Abstract
Stiff person syndrome (SPS) presents with stiffness in the limbs and axial muscles, stiff gait with uncontrolled falls, and episodic painful muscle spasms triggered by anxiety, task-specific phobias, and startle responses. 1 Stiffness and painful muscle spasms are the most disabling symptoms, especially when they occur concurrently, felt and observed most often in the thoracic and abdominal muscles resulting in hyperlordotic posture, in the hip flexors and extensors causing stiff leg, in the neck extensors and flexors causing stiff neck, or the tibialis posterior/extensor digitorum longus and gastrocnemius muscles causing stiff foot with painful spastic eversion of the foot and claw-toe-like formation that prevents full steppage resulting in gait dysfunction and falls.1–3
Mechanisms of muscle stiffness, unique to SPS
The SPS stiffness, erroneously referred in the literature as “rigidity” or “spasticity,” is true “muscle stiffness” mechanistically due to impaired reciprocal GABAergic inhibition.1–3 Reciprocal inhibition is the fundamental neurophysiological process during which when a prime mover (i.e., agonist muscle) contracts, its antagonist muscle is concurrently relaxed because it is silenced by the spinal cord GABAergic and glycinergic inhibitory interneurons which directly inhibit the firing of motor neurons to the antagonist muscles.1,4 This normal physiologic process is disturbed in SPS due to impaired intracortical GABAergic inhibition associated with GAD-antibodies and reduction of brain and CSF GABA1–7; as a result, when an agonist SPS muscle contracts in one direction, its antagonist does not relax but is pulling the muscle in the opposite direction resulting in co-contraction of agonists and antagonists, clinically manifested as stiffness of the whole extremity and electrophysiologically by motor unit action potentials firing concurrently from both opposing muscles groups.1–5 The reduction of GABA is also connected to sudden, episodic, and painful muscle spasms, triggered by anxiety, phobias, and startles from visual, tactile, or auditory stimuli.1,6,7 Considering that the main cause of SPS stiffness is the impaired GABAergic neurotransmission, the target-specific treatment for symptomatic relief not only of stiffness but also of spasms is with GABA-enhancing agents, consisting of GABAA receptor-binding drugs (diazepam, clonazepam), GABAB receptor-binding drugs (baclofen); and agents enhancing GABA-synthesis or facilitating GABAergic neurotransmission (Gabapentin).3,8 These agents are combined with immunotherapies aimed to improve autoimmunity and arrest disease progression.1–8
In an article recently published in Therapeutic Advances in Neurological Disorders, Roman et al. 9 in a retrospective observational study of 37 patients with SPS, but with clinically and immunologically heterogeneous disease subtypes, report that botulinum toxin (Botox) was variably beneficial because several patients experienced subjective symptomatic benefits lasting about 10.5 weeks; they conclude that Botox, injected in accessible localized areas, can offer adjunctive symptomatic relief in painful spasms and stiffness based on the patients’ own assessments and the authors’ retrospective interpretation. Although first tried several years ago in the paraspinal muscles of one SPS patient, 10 Botox has not been routinely used in practice of SPS patients because of limited overall efficacy, transient if any benefits, practical complexities associated with repeated Botox injections in many muscle groups and the concern that they can trigger painful spasms.1,3 This study, 9 despite the limitations highlighted below, also generates several practical questions about (a) the rationale of using Botox in SPS considering the unique pathophysiology of SPS stiffness; (b) the challenge of objectively assessing stiffness reduction; and (c) the balance between meaningful efficacy, safety, patients’ satisfaction, convenience, cost, and tolerance considering the very high doses used to inject several muscles at each visit and their triggering new spasms.
