|Year : 2007 | Volume
| Issue : 2 | Page : 88-91
All that ripples is not "Motor neuron disease"
Ashok Panagariya, Vinay Agarwal, Neeraj Agarwal
Department of Neurology, SMS Medical College, Jaipur, Rajasthan, India
7, Raj Niketan, Moti Doongri Road, Jaipur - 302 004
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Until early 80's most patients presenting with lower motor neuron syndrome characterized by weakness, wasting, diminished reflexes, fasciculations, cramps and minimal sensory involvement would have been diagnosed as motor neuron disease- LMN variant. But similar clinical picture can be seen in various disorders right from degenerative illnesses like motor neuron disease to inflammatory ones like multifocal motor neuropathy (MMN). Some of them are potentially treatable conditions with immunomodulatory therapies and are associated with characteristic electrophysiological features and high serum antibody titers. Thus every patient presenting with pure motor LMN weakness and fasciculations should not be labeled as motor neuron disease and extensive electrophysiological search is warranted to diagnose these potentially treatable conditions, changing the grim prognosis to more favorable one.
Keywords: Fasciculations, motor neuron disease, multi focal motor neuropathy
|How to cite this article:|
Panagariya A, Agarwal V, Agarwal N. All that ripples is not "Motor neuron disease". Ann Indian Acad Neurol 2007;10:88-91
| Introduction|| |
Until early 80's most patients presenting with lower motor neuron syndrome characterized by weakness, wasting, diminished reflexes, fasciculations, cramps and minimal sensory involvement would have been diagnosed as motor neuron disease- LMN variant. But similar clinical picture may be seen in various other disorders. Some of them are potentially treatable conditions with immunomodulatory therapies and are associated with characteristic electrophysiological features and high serum antibody titers.
The clinical overlap
Predominantly lower motor neuron syndrome can be seen in various disorders right from degenerative to inflammatory illnesses.
In 1985 Parry and Clarke found conduction block in patients with pure motor LMN syndromes. Weakness in such patients was found reversible with immunomodulating therapies and were often associated with high titers of auto antibody. Hence a separate disorder emerged i.e., Multifocal motor neuropathy (MMN) with conduction block.,,,,,,,
MMN is characterized by asymmetric pure motor LMN weakness, distal more than proximal and involving most often upper limbs with fasciculations, cramps (2/3rd of cases) and reflexes that are poor or absent only in affected limbs. Weakness is typically more than the degree of wasting. Initially weakness is in individual nerve distribution.
Conduction block, the failure of nerve impulse to propagate through a structurally intact axon is the electrophysiological hallmark of the MMN.,,,,,,, Conduction block can be detected as a lower amplitude or area of the compound muscle action potential (CMAP) on proximal stimulation of a nerve segment as compared to distal stimulation. It should not be present at the common sites of nerve entrapment. There are various criteria for conduction block but a decrease in CMAP area of > 50% is the most common reference value for defining conduction block. Other evidences of demyelination (decreased conduction velocity, prolonged terminal latencies, temporal dispersion and delayed F latencies) are present in the blocked segment, rest of the nerve is relatively unaffected. Electromyography (EMG) may show presence of fasciculations but unlike anterior horn cell disorders, they are not diffuse.
Ig M anti GM 1 antibody are found in > 50% of patients.,,,,,,, T2 weighted MRI images shows asymmetric high signal intensity of Brachial plexus, (which corresponds with the distribution of symptoms). Cerebrospinal fluid (CSF) examination is usually normal but may show elevated protein levels (<100 mg%). Serum Creatine Kinase (CK) levels are frequently elevated (< 3 times of reference range). Other blood examination and serum immunoelectrophoresis are unremarkable.
