Atlas of Neuromuscular Diseases - part 8 pps

330 Biopsy is not usually performed, as the EMG and genetic information is decisive. HNPP may resemble CMT, but the occurrence of pressure palsies and the EMG findings make HNPP distinctive. Inflammatory neuropathies like CIDP and multifocal motor neuropathy (MMN) with conduction block should also be considered. MMN does not usually show signs of sensory impairment with electrodiagnostic studies. The electrodiagnostic findings in CIDP are symmetri- cal. HNPP is usually treated with support. Surgical intervention for entrapment is controversial, as manipulations frequently cause nerve injury. Genetic counseling can be provided to family members. The course of HNPP is usually benign. Andersson PB, Yuen E, Parko K, et al (2000) Electrodiagnostic features of hereditary neuropathy with liability to pressure palsies. Neurology 54: 40–44 Chance PF (1999) Overview of hereditary neuropathy with liability to pressure palsies. Ann NY Acad Sci 883: 14–21 De Jonghe P, Timmerman V, Nelis E, et al (1997) Charcot-Marie-Tooth disease and related peripheral neuropathies. J Peripher Nerv Syst 2: 370–387 Pareyson D, Taroni F (1996) Deletion of the PMP22 gene and hereditary neuropathy with liability to pressure palsies. Curr Opin Neurol 9: 348–354 Differential diagnosis Therapy References Prognosis 331 Porphyria causes axonal degeneration with some regions of demyelination. Patients typically present with debilitating abdominal pain, changes in urine color, constipation, and vomiting. Neuropathy usually follows the abdominal signs by several days, and resembles AIDP, with pain and potentially asymmet- ric weakness. CNS disturbances can precede neuropathy, including agitation, psychosis, seizures, and eventually coma. Weakness can involve the face and respiratory muscles. Autonomic dysfunction is common. In some forms of porphyria, skin blisters can accompany an acute attack. Attacks can be precipitated by drugs that stress liver function, fasting, stress, and alcohol. Porphyria is rare and caused by disruption of heme biosynthesis. Subtypes of porphyria result from dysfunction of each of the enzymes in the heme synthetic pathway, but only the subtypes that involve liver enzymes cause neuropathy. These subtypes are aminolevulinic acid dehydrase deficiency, acute intermit- tent prophyria, hereditary coproporphyria, and variegate porphyria. Electrodiagnosis shows predominantly motor impairment. The primary diagnositic tool for an acute attack is a rapid urine test for porphobilinogen. Genetic testing is useful for exact diagnosis and for family counseling. AIDP does not involve such intense abdominal pain. Changes in urine color should raise suspicion of porphyria. Poisoning by lead, arsenic, or thallium can appear similar to porphyria, and even cause increases in urine porphobilino- gen. The most important treatment for an acute attack is IV heme, with attention to carbohydrate and fluid maintenance. Hyponatremia may occur and needs to be corrected. Any precipitating drugs should be withdrawn. Pain and vomiting should be treated. CNS disturbances can be difficult to treat, although gabapen- tin may help control seizures. Porphyria Anatomy/distribution Genetic testing NCV/EMG Laboratory Imaging Biopsy ++ ++ Symptoms Clinical syndrome/ signs Pathogenesis Diagnosis Differential diagnosis Therapy 332 In the long term, prevention is the best therapy. Drugs that can precipitate attacks should be avoided. Some porphyria can be triggered by hormonal changes during menstruation, and these cases can be very difficult to control. Heme therapy is very effective at quelling acute attacks, although mortality may still be as high as 10%. Most patients recover on the whole, but severe neuropathy may be resistant because of the axonal degeneration. Kochar DK, Poonia A, Kumawat BL, et al (2000) Study of motor and sensory nerve conduction velocities, late responses (F-wave and H-reflex) and somatosensory evoked potential in latent phase of intermittent acute porphyria. Electromyogr Clin Neurophysiol 40 (2): 73–79 Meyer UA, Schuurmans MM, Lindberg RL (1998) Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis 18 (1): 43–52 Muley SA, Midani HA, Rank JM, et al (1998) Neuropathy in erythropoietic protoporphyr- ias. Neurology 51 (1): 262–265 Wikberg A, Andersson C, Lithner F (2000) Signs of neuropathy in the lower legs and feet of patients with acute intermittent porphyria. J Intern Med 248 (1): 27–32 Prognosis References 333 Many other hereditary neuropathies have been identified, often in just a handful of families in a particular ethnic and geographic region. Several of the more common disorders are summarized in the chart below. X-linked CMT is more common than CMT-2, and Riley-Day syndrome is fairly common in Ashkenazi Jews. All are treated symptomatically and are gradually progressive. Kuhlenbaumer G, Young P, Hunermund G, et al (2002) Clinical features and molecular genetics of hereditary peripheral neuropathies. J Neurol 249(12): 1629–1650 Other rare hereditary neuropathies Reference Neuropathy Genetics Clinical features CMT-3 Autosomal dominant, Severe demyelinating (Dejerine-Sottas sporadic, or recessive. neuropathy of childhood. disease) Linked to mutations or Both motor and sensory see Fig. 16 deletions in PMP22 or involvement. Po. Very slow NCVs. CMT-4 Autosomal recessive. Demyelinating motor and Several subclassifications sensory neuropathy with have been identified in slow NCVs. different families with distinct loci. X-linked CMT X-linked dominant, more Demyelinating neuropathy severe in males. with axonal degeneration. Mutation in Connexin 32. Slow or intermediate NCVs. Genetic testing is available. Hereditary Autosomal dominant Axonal sensory neuropathy. Sensory neuropathy identified Normal NCVs. Neuropathy in several Australian (HSN) families. Riley-Day Autosomal recessive, Severe small fiber neuro- syndrome occurs in 1:50,000 pathy with pulmonary and (familial Ashkenazi Jews. renal complications. dysautonomia) NCV is normal. 335 Neuromuscular transmission disorders and other conditions 337 Myasthenia gravis Stages of MG Symptoms Neonatal Transient form acquired from MG mothers Juvenile – see congenital MG Adult group I Localized, usually ocular Adult group II Generalized, bulbar Adult group III Acute fulminating, bulbar and generalized, respiration failing Adult group IV Late severe developing from I and II Adult group V With muscle atrophy from II Classification (Osserman 1958) Genetic testing NCV/EMG Laboratory Imaging Biopsy Repetitive Acetylcholine receptor CT: Thymus stimulation antibodies (AChR-Ab) Single fiber Muscle specific tyrosine EMG (SFEMG) kinase antibodies (MuSK) Fig. 1. Generalized myasthenia gravis, key features. A Ptosis B Attempted gaze to the right. Only right eye abducts incom- pletely. C Demonstrates proxi- mal weakness upon attempt to raise the arms. D Holding the arms and fingers extended the extensor muscles weaken and finger drop occurs 338 The incidence in a European study was 7/1,000,000, the prevalence 70/1,000,000. The MG mortality is 0.67/million, and cause of death attributed to MG is only 0.4/1,000,000. The sex prevalence is female to male of 1.4/1. Myasthenia gravis (MG) is an autoimmune disease. Autoantibodies to acetyl- choline receptor epitopes block neuromuscular transmission. Long duration badly controlled disease results in a reduced number of acetylcholine receptors (AChR) and damage to the post-synaptic membrane. Lymphorrhagia in affected muscles has been observed in the past, when immunosuppression was not available. Congenital myasthenic syndromes Acquired autoimmune – Transient neonatal – Ocular MG – Generalized MG Fatigability and weakness are the hallmark (see Fig. 1). Weakness predominant- ly involves eyelids and extraocular muscles, resulting in diplopia. Ocular, bulbar, truncal, and proximal limb muscles are most commonly affected. Respiration muscles may be involved. MG is characterized by fluctuations. The symptoms are generally less severe in the morning and worsen over the day. Intensity of the disease can fluctuate over weeks and