EXPLAIN IN DETAIL THE CLINICAL AND ELECTROPHYSIOLOGIC FEATURES OF STIFF PERSON SYNDROME ?
A 1 INTRODUCTION
1 Stiff Person Syndrome (SPS) was first described in 1956 as a new clinical entity by Moersch and Woltman in a series of 14 patients
2 It is a rare CNS disorder characterized by progressive rigidity of the truncal muscles, superimposed spasms, and an exquisite sensitivity to external stimuli
3 Co-contractions of agonist and antagonist muscles and continuous involuntary firing of motor units at rest are the clinical and electrophysiological hallmarks of the disease.( vv imp )
4 SPS is commonly associated with high anti-glutamic acid decarboxylase (GAD) antibody titers and a variety of other organ-specific autoantibodies across a wide spectrum of clinical presentations.
5 The antibodies are believed to cause primarily a functional blockade in SPS by targeting antigens expressed in neurons of the brain and spinal cord at synapses using the neurotransmitter gamma-aminobutyric acid (GABA).
6 Although some autopsies have shown evidence of perivascular inflammation, and, in the rapidly progressive encephalomyelitis variant, structural damage in the CNS,autopsies of typical cases showed no inflammation and relatively little decrease in neuronal numbers.
7 vv imp High titers of anti-GAD antibodies in the serum and CSF of SPS patients seem to be directed against conformational forms of GAD selectively expressed in GABAergic neurons and can cause a blockade of GABA synthesis.
8 The acquired malfunction of the spinal and supra-segmental inhibitory networks utilizing GABA is hypothesized to be the mechanism underlying the excessive motor neuron firing in SPS.( vv imp )
9 GAD is also a major autoantigen in Insulin-dependant diabetes mellitus (IDDM), which is often associated with SPS
10 Although anti-GAD antibodies are detected in up to 80% of newly diagnosed type I diabetes patients, the titers are usually 50- to 100-fold less than in SPS patients with or without IDDM.
11 Approximately 70% of SPS patients with high-titer GAD antibody also have antibodies against a synaptic protein, GABA-receptor-associated protein (GABARAP), that is involved in the endocytosis, recycling and maintenance of synaptic vesicles and receptors.
12 In a subgroup of SPS patients, proximal muscle stiffness is a paraneoplastic manifestation of breast, ovarian or small-cell lung carcinomas (SCLC), associated with antibodies against amphiphysin,and gephyrin two synaptic proteins.
13 Paraneoplastic SPS with anti-amphiphysin antibodies is most commonly found in association with breast adenocarcinoma and SCLC.
14 anti-GAD antibody is conspicuously absent in these patients; in only one reported paraneoplastic SPS case with co-morbid renal carcinoma, anti-GAD, but not amphiphysin antibodies were present
15 vv imp Currently, there are no immunoassays or ‘gold-standard’ diagnostic electrophysiological tests that unambiguously distinguish SPS from patients with other neurological syndromes associated with anti-GAD antibodies or IDDM
16 Although anti-GAD and amphiphysin antibodies are presumed to be pathogenic in SPS, proof of their direct causative role is still lacking.
CLINICAL FEATURES AND COURSE
1 SPS rigidity usually begins insidiously in the thoracolumbar paraspinal muscles in patients in their mid-to-late 30s, usually without antecedent infection or other triggering factors, and extends over time to involve proximal leg and abdominal wall muscles.
A ) As a result of the muscle rigidity, patients develop a stiff, robotic gait and hyperlordosis of the spine with ‘a board-like’ appearance.
B ) Muscle rigidity may fluctuate at first but gradually becomes fixed and impairs the ability to bend and walk independently.
C ) SPS patients can exhibit major fluctuations of stiffness and spasms during a week or even over the course of a day.
D ) In general, they experience more symptoms and falls during times of physical or emotional stress, cold weather, and intercurrent infections.
E ) Rigidity typically improves during sleep.
