Exacerbation of Stiff Person Syndrome by Selective Serotonin Reuptake Inhibitors

Stiff person syndrome (SPS) is a rare autoimmune disorder most frequently associated with autoantibodies directed against glutamic acid decarboxylase (GAD) which leads to decreased levels of γ‐aminobutyric acid (GABA) and muscle hyperexcitability, resulting in muscle stiffness and painful spasms. ¹

Case Report

We report profound worsening of symptoms in response to citalopram in an 80‐year‐old‐right handed woman with a 16‐year history of a SPS. She presented originally at the age of 64 with isolated stiff limb syndrome, manifesting left leg stiffness and painful spasms (precipitated by movement/tactile stimuli) resulting in frequent falls and necessity to use a walker (Video 1). MRI of the brain and spine, and paraneoplastic investigations were unremarkable. The serum GAD antibodies were elevated (>120 IU/ml, ELISA). Electrophysiological studies showed abnormal cutaneo‐muscular reflex, continuous motor unit activity and co‐contraction segmental spasms. The patient responded well to diazepam 16 mg/days and gabapentin 1500 mg/days and was able to ambulate for a few years (Video 2). Botulinum toxin injections were not tried. She had long‐standing anxiety and depression unsuccessfully treated with short courses of sertraline, escitalopram (possibly increased her stiffness), and venlafaxine. Over the course of follow‐up, she also developed slowly progressive dementia, presumed to be secondary to Alzheimer's disease. Associated with her dementia, anxiety and depression became more problematic. At the age of 79 she was given a trial of citalopram 20 mg/days. Within a week of starting citalopram, she developed a profound worsening of bilateral leg stiffness, making it impossible for her to bend her left knee and requiring use of a walker again (there were no other new medications). At the time, the temporal association between worsening of stiffness and the use of citalopram was not appreciated. She was hospitalized with urinary retention, diaphoresis, elevated creatine kinase (3670 U/L) and serum GAD antibodies (>250 IU/ml). There was no fever, other autonomic symptoms, myoclonus, startle‐reflex or history of trauma. Treatment with an intravenous immunoglobulin (IVIg), resulted in about 10% improvement in stiffness (minimal improvement in the range of motion/pain) with a benefit lasting 3 weeks each time. She received 8 courses of IVIg over a 9‐month period. At that point, she was largely wheelchair bound, only able to tiptoe a few steps. On examination there was mild arm and paraspinal muscles stiffness, bilateral leg stiffness, profound on the left and moderate on the right and right leg spasms brought on by tactile stimuli. The clinical severity of symptoms pre−/during/post‐citalopram was determined using changes in the validated and utilized in clinical trials Stiffness Index and Heightened Sensitivity scales, as well as overall stiffness intensity score (Table 1). ² Once the connection between the increased stiffness and citalopram use was made it was weaned off with clear temporal improvement; 5 months later there was a 33% reduction in her symptoms based on the objective scales used. Subjectively the improvement was close to 50% as there was only a slight remaining stiffness in both legs with full range of motion. She needed help getting out of a wheelchair; however, she could walk with help. The GAD antibodies remained high.

VIDEO 1.

Patient's video at age 66 demonstrates stiffness in the left leg, inability to bend the knee and painful spasms in the left leg precipitated by the tactile stimuli. The left leg is stiff when walking and the patient falls back into the examiner's hands on the pull test. There are no abnormalities found in her abdominal or back muscles. Video content can be viewed at https://onlinelibrary.wiley.com/doi/mdc313199.

VIDEO 2.

Patient at age 67 and 68 is able to walk, run and bend her legs with no stiffness. Her pull test much improved (the patient is not falling en bloc). Video content can be viewed at https://onlinelibrary.wiley.com/doi/mdc313199.

TABLE 1.

The stiffness index

	Pre‐citalopram	On citalopram	Post‐citalopram
Stiffness in face	0	0	0
Stiffness in arms	0	1	0
Stiffness in upper trunk	0	0	0
Stiffness in abdomen	0	0	0
Stiffness in lower trunk	0	1	0
Stiffness in legs	1	1	1
Total	1	3	1
The Heightened Sensitivity scale
Noise‐induced stiffness and cramps	0	0	0
Visually induced stiffness and cramps	0	0	0
Somatosensory‐induced stiffness and cramps	0	1	0
Voluntary activity induced spasms	0	0	0
Emotional upset and “stress”‐induced spasms	1	1	0
Awakening due to nocturnal spasms	0	1	0
Untriggered cramps and spasms	0	0	0
Total	1	3	0
Overall stiffness intensity score
Intensity	1 (mild)*	3 (severe)	1 (mild)*

The Stiffness Index, Heightened Sensitivity scale and overall stiffness sensitivity score pre−/during/post‐citalopram use. 0 absent, 1 present.