Challenges in using Botox to improve stiffness in agonists and antagonist muscles
In contrast to using Botox for other diseases, like spasticity due to upper motor neuron diseases or dystonias, the stiffness in SPS relates to co-contraction of agonist and antagonist muscles, requiring targeted injections in both opposing muscle groups. This is challenging because some of the critical pairs of stiff muscles cannot be easily assessed for concurrent injections due to their anatomy, location, and the long-distance the toxin itself needs to travel from the injection sites to the stiff muscles without inducing painful spasms. Specifically, for the neck stiffness, you can easily reach the cervical paraspinals in the back but not the opposing anterior flexor muscles; for the thoracolumbar/abdominal muscles, the anterior abdominal groups can only be partially injected; and for the knee flexors/extensors, it is very difficult to inject the iliopsoas from the inguinal area despite the authors’ claims. 9 On the other hand, for the forearm and feet spasms and stiffness, you can easily and effectively inject forearm flexors/extensors and foot extensors/flexors or evertors/invertors. Despite the authors’ effort to perform targeted injections, as stated, 9 this was not fully accomplished because the most frequently injected muscles in the posterior region were the lumbar paraspinals (92.3%), trapezius (77%), scapular (69%), and thoracic paraspinals (42%), but their corresponding anterior antagonist muscles could not be easily reached based on anatomy; the muscles chosen instead by the authors, like rectus abdominis reached only in 15%, external obliques and semitendinosus in 38%, and tensor fascia latae in 76%, cannot effectively counteract the torso stiffness. Importantly, the iliopsoas, a large hip flexor originating from T12 to L5, was stated as injected in 61%; iliopsoas is however a very difficult muscle to reach with a needle from the inguinal area because only a bundle crosses below the inguinal ligament to the hip and, even if this is injected, only a small and insufficient amount of toxin can travel the distance to the main muscle that lies in the posterior abdominal wall to counteract the co-contracted opposing hip extensors. Overall, although the authors’ effort to select and inject specific muscles groups is commendable, the complexity of SPS stiffness, muscle accessibility, and extreme sensitivity of patients to external stimuli that trigger painful spasms, make it difficult to inject the co-contracted agonists/antagonists in the most symptomatic key areas, like the torso, hips, or neck, for sufficient stiffness reduction and symptomatic relief.
The need to objectively quantify degree of stiffness and assess its impact in patients’ mobility
Objectively assessing the magnitude of stiffness in SPS patients has been a concern since the first time we studied SPS more than 30 years ago due to its subjective nature and variability in stiffness severity, even from minute-to-minute, especially when associated with triggered spasms. Although we had validated the stiffness index 2 and used it in clinical trials or in assessing disease progression,11–13 this index mostly counts the number of stiff areas rather than the severity of stiffness in each region. Considering that placebo effect can be often seen with invasive procedures like injections, objective measures in assessing changes in the magnitude of muscle stiffness and their clinical impact is essential but quite challenging. Apart from the stiffness index, the degree of stiffness is indirectly assessed by other associated quantifiable factors such as pain, time to walk, or perform specific functions.
Accordingly, the authors’ conclusions as stated, 9 that Botox was effective in reducing stiffness, has many limitations: first, assessments were retrospective and no actual data were available, as the authors acknowledged that “improvement was not captured during visits to quantify it”; second, they relied on patients’ own subjective assessments based on the Likert scale, which not only does not quantify stiffness severity and spasm frequency but is also a simplistic psychometric scale with entirely subjective bias, expressing nuanced opinions, impossible to distinguish a placebo effect; and third, if Botox was effective, why there was a need for escalating immunotherapy in all the patients, even in those with >8 visits, while up to 76% of patients had to also increase the dose and frequency of antispasmodics? These concerns collectively suggest that the overall benefit was inconsequential or insufficiently dissected and documented.