F ) Although muscle stiffness is the ‘sine qua non’ in SPS, not all patients experience prominent rigidity and muscle spasms initially, but they develop the classic symptoms over time.
G ) The increasing stiffness over time results in substantial progression of functional impairment, and, in general, most patients require increasing doses or addition of new symptomatic therapies in order to achieve the same level of function.
2 The second set of pathognomonic symptoms is episodic spasms, which are sudden and sometimes painful.
A ) They are often precipitated by external stimuli and physical obstacles and may result in unprotected falls.
B ) Besides a heightened response to unexpected stimuli, SPS patients also suffer from marked anticipatory anxiety and task-specific phobias, and often from reactive depression as well.
C ) Much of the anxiety in SPS patients appears to be a realistic fear of falling, rather than an inherent psychiatric disorder.
D ) However, conditioned responses and acquired dysregulation of hippocampus and amygdala circuits may play a role in the neuropsychological manifestations of SPS
E ) As SPS progresses, the majority of patients have an increasing frequency of falls, require assistance for walking and activities of daily living, and frequently lose their ability to work.
F ) Several subsets of SPS with more-or-less distinct clinical phenomenology and disease course have been described: ‘Stiff-limb syndrome’ , SPS associated with myoclonus (Jerking stiff man syndrome), presumably from predominant brainstem involvement , SPS associated with epilepsy and dystonia or SPS with neurophthalmologic manifestations such as autoimmune retinopathy.
G ) Stiff person syndrome with progressive rigidity and encephalomyelitis is a much rarer form of SPS. It is characterized by a subacute encephalomyelitis that primarily affects the grey matter, resulting in widespread rigidity and rapid decline of cognitive capacities and typically leads to premature death.
H ) A cerebellar variant of SPS is characterized by prominent gait ataxia and dysmetria, as well as ocular findings consistent with cerebellar dysfunction without evidence of structural brain abnormalities.
3 The diagnosis of SPS is established by clinical findings and exclusion of pyramidal and extrapyramidal disorders, with supportive evidence from electrophysiological findings on EMG studies and serological and CSF testing that show elevated anti-GAD antibodies.
4 Conventional MR imaging studies of the nervous system are usually normal.
5 Magnetic resonance spectroscopy has demonstrated a significant regional decrease in GABA levels in the motor cortex, providing supportive evidence of deficient GABAergic inhibition as a pathophysiological mechanism in SPS.
6 Diseases that should be differentiated from SPS include myelopathies, dystonias and other extrapyramidal diseases, neurodegenerative disorders such as spinocerebellar degenerations, primary lateral sclerosis, neuromyotonia or ‘Isaacs syndrome’, as well as rare forms of chronic tetanus and psychogenic disorders.
7 Magnetic resonance imaging studies of the brain and spine are useful to exclude certain structural disorders, such as myelopathies.
8 Electromyography plays an important role in establishing a diagnosis of SPS by demonstrating the characteristic involuntary firing of motor units.
9 Up to 35% of SPS patients have coexistent Type I diabetes, which may precede the onset of SPS by months to years or, more commonly, develop soon after the onset of stiffness
10 Besides the relatively high prevalence of IDDM, there are several other organ-specific autoimmune diseases associated with SPS, including autoimmune thyroiditis, Graves’ disease, pernicious anemia, vitiligo and celiac disease.
11 Anti-GAD antibodies are an excellent serological marker for SPS
12 in addition, various other antibodies such as anti-thyroid, anti-intrinsic factor, anti-nuclear, anti-RNP, anti-gliadin and others are frequently present in serum. These likely represent a dysregulated immune system targeting different organs, as it is also observed in myasthenia gravis and other autoimmune disorders.
ELECTROPHYSIOLOGIC FINDINGS
1 The muscle stiffness in SPS is produced by involuntary firing of motor neurons resembling a normal voluntary contraction in needle EMG recordings
2 The motor unit potentials (MUPs) have normal configurations and firing rates, and there are no findings suggestive of denervation.
