(Marco digs into a controversial subject in this second of two blogs on Stiff Person Syndrome and ME/CFS – “Is the depression/anxiety present in Stiff Person Syndrome and, possibly by reflection, chronic fatigue syndrome (ME/CFS), a consequence of having a difficult disease or is it an inherent part of the illness itself?   This debate – what belongs to the mind and what belongs to the body  – is being played out in many other diseases, including, of course, ME/CFS.  Let’s see what’s happening with it in Stiff Person Syndrome)

Is the depression and anxiety in SPS and ME/CFS a function of the disease itself or simply the result of having a chronic illness?

Is the depression and anxiety in SPS and ME/CFS a function of the disease itself or simply the result of having a chronic illness?

Are ‘Co-morbid’ Anxiety and Depression An Essential Part of Stiff Person Syndrome ?

Like chronic fatigue syndrome there are questions whether the anxiety (arousal) or depression found in SPS is an inherent part of it or whether they are simply normal reactions to having a chronic illness .

No one believes chronic fatigue syndrome is major depression or generalized anxiety disorder;  the question is whether the two, in some places, share some common ground with ME/CFS  and if they do, is it due to the illness or the consequences of having a chronic illness?

For instance, while some studies find differences between major depression and ME/CFS (cortisol (Cleare et. al. 1995), EEG (Duffy et. al, 2011), Beta endorphins (Panerai  et al,2002), cognitive patterns (Moss-Morris et al, 2001) others have had difficulty separating the two;  brain glutathione levels (Shungu et al, 2012) ventricular lactate (Murrough  et. al. 2010), cerebral hypoperfusion (MacHale et al, 2000, (motor evoked potentials  (Samii 1996), SPECT scans (Schwartz et. al, 1995).

In her Nova Southeastern University (NSU) talk Dr. Hornig noted that some of the same brain structures are found in both ME/CFS and Dr. Maes (Maes et al, 2012) believes a similar inflammatory context underlies both disorders.  Significantly increased immune factors in ME/CFS and people with major depression versus controls suggested similar immune processes were at work in both disorders. Significantly higher immune factors in ME/CFS patients vs depressed patients suggested increased immune dysfunction was present in ME/CFS but that immune dysfunction played a role in both (Maes, Mihaylova et al 2012, Maes, Twisk et al,2012). 

This study has detected a shared ‘pathway phenotype’, i.e. disorders in inflammatory and CMI pathways, which underpins both ME/CFS and depression and, therefore, may explain the co-occurrence of both disorders. “ Maes et al.

Maes, a psychiatrist with a pathophysiological bent, takes the concept even further in another study stating that ‘co-ordinated and interacting biological pathways’ involving pro-inflammatory cytokines, tryptophan and other factors  drive the symptoms found in ME/CFS, depression and ‘somatization disorder’.  (Anderson et al, 2012).

Maes and Hornig combine both body and mind in their conception of ME/CFS but others do not.  In her ME/CFS treatment manual,  “Let The Light Shine Through”, Dr. Eleanor Stein, an ME/CFS patient herself, has this to say about the general vibe in the medical community around ME/CFS.

“In spite  of the thousands of published peer reviewed papers since the 1980’s reporting abnormal biological findings in ME/CFS, FM and MCS that are different from findings in depression or any other psychiatric disorder, the ‘primary psychiatric’ view continues to have influence. In the absence of valid diagnostic tests, the fallback position seems to be that these conditions are essentially psychological.”

Back to the question SPS researchers are facing.  Is the anxiety/depression found in SPS a reaction to the stresses of the disease or are anxiety and depression also manifestations of the underlying autoimmune disease?  Maes believes immune findings help explain both chronic fatigue syndrome and depression. What about Stiff Person Syndrome?

Fear of Falling?

Like ME/CFS, SPS appears to be accompanied by high levels of ‘co-morbid’ anxiety and depression which are assumed to arise in response to a much reduced quality of life and the real risk of serious injury (Rodrigues de Cerqueira et al, 2010 – correspondence). It appears that there are frequent anecdotal and case study reports of co-morbid anxiety which  may be either a context specific phobia related to movement difficulties or more of a generalised anxiety disorder.

This is hardly surprising given the risk of falling present in this disorder. It also explains why many SPS sufferers are originally diagnosed (sic) as suffering from a psychogenic movement disorder.

Or Low GABA?

The fact that high levels of anxiety/specific phobia correlate with GAD antibody levels and reduced locomotor function (Henningsen and Meinck, 2002) is usually taken as merely indicative of phobic avoidance due to increased morbidity and thus likelihood of injury – e.g.  going into spasm while crossing a road.