Other limitations regarding the stated 9 overall efficacy assessment were the significant variability in the number of injections, doses, visits, targeted muscles, and clinical phenotypes. Specifically, 14 patients had 1–2 visits, 10 had 3–7 visits, and only 13 had >8 visits where the benefit was said to be clearer; among all the 37 patients, 9 completed only 1 visit and did not return (which probably means poor satisfaction), while among the 28 patients with follow-up visits, 19 (67.9%) noted improvement which accounts for an overall 51% of the whole cohort. The clinical phenotype was also quite variable as only half of the patients had GAD65 titers >1000 and 8% were seronegative suggesting diagnostic uncertainty. Collectively, so many variables raise questions about the conclusions on efficacy.
Useful observations for neurologists and SPS patients when considering Botox
Despite the noted efficacy concerns, this study 9 has triggered key questions useful in counseling neurologists and SPS patients whenever Botox is considered.
Can Botox injections trigger spasms and pains?
Considering the sensitivity of SPS patients to external stimuli, the main concern for years has been the possibility that intramuscular injections in stiff areas can trigger spasms and temporarily worsen the patients. As expected, painful spasms occurred after the injections in 21.6% of all patients, while 26.1% at visit 3, and 61.5% at visit 8 had ongoing spasms during the injections. 9 Although the authors noticed that the Botox-triggered painful spasms were transient up to 1 week, 76.9% of all patients, even those with >8 visits, required higher doses of antispasmodics raising concerns as to whether the stated benefit after 8 visits might have been due to increased oral symptomatic therapy rather than due to Botox.
Is Botox safe at supramaximal dosing?
Although Botox can inhibit neurotransmitter release as can travel via the cholinergic nerve terminals to being internalized into neuronal nerve terminals causing muscle paralysis, no such a side effect was observed (except in one patient who developed leg weakness), even with the high, up to 980 units used, 9 providing safety reassurance.
How often are Botox injections needed, for how long, and is there generalized benefit in daily activities and mobility beyond the injected areas?
Because the study was retrospective without objective assessments, 9 no definite conclusion on these key questions can be extracted as the follow-up visits were pre-scheduled based on standardized 3-monthly intervals, but not on declining benefits according to predefined efficacy scales. Based on the authors’ data, however, that only 13 of the 37 (35%) patients returned for more than 8 visits, 9 (24%) never returned, 76.9% with >8 visits had to increase antispasmodics, and all required escalation of immunotherapy, the stated benefits do not appear substantial; this is in contrast to patients with dystonia or spasticity who experience benefits 2–4 weeks after each Botox, and they look forward to returning even before the 3-month-time.
Conclusions regarding the value of Botox in SPS
Because electrophysiologically Botox has no effect on GABAergic pathways as the currently used common antispasmodics drugs do,1–3 and stiffness reduction or changes in mobility and QoL were not objectively documented, while there was concurrently a need to escalate all other therapies, 9 the value of Botox in SPS may be rather limited; this especially applies to patients with treatment-refractory chronic painful and debilitating cervical or thoracolumbar and abdominal stiffness with hyperlordosis and stiff gait, where co-injecting the opposing pairs of stiff muscles is challenging. On the other hand, for painful local or focal limp stiffness, like the quadriceps (where its antagonist hamstring can be easily co-injected) or the foot invertors and toe flexors (with easy co-injection of foot evertors and toe extensors), Botox may be considered if the spasms and stiffness are prominent and affect walking ability or stepping pattern. Doing a control Botox study as the authors proposed, 9 is not a priority in SPS not only due to uncertain efficacy and the Botox-triggered spasms, but mostly because all symptomatic therapies have transient benefits or limited efficacy with no effect on disease progression; controlled studies are mostly needed for immunotherapies that offer hope for improving all SPS symptomatology, not regionally as expected with Botox.
Overall, this study 9 gave us the opportunity to highlight that (a) careful patient selection is needed by neurology teams experienced not only in Botox but also in SPS pathophysiology to ensure that injections would target accessible co-contracted agonist and antagonist muscles with reduced possibility of triggering spasms; and (b) need to establish efficacy scales that objectively assess and quantify degree of stiffness and its effects on mobility and daily functions.