months. Exacerbations (“myasthenic crisis”) and remissions occur. In clinical terminology the disease is classified into ocular and generalized myasthenia. Weakness in the cranial nerves results predominantly in ocular and bulbar weakness, often asymmetrical. Weakness increases with the time of day, de- pending on muscle activity. Diplopia, dysarthria and dysphagia may result. Speech may become nasal during prolonged talking. Oculobulbar muscles are spared in a few patients. Weakness in the trunk and extremities tends to be proximal. Also flexors and extensors of the neck may be involved. Subtle weakness may be increased by contractions or outstretched extremities. Ventilation may be involved in gener- alized forms; occasionally, it can be the presentation of MG. Antibodies against the AChR are present in 80% of generalized cases and 50% of ocular/bulbar cases. 15% of cases are seronegative. Some of these “sero- negative” cases harbor a MuSK auto-antibody. Found in adult onset MG patients. Increases with age, more often with thymoma. Rise in titer may herald a thymoma recurrence. Occurs in MG patients with thymoma (70% to 100%) and occasionally without thymoma. Prevalence Anatomical-functional relations Types Pathogenesis Other associated antibodies Anti-striatal antibodies Signs Symptoms Anti-titin antibodies 339 Anti-nuclear antibodies in 20% to 40% of cases Anti-thyroid (microsomal and thyroglobulin; 15% to 40%) and anti-parietal cell (10% to 20%), more common in ocular MG Smooth muscle antibodies: 5% to 10% Rheumatoid factor: 10% to 40% Coomb’s antibodies in 10% Anti-lymphocyte antibodies: 40% to 80% Anti-platelet antibodies: 5% to 50% MG is often associated with pathology of the thymus. Thymic hyperplasia is found in most young patients. Thymoma is found in approximately 10% of MG patients. MG occasionally appears after removal of a thymoma. MG can also be associated with HLA-B8-DR3 haplotype. Thyroid disorders: Thyroid disorders in ~ 15% of MG patients Hyperthyroidism more common than hypothyroidism Thyroid testing is always indicated Increased incidence of other autoimmune disorders: Rheumatoid arthritis Lupus erythematosus Polymyositis Pernicious anemia The course of MG during pregnancy is unpredictable. It tends to worsen at the beginning of pregnancy and the post-partum period. In the long run, there is no influence on prognosis. Treatment: Acetylcholinesterase inhibitors, corticosteroids, plasma exchange, intravenous immune globulin (IVIG). Immunosuppressant use in pregnancy: Some risk: Cyclosporine A is associated with more spontaneous abortions and preterm deliveries. Higher risk: Methotrexate should not be used during pregnancy. Breast feeding: High doses of acetylcholinesterase inhibitors may produce gastrointestinal disorders in the neonate. Immunosuppressants may also produce immunosup- pression in the neonate. Effect of pregnancy on the child: May lead to the development of “neonatal MG”: general weakness, sucking difficulties. Wears off according to the IgG half-life (several weeks) and does not induce myasthenia in the child. Congenital arthrogryposis has been described, with antibodies directed to- wards fetal acetylcholine receptor protein. Other antibodies Pregnancy and MG Role of the thymus Associated systemic disease 340 Presynaptic defects: Congenital MG and episodic apnea Paucity of synaptic vesicles and reduced quantal release Congenital Lambert Eaton myasthenic syndrome (LEMS) Synaptic defects: Acetylcholinesterase deficiency at the neuromuscular junction Postsynaptic defects: Kinetic abnormalities in AChR junction Reduced numbers of AChRs Increased response to AChR: slow AChR syndrome Delayed channel closure Repeated channel reopenings Reduced response to ACh Fast channel syndrome: epsilon, alpha subunits gating abnormality: delta subunit Normal numbers of AChR at the neuromuscular junction: Reduced response to ACh Fast channel, low ACh affinity Reduced channel opening High conductance and fast closure of AChRs Slow AChR channel syndrome Reduced numbers of AChR at neuromuscular junction: AChR mutation, usually epsilon subunit Other: Benign and congenital MG Congenital MG Familial autoimmune Limb girdle MG Plectin deficiency Clinical course: Symptoms fluctuate and worsen as the day progresses. Strength measurements: Myometer Imaging: Imaging of the mediastinum for thymoma Edrophonium test: Edrophonium (tensilon) is a short-acting acetylcholinest- erase inhibitor. The Tensilon test does not distinguish between pre- and post- synaptic transmission disorders. Antibody testing: Antibodies against the AChR is the standard immunologic test for MG. MuSK antibody testing is reserved for seronegative cases. Other antibodies: Titin, smooth muscle (see above) Anti-AChR antibody testing is positive in 50% of ocular and 80% of generalized MG cases. The antibody titer does not correlate with disease severity. Test results may vary with different institutions as test sitemaps and antigen prepara- tions vary. Other types of myasthenic syndromes Diagnosis 341 Immune MG: Negative anti-AChR antibody testing by routine assay – Negative findings are more common with ocular and childhood disease – AChR abs can be detected by other methods – Rarely (3%) detected by AChR modulating assay – Some patients have plasma antibody (IgM) that alters AChR function – Present in children and adults – Not present with: Thymoma; Anti-AChR antibodies – MuSK IgG is often directed against amino terminal (extracellular) sequences – MuSK IgG may induce some AChR aggregation on myotubes – In children, rule out congenital and hereditary MG Repetitive stimulation (RNS): RNS is the most important electrophysiological test. It is positive in generalized MGIR 60–70% and 50% or less in ocular MG. The specificity is around 90%. Warming the affected muscles gives the best results. Five shocks at 3 Hz supramaximal stimulation are given, usually to proximal muscles (deltoid, trapezius muscle). Errors in RNS: The most common source of error is electrode movement. Fix the electrode with tape and immobilize the stimulated area. Avoid submaximal stimulation. Temperature should be recorded. Stimulation above 10 Hz may produce “pseudo-facilitation” (increase of amplitude and decrease of duration without changing the area under the curve). RNS abnormalities in other neuromuscular diseases: Lambert Eaton myasthenic syndrome Motor neuron disease Myotonic syndromes Periodic paralysis Phosphorylase and phosphofructokinase deficiency Polymyositis Needle EMG: Normal or short MUAPs. Long standing: minimally neurogenic. Spontaneous activity is unusual. Single fiber EMG (SFEMG): Variability of NM transmission, such as a discharge to discharge variability in timing of single muscle fibers. This is a sensitive method for the detection of MG: 85–90% positive in ocular and 90–95% positive in generalized MG. Most commonly, the extensor digi- torum communis and frontal muscles are examined. Jitter and blocking usually increase with prolonged muscle activation. Stimulation jitter can be used for evaluation in uncooperative patients. For both RNS and SFEMG, the concomitant application of acetylcholinesterase inhibitors drugs can induce false negative results. Brainstem disorders Cranial nerve compression syndromes Lambert Eaton myasthenic syndrome (LEMS) Mitochondrial myopathy Motor neuron disease (MND) Antibody negative myasthenia Electrophysiology Differential diagnosis [...]... cytotoxic T cells possibly by produc- 363 tion of the pore forming protein perforin, by upregulation of Fas-induced apoptosis, or by induction of oxidative intermediates such as nitric oxide and peroxynitrites due to upregulation of nitric oxide synthase There is also upregulation of anti-apoptotic molecules for example Bcl-2 on the surface of muscle fibers, implying that loss of muscle cells eventually occurs... syndrome Neurology 59: 1773–1775 Oh SJ (1 989 ) Diverse electrophysiological spectrum of the Lambert Eaton myasthenic syndrome Muscle Nerve 12: 464–469 O’Neill JH, Murray NMF, Newsom-Davies J (1 988 ) The Lambert Eaton myasthenic syndrome Brain 111: 577–596 O’Suilleabhain P, Low