Since MMN is amenable to treatment with specific immunomodulatory therapy, it needs to be differentiated from other clinical conditions with similar phenotypic presentation [Figure - 1]. Included in these are diseases affecting anterior horn cell and various neuropathies. Various disorders affecting anterior horn cell are Progressive muscular atrophy (PMA), Monomelic amyotrophy and Spinal muscular atrophy and those affecting neurons are either auto immune diseases like chronic inflammatory demyelinating polyneuropathy (CIDP), Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM or lewis Sumner variant), Continuous muscle fiber activity (CMFA or Neuromyotonia) or various Distal LMN syndromes. Other conditions to be considered include postpolio syndrome, lead or Dapsone induced motor neuropathies, neuropathies associated with monoclonal proteins and Hexoseaminidase - A deficiency.
Spinal muscular atrophy can be infantile, juvenile or adult onset and is characterized by progressive pure motor usually symmetrical weakness of limbs accompanied by atrophy, hyporeflexia often associated with fasciculations (50- 75%). Sensory nerve conduction studies are normal. Motor nerve conduction velocities are normal unless CMAP amplitude is severely reduced. Needle EMG shows increased insertional activity with fibrillation potentials and fasciculations and increased size and complexity of individual motor unit potential, which is consistent with involvement of anterior horn cell. Serum CK levels may be elevated up to 10 times the normal value in juvenile and adult variants. Other investigations including CSF study and ganglioside antibody titers are normal.
Progressive muscular atrophy usually presents with focal asymmetric weakness in distal extremities with gradual spread to other contagious muscles. Fascicular twitchings and cramps are variably present. Bulbar or respiratory involvement eventually develops, but is not as common as in the early stages as in classical amyotrophic lateral sclerosis (ALS). Electrdiagnostic studies reveal findings consistent with involvement of anterior horn cell. Anti GM1 antibody titers are normal. Serum CK concentration can be elevated up to 10 times the normal value.
Monomelic amyotrophy presents with asymmetric pure motor weakness affecting only one limb (arm in 75% and leg in 25%). Electrodiagnostic study shows chronic neurogenic pattern in the affected muscles only. Serum CK levels may be modestly elevated, but other routine laboratory tests are normal. Segmental cord atrophy or occasionally an area of altered signal intensity on T2-weighted scans may be seen on cervical MRI.
CIDP is usually characterized by symmetrical proximal as well as distal weakness, generalized areflexia as compared to MMN where weakness is asymmetrical and distal and reflexes are only poor or absent in affected limbs. A remitting and relapsing course or a progression of symptoms in weeks is common in CIDP but not in MMN. Sensory signs and symptoms are common in CIDP. In CIDP nerve conduction studies show features of demyelination, including conduction block such as slow conduction velocities and prolonged distal latencies, which are diffuse and also involvement of sensory nerves. In CIDP, unlike in MMN CSF shows raised proteins (>1 gm%) and anti GM1 are present in <1% of cases and in low titers.
MADSAM closely mimics MMN. It presents in the same age group and in the same upper limb predominant asymmetric fashion in the distribution of individual nerves But these patients have associated sensory involvement and sometimes associated with neuropathic pain or focal nerve tenderness. Electrodiagnostic study also reveals sensory involvement in form of low action potential amplitudes in distal sensory nerves, which is not found in patients of MMN and anti GMI titers are with in normal limits, which distinguishes this entity from MMN.
Neuromyotonia presents with diffuse pain, diffuse undulating movements of muscle are also seen. Neuropathies may be associated with it. EMG findings are characteristic, showing bursts of MUPs in doublets, triplets or multiplets firing at high rates(> 150 Hz) Anti VGKC and Anti GMI antibodies are present in the majority of cases.
Distal LMN (D-LMN) syndromes have pattern of weakness similar to that of MMN but has early wasting, shows axonopathy on nerve conduction studies and do not have raised autoantibody levels.
Thus clinical presentation, electrophysiological characteristics and blood tests, specially auto antibody titers (GM1 ganglioside) can help in differentiating these various disorders from each other.
There is difference in pathophsyiological mechanisms of various pure motor LMN syndromes. While some are degenerative, others have predominantly autoimmune mechanisms. This difference in pathophysiological mechanisms, account for the difference in response to treatment with immunomodulatory therapies.
