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Jtournal of Neurology, Neurosurgery, and Psychiatry 1993;56:121-
Journal of
NEUROLOGY
NEUROSURGERY
& PSYCHIATRY
Editorial
Stiff muscles
Muscle stiffness, spasms and cramps are common com-
plaints. This review will concentrate on those rare condi-
tions in which these symptoms are caused by continuous
muscle activity of either central or peripheral origin.
Stiff-man syndrome
This syndrome is of insidious onset, usually in the 4th and
5th decades and affects men and women equally. 1-
Tightness and stiffness of the trunk are early symptoms
and are due to (^) continuous contraction of lumbar and
abdominal muscles. Axial rigidity progresses slowly over
months or years. Abdominal wall rigidity ("board-like")
and contraction of thoracolumbar paraspinal muscles
produce a characteristic hyperlordosis of the lumbar spine
which persists at rest. So typical of the condition is this
posture that the diagnosis should be questioned without
it.3 Voluntary movements of the trunk and legs become
slow, awkward and restricted. Proximal limb muscles
become involved later, but face and distal limbs are
generally spared. Muscle spasms, superimposed on the
muscle rigidity, are common early complaints; spasms are
precipitated by voluntary movement, fright or sound and
may be painful and severe. Physiological mechanisms for
the spasms include exaggerated, non-habituating exter-
oceptive or^ cutaneomuscular reflexes,6 brainstem myo-
clonus8 and exaggeration of the startle reflex.9 "^ The term
"jerking stiff-man" syndrome refers to prominence of the
latter in some cases.8 Sphincter function is normal. The
remainder of the neurological examination, including
cognition, cranial nerves, muscle strength, tendon reflexes,
sensation and coordination is normal.
Insulin dependent diabetes mellitus is present in one to
two thirds of patients.24 Autoimmune thyroid disease,
pernicious anaemia and^ vitiligo are^ also common. Epilepsy
in the stiff-man syndrome occurs in about 10%.4 l
Electromyography of^ affected^ muscles^ reveals^ con-
tinuous motor unit activity, despite attempted relaxation,
comprising motor^ units^ of^ normal^ morphology. Peripheral
nerve conduction is normal. A central origin for the
spasms, rigidity and continuous motor unit activity is
suggested by their disappearance during sleep and after
peripheral nerve^ block and^ spinal or^ general anaesthesia.
Abnormal excitability of spinal interneuronal networks
(and their descending control) has been suggested as one
cause of the stiff-man (^) syndrome,6" explaining the axial
emphasis of continuous^ motor^ unit^ activity and^ the
exaggerated cutaneomuscular reflexes. This hypothesis is
consistent with pharmacological observations that suggest
an imbalance between descending aminergic effects, facili-
tating long latency spinal flexor reflex pathways,"2 and the
inhibitory effects of gamma-aminobutyric-acid (GABA) in
the brainstem and spinal cord.6 79 13-15 Drugs that increase
aminergic (noradrenergic or serotonergic) activity in the
central nervous system such as levodopa,'3 clomipramine,
reserpine,6metamphetamine7 increased the severity of
spasms while those that reduce central catecholamine
effects, such as clonidine6 and (^) tizanidine,7 or enhance
GABA activity (baclofen or benzodiazepines) diminish the
spasms.
Antibodies against GABA-ergic neurons were detected
in serum and CSF in 19 of 32 patients (60%) with a
clinical diagnosis of the stiff-man syndrome;4 antibodies to
pancreatic islet cells were found in 18 of these patients
(one third had insulin dependent diabetes mellitus), to
gastric parietal cells in 15 and to thyroid microsomes in 9.
In the majority of cases antiGABA-ergic antibodies had
similar electrophoretic mobility to antiglutamic acid
decarboxylase (GAD) antibodies, suggesting that anti-
GAD antibodies were responsible for the antiGABA-ergic
neuron activity.4 These antiGAD antibodies are the same
as those in insulin dependent diabetes mellitus.'6 Whether
the 40% of patients with a clinical diagnosis of the stiff-
man syndrome and no detectable antiGAD antibodies
have the same condition is not clear. Reasons for sero-
negativity may include the assay method and GABA-ergic
autoantigen heterogeneity. Furthermore, not all GABA-
ergic antibodies in the stiff-man syndrome exhibit anti-
GAD reactivity.'7 The relationship of these antibodies to
the pathogenesis of the disease remains to be
determined.