3 However, MUP firing continues when the SPS patient is at rest and during maneuvers, such as contraction of the antagonist muscle, which normally induce a reflex relaxation of the agonist muscle vv imp
A ) Demonstrating failure of reciprocal inhibition by recording from antagonist muscle pairs can be helpful to support the diagnosis of SPS and to illustrate the involuntary nature of the contraction.
4 In SPS, MUP firing at rest is particularly prominent in those muscles which exhibit clinical stiffness, typically the proximal leg and paraspinal muscles, and EMG recording from paraspinal muscles may be useful when limb muscle recordings are equivocal.
5 Although the MUP activity is typically referred to as ‘continuous MUP firing’, the amount of activity observed in individual muscles fluctuates, and periods of relative relaxation can be appreciated in prolonged recordings made with surface EMG.
6 Sleep, treatment with benzodiazepines or baclofen, and general anesthesia reduce MUP firing as well as the stiffness and spasms.
7 Reduction of MUP firing and spasms by diazepam has been used as one of the clinical diagnostic criteria for SPS
8 The spasms that occur in SPS can occur spontaneously or be triggered by external stimuli such as touch or loud sounds.
A ) Spasms typically begin abruptly, involve co-contraction of multiple muscles, are often bilateral, and may last for minutes or recur over several hours.
B ) Spasms can be strong enough to produce posturing of the limbs or spine and cause bone fractures.
C ) When spasms are elicited by cutaneous or acoustic stimuli, the timing and pattern of the initial muscle activation may resemble an exaggerated segmental or brainstem reflex, although there is abnormal spread of activity to additional muscles, particularly the clinically stiff muscles.
D ) However, following the normal reflex, a prolonged muscle activation with co-contraction of antagonist muscles typically occurs, and is clinically observed as a spasm.
E ) This excessive spread of reflexes and spasms occurs with stimulation of cutaneous nerves at non-noxious intensities, as shown for the leg flexor reflex in an example from one patient and for blink reflexes from another patient
F ) Demonstrating that stimulation of a cutaneous or mixed nerve produces EMG activity in distant limbs or paraspinal muscles can provide supportive evidence for the clinical impression of SPS.
G ) Acoustic startle responses are also abnormal in SPS, with spread to limb muscles and prominent spasms in leg or axial muscles where stiffness predominates.
H ) The disinhibition of startle responses and other brainstem reflexes in SPS is also seen in hereditary hyperekplexia, a disorder of glycinergic transmission, leading to the proposal that the excessive responsiveness to stimuli may reflect loss of inhibition at brainstem as well as spinal levels.
I ) The prolonged spasms following acousic stimuli that occur in SPS are not seen, however, in hereditary hyperekplexia.
9 The involuntary motor neuron firing observed in SPS is not a primary abnormality of the motor neuron or of the monosynaptic stretch reflex arc.
10 The MUPs fire at normal rates, and volitional recruitment is normal – except for co-contraction of antagonists.
11 vv imp There is notable absence of the doublets, multiplets or repetitive discharges that are commonly seen with peripheral nerve hyperexcitability syndromes such as Isaacs disease
12 Motor nerve conduction velocities, F-waves, T-waves, and H-reflexes are normal, as are the silent periods induced by mixed nerve stimulation and muscle stretch which contrasts to findings in patients with tetanus.
13 Despite the patient’s muscle rigidity, stretch reflexes are brisk, and untreated SPS patients may exhibit clonus, but without abnormal plantar responses.
14 Following the discovery of anti-GAD antibodies in SPS patients, several studies investigated the actions of interneuron circuits believed to use GABA as a neurotransmitter, with an initial focus on the inhibitory spinal cord interneuron circuits.
15 Several studies reported enhanced H-reflex recovery and reduced vibration-induced H-reflex inhibition, phenomena which are believed to be mediated by GABAergic interneurons that produce presynaptic inhibition of stretch reflex afferents.