In diseases affecting anterior horn cell (PMA, SMA, monomelic amyotrophy) damage results from complex chain of events involving excitotoxins, oxidative stress, neurofilament dysfunction, altered calcium homeostasis, mitochondrial dysfunction, enhanced motor neuron apoptosis and release of proinflammatory cytokines.
In MMN, positive response to immunomodulatory therapy, high levels of anti GMI antibody antibody in>50% of patients and expression of GMI on axon and myelin membranes suggest that GMI antibody are pathognomic., Anti GMI antibody causes blockade of voltage gated Na 2 /K 2 channels at the nodes of Ranvier, which leads to Na 4 and Ca 2+ accumulation leading to persistent hyperpolarization and conduction block. Difference in fatty acid and long chain base composition of peripheral nerve ganglioside GMI between sensory and motor nerves could contribute to the selective involvement of motor nerves in MMN.,,
Presence of anti VGKC (Voltage gated potassium channels), anti GMI antibodies, association with other autoimmune disorders and improvement after immunomodulating therapy point towards autoimmune basis in neuromyotonia.
A role for humoral-immune reactions in the pathogenesis of CIDP is suggested by dramatic therapeutic response to plasmapheresis and by presence of compliment fixing anti peripheral myelin antibodies in occasional patients.
Response to treatment is different in various pure motor LMN syndromes. While on the one hand immuno-modulatory therapies are ineffective in various anterior horn cell disorders and treatment is largely supportive, on the other hand these are effective in autoimmune neuropathies and neuromyotonia.
IVIG and Cyclophosphamide produces useful functional improvement in MMN but neither plasmapheresis nor steroids are useful., In fact rapid deterioration can occur with use of steroids. IVIG, plasmapheresis and steroids all are effective in CIDP. Neuromyotonia shows good response to both IVIG and methylprednisolone.,,
| Conclusion|| |
Thus in every patient presenting with pure motor LMN weakness and fasciculations extensive electrophysiological search for conduction block and characteristic discharges of neuromyotonia is warranted to diagnose these potentially treatable condition, changing the grim prognosis to more favorable one. Untreated these are progressive and not necessarily benign so early treatment is required.
| References|| |
|1.||Parry GJ, Clarke S. Pure motor neuropathy with multifocal conduction block masquerading as motor neuron disease. Muscle Nerve 1988;11:103-7. [PUBMED] |
|2.||Chad DA, Hammer K, Sargent J. Slow resolution of multifocal weakness and fasciculation: A reversible motor neuron syndrome. Neurology 1986;36:1260-3. [PUBMED] |
|3.||Roth G, Rohr J, Magistris MR, Ochsner F. Motor neuropathy with proximal multifocal persistent conduction block, fasciculations and myokymia: Evolution to tetraplegia. Eur Neurol 1986;25:416-23. [PUBMED] |
|4.||Pestronk A, Cornblath DR, Ilyas AA, Baba H, Quarles RH, Griffin JW, et al . A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann Neurol 1988;24:73-8. [PUBMED] |
|5.||Lange DJ, Trojaborg W, Latov N, Hays AP, Younger DS, Uncini A, et al . Multifocal motor neuropathy with conduction block: Is it a distinct clinical entity? Neurology 1992;42:497-505. [PUBMED] |
|6.||Parry GJ, Sumner AJ. Multifocal motor neuropathy. Neurol Clin 1992;10:671-84. [PUBMED] |
