Stiff man syndrome: A neuromotor disorder- Know how for physios

Synonyms: stiff man syndrome (SMS), stiff person syndrome (SPS), stiff leg syndrome (a focal SMS) etc

Introduction & definition:

Moerch and Woltman reported the first 14 cases with this syndrome for more than 50 years since 2010.

Stiff man syndrome (SMS) is an uncommon (rare) neurological disease that manifests with disorder of motor function which is characterized by rigidity of axial musculature and fluctuating painful spasms, which are often induced by startle or emotional stimuli.

Clinical and immunological findings indicate that SMS is a heterogeneous disease, suggesting the need to define its diagnostic criteria. But it has basic 2 forms either it can be generalized or focal. Criteria for the diagnosis of SPS were proposed but there are several variants of this syndrome described. These variants include focal variants of SMS.

Variants include stiff limb syndrome (SLS), jerking SMS and progressive encephalomyelitis with rigidity and myoclonus (PERM). Recognition of the clinical spectrum of SMS is important, particularly the upper-limb, cervical, and cranial nerve involvement that occurs in paraneoplastic variants (Paraneoplastic SMS accounts for approximately 5% of all cases of SMS). However they all share the core clinical features of appendicular and axial rigidity caused by continuous involuntary motor unit activity, and superimposed stimulus-sensitive spasms.

It is associated antineuronal autoimmunity and accompanying autoimmune diseases, most often noted in insulin-dependent diabetes mellitus with following C/F (see below). Several features suggest that SMS is an autoimmune-mediated chronic encephalomyelitis. Neurophysiological studies have demonstrated the presence of continuous motor unit activity in muscle at rest, with abnormally enhanced extereoceptive reflexes.

The disease progresses over the span of months to years rendering many patients wheelchair-bound or bedridden.

Clinical features:

1. Onset: Insidious & progressive
2. Fluctuating stiffness and paroxysmal spasms of the trunk and legs.
3. Symmetrical muscle stiffness and spasms that often lead to skeletal deformity.
4. The spasms characterized by hyperextension of the back (hyper-lordosis) and legs are both spontaneous as well as stimulus-sensitive. Spasms are excruciatingly painful.
5. SMS is frequently accompanied by symptoms of autonomic dysregulation.
6. Sometimes Hyperreflexia may be the only pathological finding on the neurological examination.
7. Mostly there is progressive gait impairment.
8. There may be a variety of additional neurological symptoms and signs such as eye movement disturbances, ataxia, or Babinski signs (progressive encephalomyelitis with rigidity and myoclonus), or be associated with malignant disease (paraneoplastic SMS).
9. Most patients show psychiatric disturbances suggestive of psychogenic movement disorder and this may cause delays in adequate pharmacotherapy.

EMG:

The electromyographic examination shows continuous motor unit activity of the affected muscles at rest. Spasmodic reflex myoclonus is observed in nearly all SMS patients. It consists of well-reproduced reflex EMG-activity commencing 50-80 ms after medial or tibial nerve stimulation and lasting several seconds thereafter. The activity is first myoclonic then spasmodic in nature, and commonly begins in the muscles most severely affected before spreading bidirectionally along the neuraxis.

Commonest clinical indicators to suspect SMS:

The diagnosis is based on clinical, biochemical and electrophysiological findings.

A characteristic group of symptoms and signs allows a tentative clinical diagnosis. Supportive ancillary findings include (1) the demonstration of continuous muscle activity in trunk and proximal limb muscles despite attempted relaxation, (2) enhanced exteroceptive reflexes, and (3) antibodies to glutamic acid decarboxylase (GAD) in both serum and spinal fluid.

