Pseudoagoraphobia, a Diagnostic Clue in Stiff‐Limb Syndrome

ABSTRACT

Background

Stiff‐limb syndrome is part of stiff person spectrum, presenting with fluctuating gait disorders attributed to leg stiffness, spasms, and posturing. It could also manifest with anxiety and specific phobias such as pseudoagoraphobia. We aimed to describe the importance of specific gait phobia as a diagnostic clue to anti–glutamic acid decarboxylase stiff‐limb syndrome.

Cases

We reported on 2 cases of stiff‐limb syndrome sharing a similar diagnostic path and phenomenology. Both were featured by pseudoagoraphobia, which has documented to typically cover organic conditions, and a remarkable diagnostic delay attributed to misdiagnoses. Presence of pseudoagoraphobia should not point to the diagnosis of a functional disorder—although a negative instrumental workup is documented.

Conclusions

Both cases are emblematic of the high misdiagnosis rate affecting stiff person syndrome patients. A proper diagnostic process, including the identification of a pseudoagoraphobia, should help in reaching a diagnosis and providing an early and effective treatment.

https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312911-sup-v001_1.htm

Gait disturbances are frequently reported in movement disorder clinics and some of them could fluctuate, making the diagnostic processes challenging.1 Stiff person syndrome (SPS) is a rare and heterogeneous autoimmune disorder which could present with fluctuating gait impairment and superimposed episodic muscle spasms, especially in stiff‐limb syndrome (SLS)—a focal variant of stiff person spectrum disorder (SPSD) that could affect the leg.2, 3, 4 Anxiety is the psychiatric counterpart of the syndrome, which could also manifest with task‐specific paroxysmal phobias, such as pseudoagoraphobia (i.e., gait‐specific phobia).5, 6 The latter could abruptly modify the patient's walking behavior because of the fear of falling, making the differential diagnosis even more complex.1 Here, we report on 2 analogous cases of SLS, both characterized by pseudoagoraphobia and by a remarkable diagnostic delay, in order to discuss challenges in clinical approach and differential diagnosis.

Case Series

Case 1

A 60‐year‐old woman with a history of autoimmune thyroiditis came to our clinic in 2014 complaining of right foot pain and fluctuating ipsilateral foot cramps, resulting in abnormal foot posturing while walking (Video 1). At that time, neurophysiological and neuroimage exams resulted as unremarkable. Because of the fluctuation of symptoms/signs, and the presence of anxiety, she was initially suspected to be psychogenic and unfortunately lost at follow‐up. Between 2014 and 2018, she was treated with psychotherapy, antidepressants, and benzodiazepines with a satisfactory outcome. The latter were discontinued in 2018, and symptoms showed a subtle worsening. Additionally, she developed diabetes and secondary depression, together with the acknowledged anxiety. Interestingly, she presented difficulty walking in open spaces, being possible only with her husband aside. During walking, she also complained of an intense fear of falling because of right foot spasms and stiffening. She had also been treated with levodopa in the suspicion of dystonia secondary to parkinsonism, with no clear improvement. We met the patient again in 2019, when she presented with right foot deformities (Supporting Information Fig. S1), bizarre gait attributed to right leg stiffness, ipsilateral toe walking with step evoked spasms, freezing‐like episodes, and fluctuating inability to walk without support (Video 1). The neurological examination revealed the presence of right leg stiffness, step‐evoked spasms with leg retraction, and brisk deep‐tendon reflexes. The rest of the examination was normal. Neuroimages (brain and spine MR) and cognitive assessment were unremarkable except for mild lumbosacral spondylosis; the behavioral profiling is reported in Figure 1. A new electromyogram (EMG) demonstrated the presence of continuous motor‐unit activity in right flexors and extensors muscles (Video 2), with concurrent EMG signs of mild lumbar radiculopathy. The nerve conduction study was unremarkable. An SLS was suspected and anti–glutamic acid decarboxylase antibodies (anti‐GAD) were tested, resulting in 2,000 U/mL (normal values: <5). She was treated with benzodiazepines, a cycle of high‐dose methylprednisolone and plasma exchange, with improvement of gait and neuropsychiatric manifestations, followed by a maintenance therapy with low‐dose oral corticosteroids7 and discontinuation of benzodiazepines (Video 1) See Figure 2A for patient history.

Figure 1.

(A) The Hamilton Depression/Anxiety (HAM‐D/HAM‐A) scales. (B) The Symptom‐Checklist‐90 (SCL‐90) scale: somatization, obsessions‐compulsions, interpersonal‐sensitivity, depression, anxiety, hostility, phobic‐anxiety, paranoid‐ideation, psychoticism, sleep‐problems (SOM/O‐C/INT/DEP/ANX/HOS/PHOB/PAR/PSY/SLEEP).

