with CIDP and patients with disease persistence after standard therapy may have a response that lasts for over 3 years and results in long-term disease remission.

Inclusion body myositis mimicking motor neuron disease.

OBJECTIVE: To describe the clinical and electrophysiologic features of patients with inclusion body myositis that was misinterpreted as motor neuron disease. PATIENTS AND METHODS: We retrospectively retrieved the medical records of 70 patients with a pathologic diagnosis of inclusion body myositis. From this group, we selected those who had been first diagnosed as having motor neuron disease or amyotrophic lateral sclerosis. We reviewed the clinical, electrophysiologic, laboratory, and morphologic studies. RESULTS: Nine (13%) of 70 patients with inclusion body myositis had been diagnosed as having motor neuron disease. Six of the 9 patients had asymmetric weakness; in 4 the distal arm muscles were affected. Eight patients had finger flexor weakness. Tendon reflexes were preserved in weak limbs in 6, hyperactive in 2, and absent in 1. Four patients had dysphagia. Fasciculation was seen in 2 patients. None had definite upper motor neuron signs or muscle cramps. Routine electromyographic studies showed fibrillation potentials and positive sharp waves in all 9. Fasciculation potentials were seen in 7 and long-duration polyphasic motor unit potentials were seen in 8. There was no evidence of a myogenic disorder in these 9 patients. Muscle biopsy was done because of slow progression or prominent weakness of the finger flexors and was diagnostic of inclusion body myositis. A quantitative electromyogram was myopathic in 4 of the 5 patients studied. CONCLUSIONS: Inclusion body myositis may mimic motor neuron disease. Muscle biopsy and quantitative electromyographic analysis are indicated in patients with atypical motor neuron disease, especially those with slow progression or early and disproportionate weakness of the finger flexors.

Proximal diabetic neuropathy presenting with respiratory weakness.

A patient is described with proximal diabetic neuropathy presenting with respiratory weakness. A 50 year old man developed progressive shortness of breath over 2 months. He also had weakness of hip flexion. Phrenic nerve responses were absent, and spontaneous activity was seen in the intercostal and lumbar paraspinal muscles with long duration neurogenic MUPs and reduced recruitment in the diaphragm. Without treatment, the patient began to improve with resolution of his proximal leg weakness and breathing difficulties. Proximal diabetic neuropathy is another cause of neuromuscular respiratory weakness.

Human immunodeficiency virus infection of dorsal root ganglion neurons detected by polymerase chain reaction in situ hybridization.

A predominantly sensory peripheral neuropathy is common with human immunodeficiency virus (HIV) infection, but the cause is unknown. Formalin-fixed dorsal root ganglia (DRG), obtained at postmortem from patients with neuropathy and HIV infection and from control subjects, were examined for the presence of HIV DNA by using polymerase chain reaction (PCR)-amplified in situ hybridization. Viral message RNA was detected using reverse transcription in situ PCR with gag-specific primers. HIV DNA and RNA sequences were detected in many satellite cells, mononuclear cells, and occasional neurons in 5 of 5 patients with HIV and neuropathy. HIV DNA was detected only in rare interstitial and satellite cells from 3 of 4 patients with HIV infection without neuropathy and was not detected in 6 patients without HIV infection. HIV infection of DRG neurons and supporting cells may contribute to the HIV-associated sensory neuropathy.

Myasthenic crisis: clinical features, mortality, complications, and risk factors for prolonged intubation.

We retrospectively reviewed the hospital records of 53 patients admitted for 73 episodes of myasthenic crisis at Columbia-Presbyterian Medical Center over a period of 12 years, from 1983 to 1994. Median age at the onset of first crisis was 55 (range, 20 to 82), the ratio of women to men was 2:1, and the median interval from onset of symptoms to first crisis was 8 months. Infection (usually pneumonia or upper respiratory infection) was the most common precipitating factor (38%), followed by no obvious cause (30%) and aspiration (10%). Twenty-five percent of patients were extubated at 7 days, 50% at 13 days, and 75% at 31 days; the longest crisis exceeded 5 months. Using survival analysis and backward stepwise Cox regression, we identified three independent predictors of prolonged intubation: (1) pre-intubation serum bicarbonate > or = 30 mg/dl (p = 0.0004, relative hazard 4.5), (2) peak vital capacity day 1 to 6 post-intubation < 25 ml/kg (p = 0.001, relative hazard 2.9), and (3) age > 50 (p = 0.01, relative hazard 2.4). The proportion of patients intubated longer than 2 weeks was 0% among those with no risk factors, 21% with one risk factor, 46% with two risk factors, and 88% with three risk factors (p = 0.0004). Complications independently associated with prolonged intubation included atelectasis (p = 0.002), anemia treated with transfusion (p = 0.03), Clostridium difficile infection (p = 0.01), and congestive heart failure (p = 0.03). Three episodes of crisis were fatal, for a mortality rate of 4% (3/73); four additional patients died after extubation. All seven deaths were due to overwhelming medical comorbidity. Over half of those who survived were functionally dependent (home or institutionalized) at discharge. In addition to prospective controlled studies of immunotherapies, the prevention and treatment of medical complications offers the best opportunity for further improving the outcome of myasthenic crisis.