|7.||Nobile-Orazio E. Multifocal motor neuropathy. J Neurol Neurosurg Psychiatry 1996;60:599-603. [PUBMED] |
|8.||Biessels GJ, Franssen H, Van den Berg LH, Gibson A, Kappelle LJ, Venables GS, et al . Multifocal motor neuropathy. J Neurol 1997;244:143-52. [PUBMED] [FULLTEXT]|
|9.||Chaudhry V. Multifocal motor neuropathy. Semin Neurol 1998;18:73-81. [PUBMED] |
|10.||Chaudhry V, Corse AM, Cornblath DR, Kuncl RW, Freimer ML, Griffin JW. Multifocal motor neuropathy: Electrodiagnostic features. Muscle Nerve 1994;17:198-205. [PUBMED] |
|11.||Bouche P, Moulonguet A, Younes-Chennoufi AB, Adam SD, Baumann N, Meininger V, et al . Multifocal motor neuropathy with conduction block: A study of 24 patients. J Neurol Neurosurg Psychiatry 1995;59:38-44. |
|12.||Katz JS, Wolfe GI, Bryan WW, Jackson CE, Amato AA, Barohn RJ. Electrophysiologic findings in multifocal motor neuropathy. Neurology 1997;48:700-7. [PUBMED] |
|13.||Le Forestier N, Chassande B, Moulonguet A, Maisonobe T, Schaeffer S, Birouk N, et al . Multifocal motor neuropathies with conduction blocks: 39 cases. Rev Neurol (Paris) 1997;153:579-86. [PUBMED] [FULLTEXT]|
|14.||Taylor BV, Wright RA, Harper CM, Dyck PJ. Natural history of 46 patients with multifocal motor neuropathy with conduction block. Muscle Nerve 2000;23:900-8. [PUBMED] [FULLTEXT]|
|15.||Van Asseldonk JT, Van den Berg LH, Van den Berg-Vos RM, Wieneke GH, Wokke JH, Franssen H. Demyelination and axonalloss in multifocal motor neuropathy: Distribution and relation to weakness. Brain 2003;126:186-98. [PUBMED] [FULLTEXT]|
|16.||Parry GJ, Clarke S. Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease. Muscle Nerve 1988;11:103-7. [PUBMED] |
|17.||Jaspert A, Claus D, Grehl H, Neundorfer B. Multifocal motor neuropathy: Clinical and electrophysiological findings. J Neurol 1996;243:684-92. |
|18.||Van Asseldonk JT, Franssen H, Van den Berg-Vos RM, Wokke JH, Van den Berg LH. Multifocal motor neuropathy. Lancet Neurol 2005;4:309-19. [PUBMED] [FULLTEXT]|
|19.||Azulay JP, Blin O, Pouget J, Boucraut J, Bille-Turc F, Carles G, et al . Intravenous immunoglobulin treatment in patients with motor neuron syndromes associated with anti-GM1 antibodies: A double-blind, placebo-controlled study. Neurology 1994;44:429-32. |
|20.||Latov N, Hays AP, Donofrio PD, Liao J, Ito H, McGinnis S, et al . Monoclonal IgM with unique specificity to gangliosides GM1 and GD1b and to lacto-N-tetraose associated with human motor neuron disease. Neurology 1988;38:763-8. [PUBMED] |
|21.||Nobile-Orazio E, Legname G, Daverio R, Carpo M, Giuliani A, Sonnino S, et al . Motor neurondisease in a patient with a monoclonal IgMk directed against GM1,GD1b and high-molecular-weight neural-specific glycoproteins. Ann Neurol 1990;28:190-4. [PUBMED] |
|22.||Sadiq SA, Thomas FP, Kilidireas K, Protopsaltis S, Hays AP, Lee KW, et al . The spectrum ofneurologic disease associated with anti-GM1 antibodies. Neurology 1990;40:1067-72. [PUBMED] |
|23.||Shy ME, Heiman-Patterson T, Parry GJ, Tahmoush A, Evans VA, Schick PK. Lower motor neuron disease in a patient with auto antibodies against Gal(beta 1-3) GalNAc in gangliosides GM1and GD1b: Improvement following immunotherapy. Neurology 1990;40:842-4. [PUBMED] |
|24.||Lamb NL, Patten BM. Clinical correlations of anti-GM1 antibodies in amyotrophic lateral sclerosis and neuropathies. Muscle Nerve 1991;14:1021-7. [PUBMED] |
|25.||Kinsella LJ, Lange DJ, Trojaborg W, Sadiq SA, Younger DS, Latov N. Clinical and electrophysiologic correlates of elevated anti-GM1 antibody titers. Neurology 1994;44:1278-82. [PUBMED] |