Oligoclonal IgG bands have been reported in several
cases 18-20 and HLA associations have included the HIA
B44 (^) antigen2' 22 and the DR3 and 4 antigens.
Necropsy examinations of the CNS have not shown any
consistent or (^) striking changes' 1123-26 but detailed histo- chemical studies have not been carried out.
Benzodiazepines and^ baclofen^ help reduce spasms. Axial
rigidity (and continuous motor unit activity) respond less
well. Sodium valproate and tizanidine7 have also been
reported to be of benefit. An interesting development has
been the use of immunosuppression with steroids alone5 or
plasmapheresis and prednisolone.2627 Improvement has
been reported in some cases26 27 but not others.
Progressive encephalomyelitis with rigidity
This rare condition, also referred to as spinal inter-
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Editorial
neuronitis because of the pathological findings, may cause
axial rigidity and spasm similar to the stiff-man syn-
drome28-33 but is distinguished from it by a progressive
course and the accumulation of other neurological signs. A similar clinical picture has been described with paraneo-
plastic encephalomyelitis28 "^ and in association with
autoimmune disease with anti-GAD, gastric parietal, thyroid microsomal, thyroglobulin and acetylcholine
receptor antibodies.
Initial symptoms may be sensory (pain, dysaesthesiae and sensory loss in the limbs)" or motor^ (weakness,
stiffness, clumsiness and rigidity).3O--
" Extensor spasms
of the trunk (opisthotonus), generalised brainstem^ myo-
clonus and "alpha" rigidity may be striking features.
Tendon reflexes may be absent with extensor plantar
responses. Incoordination, limb paresis and sensory loss
correspond to^ spinal tract or^ root^ involvement.^ Cranial
nerve signs, nystagmus, opsoclonus, ophthalmoplegia,
deafness, dysarthria and^ dysphagia,^ have been^ prominent
in pathologically confirmed cases. The illness usually progresses to death within about three years.
Investigations may reveal continuous motor unit activity,
of central origin, in trunk and limb muscles, segmental
denervation and CSF abnormalities including a^ lympho-
cytic pleocytosis, elevated protein and immunoglobulin
levels and oligoclonal IgG bands. Imaging studies have
revealed brainstem atrophy37 and abnormal signal inten-
sity throughout the lower part of the brainstem and
cervical spinal cord on MRI.37 Necropsy examinations
have shown encephalomyelitis with^ perivascular lympho-
cyte cuffing, infiltration and neuronal loss in the low
brainstem and^ spinal cord,^ particularly the^ central^ grey
zones of the cervical cord.29-3' This pattern of pathological
involvement may account for the profound rigidity by
releasing spinal alpha motor neurons from the influences
of inhibitory interneuronal networks. Anterior horn cell
loss and degeneration of long tracts in the cervical spinal
cord account for the other signs.
Treatment with large doses of diazepam and baclofen
may help the^ spasms, but there is^ no^ treatment^ available^ for
the underlying condition. McCombe et al32 reported some
improvement with^ methylprednisolone in^ one case^ with
evidence of myelitis on spinal cord biopsy.
Although the^ widespread pathological^ changes^ with
cranial nerve, lower motor neuron and^ long tract^ involve-
ment distinguish these cases from the stiff-man syndrome,
the question of overlap between these^ two^ conditions
remains open, particularly in view of the finding of similar
autoantibodies in some cases.33 38 Future studies of cases
of progressive encephalomyelitis should include detailed
autoimmune screening to define the spectrum of these
conditions.
Spinal cord lesions and rigidity
The concept of "alpha rigidity" referred to above, with
continuous motor^ unit^ discharge, developed from observa-
tions in rare cases of central spinal cord lesion and
experimental ischaemia of the grey matter of the cord.
Isolation of the spinal alpha motor neurons from inhibitory
interneuronal circuits allows unrestrained anterior horn
cell discharge and this particular type of rigidity. Most
lesions in humans producing alpha rigidity have involved
the cervical spinal cord and produced a clinical picture of
pain, stiffness, stimulus induced spasms, rigidity and
abnormal limb postures, in addition to segmental amyo-
trophy, weakness,^ absent^ upper limb tendon reflexes and
brisk leg reflexes, extensor plantar responses, and segmen-
tal or tract sensory disturbances.