Physiological tremor analysis of patients with anti-myelin-associated glycoprotein associated neuropathy and tremor.

Tremor is often associated with anti-myelin-associated glycoprotein (anti-MAG) peripheral neuropathy (PN), but its physiology has never been accurately described. This study quantified the physiological characteristics of tremors in patients with anti-MAG demyelinating PN. Eighteen patients with tremor and PN with demyelinating features (ages 30-86, mean = 66.5 years) were evaluated for anti-MAG antibodies (positive considered > or = 1:3200) and for tremor amplitude, frequency, side-to-side relationships, and electromyographic (EMG) activation patterns. Thirteen patients had anti-MAG titers >1:3200 and 8 had both positive anti-MAG titers and tremors. Anti-MAG PN patients revealed tremors higher in amplitude, lower in frequency, with greater side-to-side amplitude ratios, greater amplitude variability, and more consistent cocontracting antagonist EMG patterns that do not attenuate with inertial loading. We conclude that anti-MAG PN tremor is not due only to exaggerated physiologic mechanisms but may reflect a distinctive form of neurogenic tremor.

Retroviral-associated vasculitis of the nervous system.

Vasculitis may involve the central and peripheral nervous system in HIV-infected patients. Central nervous system vasculitis is rare with HIV infection and most are owing to opportunistic infections including varicella, CMV, fungal, tuberculosis, and syphilis. Vasculitis of the peripheral nerve may cause mononeuritis multiplex or polyneuropathy, sometimes as the first symptom of HIV or after AIDS has developed. Symptoms may be limited to the peripheral nerve. The etiology may be infection of endothelial cells, hepatitis B or HIV-induced immune complexes, or dysregulation of cytokines and adhesion molecules. Treatment with steroids alone is often effective; IVIg and cytotoxic agents have also been used. It is uncertain whether vasculitis of the nervous system is ever due to other retroviruses (HIV-2, HTLV-1, and HTLV-2).

The role of quantitative electromyography in inclusion body myositis.

OBJECTIVE AND METHODS: Inclusion body myositis is said to have both myopathic and neurogenic features on electrophysiological tests. Twenty one studies from 20 patients with biopsy defined inclusion body myosis, 13 of whom had quantitative electromyography (qEMG), were reviewed to determine if this technique added diagnostic specificity (one patient had both needle EMG and a later study with qEMG before muscle biopsy). RESULTS: Excessive numbers of polyphasic motor unit potentials (MUPs) (> 12% per muscle) were seen in 11 of the 13 patients. In 10 of 13 patients, mean MUP duration was abnormally reduced (26% to 48%). In three patients, mean MUP duration was abnormally reduced only after polyphasic MUPs were excluded. In all 13 patients, the simple MUP duration was reduced. Myopathy was unequivocally diagnosed in all 13 studies that included qEMG; of the remaining eight patients, the conclusions of the electrophysiological studies without qEMG was myopathy (one), neurogenic (four) or non-diagnostic (three). CONCLUSIONS: There is no evidence of a neurogenic component in inclusion body myosis if qEMG is used. Quantitative EMG is often necessary to make an electrophysiological diagnosis of a myogenic disorder in patients with inclusion body myosis.

Motor neuron disease, lymphoproliferative disease, and bone marrow biopsy.

Some have suggested that nonfamilial motor neuron disease (MND) may be autoimmune, and the neurological disorder may benefit from immunotherapy. There have been reports of over 30 cases of lymphoproliferative disease (lymphoma, multiple myeloma, Waldenström's macroglobulinemia) with MND, and these patients might he offered immunosuppressive therapy. Bone marrow examination might increase the sensitivity of the diagnostic workup for lymphoma and other lymphoproliferative disorders. We examined the bone marrow in our first evaluation of 161 patients with MND seen at Columbia-Presbyterian Medical Center during 1991-1994. Four of 161 patients (2.5%) had lymphoproliferative disease in the marrow; only 1 of these had a monoclonal paraprotein. Routine bone marrow examination of patients with MND increases the diagnostic yield of lymphoproliferative diseases. The frequency of these bone marrow abnormalities in comparison with a group of age-matched control subjects should be studied further.