Pathology:

1. There is good evidence for a primary auto-immune aetiology. In addition to that there is clinical evidence of organ-specific autoimmunity predominantly encephalomyelopathic disorder resulting from B-cell-mediated clonal production of autoantibodies against presynaptic inhibitory epitopes on the enzyme glutamic acid decarboxylase (GAD) and the synaptic membrane protein amphiphysin.
However other antibodies such as anti-gephyrin, and anti-gamma-aminobutyric acid A receptor-associated protein (GABARAP) antibodies (14-kD protein localized at the postsynaptic regions of GABAergic synapses) are also detected along with GAD & anti-amphiphysin. In up to 65% of SMS patients, there are circulating anti-GABARAP antibodies that inhibit the GABA(A) receptor expression on GABAergic neurons. Paraneoplastic SMS is associated with anti-amphiphysin, anti-gephyrin, and anti-Ri antibodies. There is strong evidence that in SMS, GABAergic neurotransmission is impaired by these pathogenic autoantibodies; however, the exact antigenic target remains unknown.
Autoantibodies against glutamic acid decarboxylase- GAD in both serum and cerebrospinal fluid help to establish the correct diagnosis. Specifically GAD65 isoform, are present in serum or cerebrospinal fluid of 60-80% of patients with SPS and its variants. A paraneoplastic form of SPS is recognized in about 5%, associated with a different profile of auto-antibodies.
The correlation between antibody levels and severity of disease also offers evidence for a pathogenic role for the anti-GAD and anti-amphiphysin autoantibodies.

2. The scarcity of neuropathological correlates stand in sharp contrast with the severity of the disability in affected individuals and suggests that functional impairment of inhibitory circuits without structural damage is sufficient to develop the full clinical spectrum of SPS.

Treatment options:

There are 2 distinct options:
1. Immunomodulation
2. Symptomatic

The rarity of this condition limits the feasibility of controlled clinical trials in the treatment of SPS, but the available evidence suggest that drugs that increase cortical and spinal inhibition such as benzodiazepines (clonazepam 4 mg/day) and drugs that provide immune modulation such as intravenous immunoglobulin, plasmapheresis, and prednisone are effective treatments.

Rigidity and spasms may be treated symptomatically with benzodiazepines, baclofen, tiagabine and levetiracetam. An alternative of last resort is baclofen administered intrathecally via an implanted pump device.

Treatments for cancer occasionally produce symptomatic improvement in patients with paraneoplastic SPS.

Prognosis:

SPS remains a largely underdiagnosed condition.

The syndrome varies from mild to severe, but if untreated it can be progressive and disabling. Generally after an initial progressive phase, patients with SPS generally stabilize over a period of months to years. However, 10% will require prolonged admission to intensive care at some stage during the disease. Sudden death has been reported in as many as 10% of patients because of unexplained metabolic acidosis or autonomic crises.

The prognosis in paraneoplastic SPS, jerking SPS and PERM, in terms of mortality, is generally worse than in primary SPS. It has been reported that reported cases of patients with SPS who were positive for anti-GAD antibodies and subsequently developed cancer. Because SPS often develops before the diagnosis of cancer, patients diagnosed with SPS should be monitored for the development of cancer.


References:
1. Stayer C & Meinck HM; Neurologia. 1998 Feb;13(2):83-8. (Stiff-man syndrome: an overview).
2. Meinck HM; CNS Drugs. 2001;15(7):515-26. (Stiff man syndrome).
3. Fiol M et al; Neurologia. 2001 Feb;16(2):89-91. (Focal stiff-person syndrome).
4. Duddy ME & Baker MR; Front Neurol Neurosci. 2009;26:147-65. Epub 2009 Apr 6. (Stiff person syndrome).
5. Espay AJ & Chen R ; Muscle Nerve. 2006 Dec;34(6):677-90. (Rigidity and spasms from autoimmune encephalomyelopathies: stiff-person syndrome).
6. Ishii A; Brain Nerve. 2010 Apr;62(4):377-85. (Stiff-person syndrome and other myelopathies constitute paraneoplastic neurological syndromes). [Article in Japanese]
7. Dalakas MC; Curr Neurol Neurosci Rep. 2008 Jan;8(1):48-55. (Advances in the pathogenesis and treatment of patients with stiff person syndrome).
8. Meinck HM & Thompson PD; Mov Disord. 2002 Sep;17(5):853-66. (Stiff man syndrome and related conditions).
9. Saiz A et al; Ann Neurol. 1998 Mar;43(3):400-3. (Stiff-leg syndrome: a focal form of stiff-man syndrome).
10. Gürol ME et al; Mov Disord. 2001 Nov;16(6):1189-93. (Stiff leg syndrome: case report).