|26.||Kornberg AJ, Pestronk A. The clinical and diagnostic role of anti-GM1 antibody testing. Muscle Nerve 1994;17:100-4. [PUBMED] |
|27.||Van den Berg-Vos RM, Franssen H, Wokke JH, Van Es HW, Vanden Berg LH. Multifocal motor neuropathy: Diagnostic criteria that predict the response to immunoglobulin treatment. Ann Neurol 2000;48:919-26. |
|28.||Van Es HW, Van den Berg LH, Franssen H, Witkamp TD, Ramos LM, Notermans NC, et al . Magnetic resonance imaging of the brachial plexus in patients with multifocal motor neuropathy. Neurology 1997;48:1218-24. [PUBMED] |
|29.||Leger JM, Chassande B, Musset L, Meininger V, Bouche P, Baumann N. Intravenous immunoglobulin therapy in multifocalmotor neuropathy: A double-blind, placebo-controlled study. Brain 2001;124:145-53. |
|30.||Baron RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic inflammatory demyelinating polyradiculoneuropathy. Clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 1989;46:878-84. |
|31.||Lewis RA, Sumner AJ, Brown MJ, Asbury AK. Multifocal demyelinating neuropathy with persistent conduction block. Neurology 1982;32:958-64. [PUBMED] |
|32.||Panagariya A, Kumar H, Mathew V, Sharma B. Neuromyotonia: Clinical profile of twenty cases from northwest India. Neurol India 2006;24:382-6. |
|33.||Taylor BV, Gross L, Windebank AJ. The sensitivity and specificity of anti-GM1 antibody testing. Neurology 1996;47:951-5. [PUBMED] |
|34.||Pestronk A, Chaudhry V, Feldman EL, Griffin JW, Cornblath DR, Denys EH, et al . Lower motor neuron syndromes defined by patternsof weakness, nerve conduction abnormalities and high titers of antiglycolipid antibodies. Ann Neurol 1990;27:316-26. [PUBMED] |
|35.||Corbo M, Quattrini A, Lugaresi A, Santoro M, Latov N, Hays AP. Patterns of reactivity of human anti-GM1 antibodies with spinal cord and motor neurons. Ann Neurol 1992;32 : 487-93. [PUBMED] |
|36.||Thomas FP, Thomas JE, Sadiq SA, van den Berg LH, Roelofs RI, Latov N, et al . Human monoclonal IgM anti-Gal(beta 1-3) GalNAc autoantibodies bind to the surface of bovine spinal motoneurons. J Neuropathol Exp Neurol 1990;49 : 89-95. [PUBMED] |
|37.||Ogawa-Goto K, Funamoto N, Ohta Y, Abe T, Nagashima K. Myelingangliosides of human peripheral nervous system: An enrichment of GM1 in the motor nerve myelin isolated from cauda equina. J Neurochem 1992;59 : 1844-9. [PUBMED] |
|38.||Donaghy M, Mills KR, Boniface SJ, Simmons J, Wright I, Gregson N, et al . Pure motor demyelinating neuropathy: Deterioration after steroid treatment and improvement with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry 1994;57:778-83. [PUBMED] |
|39.||Van den Berg LH, Lokhorst H, Wokke JH. Pulsed high-dose dexamethasone is not effective in patients with multifocal motor neuropathy. Neurology 1997;48:1135. |
|40.||Nakatsuji Y, Kaido M, Sugai F, Nakamori M, Abe K, Watanabe O, et al . Isaacs' syndrome successfully treated by immuno adsorption plasmapheresis. Acta Neurol Scand 2000;102:271-3. [PUBMED] [FULLTEXT]|
|41.||Hayat GR, Kulkantrokan K, Campbell WW, Giuliani MJ. Neuromyotonia: Autoimmune pathogenesis and response to immune modulating therapy. J Neurol Sci 2000;181:38-43. |
|42.||van den Berg JS, van Engelen BG, Boerman RH, de Baets MH. Acquired neuromyotonia: Superiority of plasma exchange over high dose intravenous human immunoglobulin. J Neurol 1999;246:623-5. [PUBMED] [FULLTEXT]|
[Figure - 1]