Figure 2.

Patient 1 (A) and 2 (B) clinical course on timelines. *Later discontinued drugs. The diagnosis of type 2 diabetes of patient 1 was then revised as LADA (latent autoimmune diabetes in adults) attributed to anti‐GAD presence. anti‐GAD ab, anti–glutamic acid decarboxylase antibodies; CBT, cognitive‐behavioral therapy; DRD, dopa‐responsive dystonia.

Case 2

A 65‐year‐old woman came to our clinic in 2014 because of a 1‐year history of episodic “rigidity” and painful spasms of the left foot while walking, causing “freezing‐like episodes” and falls (Video 3). At that time, neuroimaging and ‐physiological examinations were unremarkable (Fig. 2B). In the suspicion of a functional movement disorder, she was started on benzodiazepines and physical rehabilitation; however, despite an initial improvement, her clinical conditions (i.e., leg/foot rigidity and painful spasms) remained substantially unmodified in the following 3 years and an ¹²³I‐Ioflupane single‐photon emission computed tomography scan was performed to rule out parkinsonism, showing no abnormalities. After orthopedic evaluation, she underwent a surgical procedure on the left foot flexors’ tendons without any benefit on gait. In 2018, she presented with marked worsening of symptoms involving also the right foot. Furthermore, she developed generalized anxiety, intense fear of falling, and walking in open spaces, significantly impairing her quality of life (Video 3). Neuroimages (brain and spine MR and a fluoro‐DOPA PET) and cognitive profile were unremarkable; the behavioral assessment is reported in Figure 1. She was referred to our botulin toxin clinic for the treatment of an “idiopathic spastic paresis.” At that time, the neurological examination revealed step‐evoked muscle spasms with leg retraction and rigidity of the left leg, and EMG showed continuous motor‐unit activity in agonist and antagonist left leg muscles, despite attempted relaxation. The rest of the examination was normal. Anti‐GADs were detected in the patient's serum with high titer (>2,000 U/mL; normal values: <5), and a diagnosis of SLS was made. No other comorbidity (e.g., diabetes) was reported; she was treated with high‐dose methylprednisolone and subsequently with plasma exchange with sustained improvement on gait and generalized anxiety.

Discussion

SPSD encloses a group of rare autoimmune movement disorders associated with antibodies targeting proteins expressed by inhibitory synapses in the central nervous system.2 The presence of anti‐GAD (the enzyme that converts glutamate to gamma‐aminobutyric acid [GABA]) is reported in approximately 70% of the SPS, the most common disorder of the group.2, 7 However, other antibodies have been associated with SPSD, such as anti‐glycine receptors, anti‐Gephyrin, anti‐dipeptidyl peptidase‐like protein 6, and anti‐amphyphisin.2

Anti‐GADs are found also among the general population with a prevalence of 1.0% to 1.7%, and an even higher prevalence can be found in patients suffering from diabetes and thyroid dysfunctions.2, 8 Given their low sensitivity and specificity, the presence of anti‐GAD has just a supporting role for the diagnosis of SPSD.2

SPSD is more common in women ages between 40 and 60, and the estimated prevalence is of 1 to 2 per 1 million subjects.2, 8 In SLS, one or more limbs are affected by distal rigidity, episodic/stimulus sensitive painful spasms, and increased exteroceptive reflexes. It represents 10% to 20% of SPSDs, and anti‐GADs are reported in almost 20% of cases.3, 4 Hypothetically, muscle spasms are caused by an exaggerated response to the descending reticulospinal pathway at a segmental level, caused by a chronic interneuronitis.4 This leads to EMG findings of continuous or subcontinuous motor unit activity at rest, attributed to a hypersynchronous segmented discharge that can be reduced by benzodiazepines.2, 3, 4 However, neurophysiological signs may develop with time; thus, normal EMG in the early course of the disease should not discourage the clinician in pursuing a diagnosis.^2–4,7

Patients with SPS exhibits a “stiff” gait, attributed to the cocontraction of agonists and corresponding antagonist muscles around joints.1, 8 The interpretation of the stiff‐limb gait could be challenging also because of the scarcity of specific symptoms, signs, or electrophysiological abnormalities attributable to the long tracts of the spinal cord.3, 4 Muscle spasms or rigidity could fluctuate, being modified by emotions and external stimuli (e.g., noise or touch), and limited to distal leg muscles (e.g., finger or ankle extensors/flexors) generating spasms, transient or fixed postures, bizarre gaits, or even pseudo‐freezing episodes. The latter should be differentiated by the freezing of gait—that is, brief episodes of inability to produce effective stepping forward—observed in Parkinson's disease and related disorders.1

In SLS, symptoms could spread from foot to the thigh, mimicking different conditions, such as spasticity attributed to stroke or spinal lesions, which could be diagnosed through neuroimages and neurophysiology (e.g., evoked potentials), which have little significance in SLS.