Continuous muscle activity of peripheral nerve ori-
gin
Syndromes of continuous muscle activity of peripheral origin present a^ relatively stereotyped clinical picture of
muscle stiffness at rest and cramps following muscle
contraction due to delay in muscle relaxation. A variety of
descriptions have been applied to this syndrome, the most
frequent being Isaacs' syndrome or the syndrome of continuous muscle fibre activity,40 neuromyotonia,41 and
myokymia with delayed muscle relaxation.42 Delayed
muscle relaxation in this syndrome has also been described
as "pseudomyotonia" to distinguish this clinical sign from
myotonia.43 Overlap between the clinical and electromyo-
graphic use of the terms myokymia ("a wave-like rippling
of muscle" in the clinical sense and motor unit discharges
in doublets or triplets in an electromyographic sense) and neuromyotonia (delayed muscle relaxation in the clinical
sense and high frequency discharges in an electromyo-
graphic sense) create further problems in the definition of
this syndrome.
The syndrome can occur without an associated periph-
eral neuropathy, may be inherited44 45 or sporadic,40 42 and
can also occur in association with hereditary motor and
sensory neuropathy,4649 chronic inflammatory demyeli-
nating polyradiculoneuropathy,50 toxic (^) neuropathies,
and neuropathies of unknown cause.4652 Continuous
muscle fibre activity has been described in association with
intrathoracic malignancies without neuropathy,53 54 with
thymoma and acetylcholine receptor antibodies without
signs of myasthenia gravis55 and with thymoma, myasthe-
nia gravis and peripheral neuropathy.
Both children and adults are affected. Symptoms begin
gradually with muscle stiffness, rippling and twitching^ at
rest. Stiffness and "cramps" are more pronounced during
and after muscle contraction producing a delay in muscle
relaxation. Pain is rare although muscle aches are com-
mon. Excessive perspiration also may be evident. Distal,
proximal and cranial muscles are involved in contrast to
the proximal emphasis of rigidity in the stiff-man syn-
drome. Symptoms persist during sleep. Abnormal postures
of the feet and hands are evident with persistent flexion or
extension of digits. The posture of the trunk is often
abnormal and the gait may be stiff. Inspection of muscles
reveals continuous rippling (myokymia) and fasciculations.
Tendon reflexes are usually absent; this may be due to
either a peripheral neuropathy or inhibition of the spinal
stretch reflex by the continuous muscle activity, since
reflexes may return after treatment.^ Distal^ motor^ and
sensory signs are more reliable indicators of an underlying
peripheral neuropathy.
The continuous motor unit and muscle fibre activity is
caused by peripheral nerve hyperexcitability; it persists
during sleep, following peripheral nerve block, is increased
by hyperventilation or ischaemia and is abolished by
curare. The^ abnormal nerve^ activity may originate in
proximal nerve segments444953 in which case a distal
nerve block suppresses the spontaneous activity, or distal
nerve segments, in which case activity persists after nerve
block.45 After-discharges following the direct compound
muscle action potential are a characteristic feature. Similar
activity follows voluntary muscle activation or, occasion-
ally, gentle percussion of peripheral nerves. The after-
discharges are responsible for the delay in relaxation after
muscle contraction. The muscle stiffness at rest and
abnormal postures are due to both continuous motor unit
discharges (fasciculations, myokymic discharges) and mus-
cle fibre discharges (high frequency repetitive discharges).