^*The overall stiffness intensity score does not include a “slight” category therefore we used “mild”.

The patient was diagnosed with a treatment‐emergent probable adverse drug reaction due to citalopram as per Naranjo algorithm (score of 7) (Table S1) and World Health Organization case causality assessment. ³ , ⁴

Discussion

Anxiety and depression are common in SPS. ⁵ , ⁶ Since there are no specific management guidelines available, standard treatment, including tricyclic antidepressants (TCA), selective serotonin uptake inhibitors (SSRI), or serotonin‐norepinephrine reuptake inhibitors (SNRI) is frequently used. ⁵ Aggravation of SPS has been noted with some of these agents, particularly clomipramine (TCA), duloxetine (SNRI), and fluoxetine (SSRI). ⁷ Benavides and colleagues reported four cases of SPS worsening associated with duloxetine use. ⁵ The exacerbation occurred within one to 4 weeks from duloxetine administration, required hospitalization, and treatment either with IVIg (n = 3) or plasmapheresis (n = 1). ⁵ The symptoms improved after the discontinuation of the offending drug. As SNRIs and TCAs increase not only serotonin but also norepinephrine levels and the use of α₂‐adrenoceptor agonist, clonidine (lowering norepinephrine level) was reported to improve the SPS, the authors speculated the involvement of the noradrenergic circuits in the SPS exacerbation. ⁵

Citalopram, however, not only belongs to a different medication class but is the most selective of the available SSRIs. There is only one previous case report of worsening of stiffness in SPS with SSRI use (fluoxetine 40 mg/days), successfully treated with clonazepam. ⁶ Further literature review did not reveal any other cases of drug‐related worsening of SPS. Interestingly, a recent study examining the autologous hematopoietic stem cell transplantation (HSCT) for SPS found that those who relapsed/never responded to the HSCT more frequently used the SSRIs/SNRIs prior to the HSCT further straightening the unfavorable outcome of using SSRI/SNRI in the SPS. ⁸

In SPS some brain areas such as the sensorimotor cortex may be more severely affected with a lower level of GABA than others (occipital cortex). ¹ Drugs enhancing GABA activity/transmission, eg, diazepam, gabapentin, or baclofen, provide symptomatic relief. It was reported that acute SSRI administration might result in an increase in relative GABA concentration in the occipital cortex, by 35%, as measured by MR spectroscopy. ⁹ Thus, in theory, by increasing GABA, the use of the SSRIs should offer some benefit. The pathophysiological mechanism underlying the acute exacerbation related to citalopram in our patient is therefore unclear. It is possible that this was not related to primary serotonin uptake blockade, but to an alternative mechanism of action recently described with fluoxetine, ¹⁰ inducing a blockade of P/Q voltage‐gated calcium channel (VGCC) leading to downregulation of the soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) complex. ¹⁰ The resultant reduction of glutamate and GABA release could provide an explanation for an exacerbation of SPS. ¹⁰ P/Q type channels belong to a subgroup of high voltage‐activated calcium channels and have an important role in neurotransmitter release, similar to N‐type VGCCs. ¹¹ It is unclear why other medications acting through the N‐type blockade (eg, gabapentin) may provide relief in patients with SPS. P/Q channels in the axon terminal are located closer to the release zone in comparison to other calcium channels in synapses. ¹¹ This may lead to a higher presynaptic concentration of calcium and co‐localization with synaptotagmin‐containing vesicle clusters. ¹¹ This is in contrast to only partial involvement of N‐type channels in vesicle clusters. ¹¹ Whether these factors play a role in the potential impact of SSRIs on SPS remains uncertain. It is important that clinicians are aware of this potential complication of SSRI use in SPS, especially given the likelihood that SPS patients would be considered for treatment with these agents.

Author Roles

1. Research project: A. Conception, B. Organization, C. Execution; 2 Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

D.A.O.: 1A, B, C, 3A

S.S.B.: 1A, B, 3B

A.E.L.: 1A, B, C, 3B

Disclosures

Ethical Compliance Statement

The authors confirm that the approval of an institutional review board was not required for this work. Written informed patient consent was obtained 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 Conflict of Interest

No specific funding was received for this work. There is no Conflict of Interest.

Financial Disclosures for the Previous 12 Months

The authors declare that there are no additional disclosures to report.

Supporting information

Table S1. The Naranjo algorithm adapted from Naranjo et al. 1981.