The presence of fluctuating symptoms and bizarre posturing and stepping are also reported in functional gait disturbances. Anxiety and specific phobia (such as an intense fear of “crossing roads” or “driving vehicles”) have been formerly associated with SPSD by Henningsen and Meinck, being recognized as main contributors of the high rate of SPSD misdiagnosis as psychogenic (i.e., 80%).5 “Space‐phobia,” also named “pseudoagoraphobia,” has been described in the seminal article by Marks in patients reporting “intense fear evoked by visuospatial cues” with severe disturbance of walking with no need of actual supports but a “visual” support nearby.6 Recent experimental findings reinforced the link between SPS and behavioral abnormalities. For instance, the passive transfer of immunoglobulins from SPS patients with anti‐GAD to rats could induce anxiety‐like behaviors probably attributable to an impairment of the GABA signaling in the amygdala.10

Subjects with pseudoagoraphobia usually present a stable personality with a low burden of psychotic symptoms (Fig. 1) that, as described by Marks, could cover the presence of an underlying organic condition.6 This should be of help in differentiating patients with pseudoagoraphobia by those with agoraphobia who conversely report a higher load of psychiatric comorbidities (e.g., fear of public places, but no fear of falling) and by subjects with functional gait disorders.

The latter are not uncommon (1–9% cases in movement disorder clinics), but their proper diagnosis has to be anchored on the presence of positive signs and clues, such as inconsistency and/or incongruity of movements, distractibility, or false “giveaway” weakness (e.g., buckling knees). Therefore, a negative instrumental workup should never be the only diagnostic support.11

In conclusion, our observations are in line with what is known about SPSD and the associated delay in establishing a diagnosis and initiating a treatment that is reported to be as long as 5 years on average.8 This confirms that SPSD still remains an under‐recognized entity deserving attention by the research community. Early detection is essential to start an appropriate treatment and avoid unbeneficial approaches, thus reducing the impact of the SPSD on patients’ quality of life.

Author Roles

(1) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

M.M., F.M., M.G.B.: 1A, 1B

J.L., A.D.S., M.R.: 1A

F.C., F.R., E.M.G., V.D.L.: 1B

Disclosures

Ethical Compliance Statement: Patients were informed and signed consents were obtained of any identifiable subject in videos or pictures. The authors confirm that the approval of an institutional review board was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: The authors declare that there are no disclosures to report.

Supporting information

Video 1. In 2014, the patient presented abnormal posturing and spasms of her right foot with toe walking, impairing gait especially in turning. Episodes of abnormal posturing (i.e., plantar flexion and subtle inversion of the foot with toes flexion) occurred also when lying on a bed (segment 1). In 2019, some imbalance can be noticed, with broad‐base gait, together with freezing‐like episodes during walking (segment 2). Gait imbalance is associated with fear of walking without support: Patient tends to walk with someone or something aside (i.e., always seeking contact with the wall; segment 3). After corticosteroids, the foot abnormal posturing and spasms became less frequent (Supporting Information Fig. S1), and freezing‐like episodes still persisted; the rest of her clinical examination showed hyper‐reflexia (segment 4).

Video 2. Needle EMG of patient 1 right gastrocnemius (segment 1) and tibialis anterior (segment 2) shows subcontinuous 8‐ to 10‐Hz activity while the patient tried to fully relax is represented by motor unit activity. There is a slight reduction of the recruitment pattern during maximum voluntary contraction of the tibialis anterior muscle (segment 2) with a few high‐amplitude rapidly firing motor unit potentials, suggesting a slight chronic lower motor neuron damage. Nerve conduction studies were normal, ruling out a peripheral neuropathy, while lumbosacral MRI revealed a slight lumbosacral spondylosis, suggesting a mild chronic right lumbar radiculopathy (not shown).

Video 3. In 2014, patient 2 presented with left toe walking that was subjectively relieved by wearing shoes with plantar orthotics; abnormal posture with plantar flexion of the left foot is only evident when walking (segment 1). In 2018, she presented with fluctuating gait disturbances, intense fear of falling, and pseudoagoraphobia, with difficulties in moving away from the wall without assistance (segment 2). The patient showed a brilliant and long‐lasting therapeutic response to plasmapheresis (segment 3).

Figure S1. Abnormal foot posture attributed to prolonged flexors/extensors cocontraction.