Large amplitude, long^ duration polyphasic motor unit
potentials, indicating denervation and reinnervation, and
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Editorial
47 Lance (^) JW, Burke D. Pollard J. Hyperexcitability of motor and sensory neurons in^ neuromyotonia. Ann Neurol^ 1979;5:523-32. 48 Vasilescu C, Alexianu^ M, Dan^ A. Neuronal^ type^ of^ Charcot-Marie-Tooth disease with a syndrome of continuous motor unit activity. J Neurol Sci 1984;63:11-25. 49 Hahn AF, Parkes AW, Bolton CF, Stewart SA. Neuromyotonia in hereditary motor neuropathy. J^ Neurol Neurosurg Psychiatry 1991;54:230-5. 50 Valenstein E, Watson RT, Parker JL. Myokymia, muscle^ hypertrophy and percussion "myotonia" in chronic recurrent polyneuropathy.^ Neurology 1978;28:1130-4. 51 Wallis WE, van Poznack A, Plum F. Generalised muscular^ stiffness, fasciculations and myokymia of peripheral nerve^ origin. Arch^ Neurol 1970;22:430-9. 52 Greenhouse AH, Bicknell JM, Pesch RN, Seelinger^ DF.^ Myotonia, myokymia, hyperhidrosis and wasting of^ muscle.^ Arch^ Neurol 1967;17:263-8. 53 Walsh JC. Neuromyotonia: an unusual presentation of^ intrathoracic malignancy. Jf Neurol Neurosurg Psychiatry 1976;39: 1086-91. 54 Partenen VSJ, Soininen H, Saska M, Riekkinen P.^ Electromyographic^ and nerve conduction findings in a patient with^ neuromyotonia,^ normo- calcaemic tetany and small-cell lung cancer.^ Acta^ Neurol^ Scand 1980;61:216-26. 55 Halbach M, Homberg V, Freund H-J. Neuromuscular,^ autonomic^ and central cholinergic hyperactivity associated^ with^ thymoma^ and^ acetylcho- line receptor-binding antibody. J^ Neurol 1987;234:433-6. 56 Garcia-Merino A, Cabello A, Mora^ JS, Liano^ H.^ Continuous muscle^ fibre activity, peripheral neuropathy and^ thymoma.^ Ann^ Neurol 1991;29:215-8. 57 Welch LK, Appenzeller 0, Bicknell^ JM.^ Peripheral^ neuropathy^ with myokymia, sustained muscular^ contraction^ and continuous^ motor^ unit activity. Neurology 1972;22:161-9. 58 Ono S, Munakata S, Kagao K, Shimizu^ N. The^ syndrome^ of continuous muscle fibre activity: light microscopic^ studies^ in^ muscle^ and^ nerve biopsies. J Neurol 1989;236:377-81.
59 Isaacs H. Continuous muscle^ fibre^ activity^ in an^ Indian^ male with^ additional evidence of terminal motor fibre^ abnormality.^ J^ Neurol^ Neurosurg Psychiatry 1967;30: 126-33. 60 Lublin FD,^ Tsiaris^ P,^ Streletz^ LJU, et^ al.^ Myokymia^ and^ impaired muscular relaxation with continuous motor unit activity. J^ Neurol Neurosurg Psychiatry 1979;42:557-62. 61 Sroka H, Bornstein M, Sandbank U. Ultrastructure of the syndrome of continuous muscle fibre activity. Acta Neuropath 1975;31:1162-3. 62 Nakashini T, Sugita H, Shimada Y, Toyokura Y Neuromyotonia. A^ mild case. J^ Neurol Sci 1975;26:599-604. 63 Sinha S, Newsom Davis J, Mills K, et al. Autoimmune aetiology^ for^ acquired neuromyotonia. Lancet 1991 ;338:75-7. 64 Shillito P, Lang J, Newsom-Davis J, Bady B, Charplannaz^ G.^ Evidence^ for an autoantibody mediated mechanism in^ acquired neuromyotonia.^ J Neurol Neurosurg Psychiatry (In press). 65 Isaacs H, Heffron JA. The syndrome of "continuous muscle^ fibre activity" cured: further studies. J Neurol Neurosurg Psychiatry 1974;37:1231-5. 66 Irani PF, Purohit AV, Wadia NH. The syndrome of^ continuous muscle^ fibre activity. Acta Neurol Scand 1977;55:273-88. 67 Wilton A, Gardner-Medwin D. 21 year follow^ up of^ myokymia^ with impaired relaxation. Lancet 1990;ii: 1138-9. 68 Ferrannini E, Perniola T, Krajewska G, Serlenga^ L,^ Trizio M.^ Schwartz- Jampel syndrome with autosomal dominant inheritance.^ Eur^ Neurol 1982;21:137-146. 69 Pascuzzi RM, Gratianne R, Azzarelli^ B,^ Kincaid^ JC.^ Schwartz-Jampel syndrome with dominant^ inheritance.^ Muscle Nerve^ 1990;13:1152-63. 70 Schwartz 0, Jampel RS.^ Congenital blepharophimosis^ associated^ with^ a unique generalized myopathy.^ Arch^ Ophthal^ 1962;68:52-7. 71 Spaans F, Theunissen P, Reekers^ AD,^ Smit^ L,^ Veldman H.^ Schwartz-Jampel syndrome: 1. Clinical, electromyographic and^ histologic^ studies.^ Muscle Nerve 1990;13:516-27. 72 Lehman-Horn F, laizzo^ PA, Franke^ C,^ Hatt^ H,^ Spaans^ F.^ Schwartz-Jampel syndrome 2.^ Na+^ channel^ defect^ causes^ myotonia.^ Muscle^ Nerve 1990;13:528-35.
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