PA, Lennon VA (19 98) Autonomic dysfunction in the Lambert-Eaton myasthenic syndrome Neurology 50: 88 –93 References 352 Botulism Genetic... Disorders of neuromuscular transmission caused by drugs N Engl J Med 301: 409–413 Barrons RW (1997) Drug-induced neuromuscular blockade and myasthenia gravis Pharmacotherapy 17: 1220–1232 Howard HF (2002) Neurotoxicology of neuromuscular transmission In: Katirji B, Kaminski HJ, Preston DC, Ruff RL, Shapiro B (eds) Neuromuscular disorders in clinical practice Butterworth and Heinemann, Boston, pp 964– 986 Senanayake... examination remain the most effective way of diagnosing the presence of myopathy, increasingly the clinician has to rely on an understanding of muscle electrophysiology, pathology, and genetics to differentiate between an ever-increasing number of complex disorders of muscle Introduction The basis of the motor system is the motor unit The motor unit consists of the anterior horn cell, axon, muscle membrane... reduction of P/Q Ca++ channels on presynaptic terminals and reduction of Ca++ dependent quantal release Also associated with N-type Ca channel antibodies (35%) GAD antibodies, thyroid antibodies, parietal cell antibodies, anti-Hu and muscle nicotinic AchR antibodies have been observed Voltage-gated calcium channels (VGCC) can be detected in 95% of patients with cancer-associated LEMS and in 90% of patients... immune-mediated response There is probably an increased risk of cancer in subjects within 3 years of diagnosis of DERM DERM following treatment with interferon α2b has also been observed Diagnosis Laboratory: Serum CK is elevated in more than 90% of patients with DERM The following antibodies may be positive: Mi-2, MAS, sometimes Jo-1, anti t-RNA synthetase (anti-synthetase syndrome – myositis, polyarteritis, Raynauds,... well-controlled prospective study The clinical effectiveness of thymectomy may lag behind While there are reported benefits to thymectomy, the efficacy is difficult to judge because of difficulties in comparing the methods of operation and the uncertainty of maximal resection Thymectomy is indicated as an initial and primary therapy of patients with generalized limb and bulbar involvement Treatment of. .. size of the gene defect, exon number, the type of gene promoter or enhancer, transcription characteristics, and the number and extent of deletions A further important effect is that of compensatory or modifying alleles e.g the utrophin gene can modify the 361 severity of some dystrophinopathies A mutation of the same gene can cause widely differing clinical phenotypes For example, the same mutation of. .. 163–1 78 Evoli A, Minisci C, Di Schino C, et al (2002) Thymoma in patients with MG Neurology 59: 184 4– 185 0 Grob D, Arsuie EL, Brunner NG, et al (1 987 ) The course of myasthesia and therapies affecting outcome Ann NY Acad Sci 505: 472–499 Mantegazza R, Beghi E, Pareyson D, et al (1990) A multicenter follow up study of 1152 patients with myasthenia gravis in Italy J Neurol 237: 339–344 Osserman KE (19 58) ... sites of NMT demonstrated with single fiber EMG General anaesthetics Potentiation of neuromuscular blocking agents in patients with MG Majority of patients can tolerate general anesthetics; postoperative waning difficulties are rare 347 Local anaesthetics Intravenous lidocaine, procaine and similar drugs potentiate the effect of neuromuscular blockings agents Myasthenic crisis after large doses of local . the presentation of MG. Antibodies against the AChR are present in 80 % of generalized cases and 50% of ocular/bulbar cases. 15% of cases are seronegative. Some of these “sero- negative” cases. without thymoma. Prevalence Anatomical-functional relations Types Pathogenesis Other associated antibodies Anti-striatal antibodies Signs Symptoms Anti-titin antibodies 339 Anti-nuclear antibodies in 20% to 40% of cases Anti-thyroid. (1 989 ) Diverse electrophysiological spectrum of the Lambert Eaton myasthenic syndrome. Muscle Nerve 12: 464–469 O’Neill JH, Murray NMF, Newsom-Davies J (1 988 ) The Lambert Eaton myasthenic syn- drome.