Anxiety and depression might also be expected with low GABA levels. Indeed, initial misdiagnoses made when there are few objective medical findings suggest that high levels of anxiety may be a result of the underlying pathology and not a maladaptive phobic response to the risk of injury which occurs later in the disease.  It bears noting that SPS patients originally misdiagnosed with  a ‘kinesiophobia’, do not respond to cognitive therapies, nor do those therapies reduce the anxiety of those correctly diagnosed with SPS. Something else appears to be causing the anxiety….

Enter the GAD antibody/GABA connection…

GAD antibodies in Psychiatry

Experimentally injecting rats with SPS antibodies results in the rats displaying high levels of anxiety like behaviour (Geis et al, 2011). Yarlagadda et al (2007)  believe GABAergic neurotransmission issues play a key role in epilepsy, anxiety disorders, schizophrenia, premenstrual dysphoric disorder and bipolar disorder.

Could an autoimmune reaction be contributing to a GABA/Glutamate imbalance in Stiff Person  Syndrome?

Could an autoimmune reaction be contributing to a GABA/Glutamate imbalance in Stiff Person Syndrome?

A small pilot study examining GAD antibody levels in chronic psychotic disorders led them to conclude :

“Antibodies to GAD65 (an isoform of GAD) are peripherally present in patients with chronic psychotic disorders (schizophrenia/schizoaffective disorders) and may potentially be used as a tool to screen for these disorders. The presence of such antibodies also suggests a possible role for autoimmune mechanism in the pathogenesis of these disorders.”

At Dr. Klimas’ recent NSU Conference,  Dr. Hornig included these disorders (plus ADHD, Fibromyalgia and ME/CFS) in a list of ‘neuropsychiatric disorders’ that may have immune causes. You may also recognize this list from the discussion of sensory gating deficits in Part I of the Neuroinflammation Seriess: Not Fatigue After All:).

You can parse out the term ‘neuropsychiatric’ in various ways but it bears mentioning that a disorder causing cognitive difficulties can fall into the ‘neuropsychiatric’ camp.

Remember also that we are looking at disorders like schizophrenia in the context of neuroinflammation and a sensory gating disorder and the evidence indicates that sensory gating issues could show up as schizophrenia in one way  and fibromyalgia or CFS in another.  The fact that similar pathological issues can manifest in very different ways was recently borne out in a study that found that the same genetic makeup could result in vastly different disorders. (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013). It’s also reflected in the fact that, as discussed in Part I,  the same drug can impact a wide range of disorders.

One possible mechanism to explain the attacks of extreme muscle rigidity in SPS involves GABA mediated inhibition from the cortex, brain stem, and cerebellum of motor neurons. If GAD levels are raised, the levels of  GABA required to be inhibit it are decreased and the muscles become continuously stimulated by the motor neurons (Rodgers-Neame, Medscape Reference).

Intriguingly, recent research (Cort will be blogging on this soon) suggests that the muscles of those with fibromyalgia also appear to be continuously ‘firing'; ie they’ve become locked in a contracted state. It’s no surprise that fibromyalgia patients often complain of muscle stiffness (Klaver-Król et al, 2012).

Infectious Onset?

The antibodies found in SPS are associated with enterovirus infections.

The antibodies found in SPS are associated with enterovirus infections.

The exact aetiology of SPS has yet to be found.  However Yarlagadda et al also report that GAD antibodies in diabetes (as previously seen, high rates of metabolic syndrome and diabetes are found in a number of neuroinflammatory conditions) have been associated with entero and coxsackie infection :

 “In the context of diabetes, GAD65 antibodies have been associated with an infectious etiology, especially entero and coxsackie viruses.  However, GAD65 antibodies interestingly bear a striking similarity with P2-C protein of coxsackie virus suggesting a cross-reactivity and interference with neuronal development.”

An additional single case report (Hassin-Baer et al, 2004) describes the onset of SPS following acute West Nile virus infection and describes a stretch of 12 amino acids in the NS1 protein of West Nile virus with a high degree of homology to the GAD65 region :

“Cross-reactivity between antibodies directed against West Nile virus and GAD may have contributed to the development of stiff-person syndrome in this patient.”

The previously discussed Anti-NMDA receptor encephalitis (an autoimmune encephalitis) has also been associated with Mycoplasma pneumoniae infection (Gable et al, 2009).


An imbalance in the excitatory and inhibitory neurotransmitters glutamate and GABA is implicated in a wide range of neuropsychiatric (ASD, schizophrenia, bipolar disorder, major depressive disorder, OCD etc) and in pain (fibromyalgia, interstitial cystitis, IBS) and movement disorders (Parkinson’s, Huntington’s).

Stiff Person Syndrome is one rare but extreme example of a condition combining a movement disorder with neuropsychiatric symptoms (anxiety, depression) where a glutamate/GABA imbalance is clearly central to the pathology,  is likely of autoimmune origin and which may have an infectious etiology.

Current research provides hints that a similar etiology may underlie a range of ‘neuroinflammatory’ conditions including ME/CFS.




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