BRAIN FOG/ RHEUMATOID ARTHRITIS AND COGNITIVE DYSFUNCTION/HOW INFLAMMATION AFFECTS BRAIN

2. INTRODUCTION
Rheumatoid arthritis is an inflammatory symmetric polyarthritis
with varied multisystem involvement.
RA is widely prevalent throughout the world. The overall
worldwide prevalence is 0.8% (40 per 100,000)3.
In India the prevalence has been estimated to be
0.7%3.
The cause of RA is not known, but many possible etiologies have
been identified.
The incidence of CNS involvement is not defined, but it is
definitely there.

3. Articular Manifestations
 Symmetric swelling of multiple joints
with tenderness and pain is
characteristic.
 >6 wk of pain, swelling, warmth in
one or more peripheral joints,
frequently with symmetric joint
involvement.
 Often associated with >1 hr of
morning stiffness.

4.  Most common joints involved include MCP, PIP, MTP, Ankles,
Elbows, Shoulders, hips and knees.
 DIP joints, Sacroiliac and vertebral joints are spared except for
C1 to C2.
 Atlantoaxial (C1–C2) subluxation can lead to myelopathy.

5. A. Joint involvement SCORE
 1 large joint 0
 2−10 large joints 1
 1−3 small joints 2
 4−10 small joints 3
 >10 joints (at least 1 small joint)†† 5
B. Serology (at least 1 test result is needed for classification)
 Negative RF and negative ACPA 0
 Low-positive RF or low-positive ACPA 2
 High-positive RF or high-positive ACP 3
C. Acute-phase reactants (at least 1 test result is needed for classification)
 Normal CRP and normal ESR 0
 Abnormal CRP or normal ESR 1
D. Duration of symptoms
 <6 weeks 0
 >6 weeks 1
2010 ACR/EULAR Classification Criteria
A score of ≥6/10 is needed for classification of a patient as having
definite RA

6. These are present in 30-40% of cases.
May occur prior to arthritis.
Patients that are more likely to have extra-articular
manifestations are:
 Having high titres of RF/ anti-CCP
 HLA DR4+
 Male sex
 Early onset disability
 History of smoking
EXTRA-ARTICULAR MANIFESTATIONS

7. Various Extra-articular Manifestations Are:
1.Constitutional symptoms ( most common)
2.Rheumatoid nodules(30%)
3.Hematological
 Normocytic normochromic anemia
 Leucocytosis /leucopenia
 Thrombocytosis
 Felty’s syndrome-
 Chronic nodular Rheumatoid Arthritis
 Spleenomegaly
 Neutropenia

8. 4.Respiratory
Pleural effusion
Pneumonitis
Pleuro-pulmonary nodules
ILD
5.CVS
Asymptomatic pericarditis
Pericardial effusion
Cardiomyopathy
6.Rheumatoid vasculitis
Mononeuritis multiplex
Cutaneous ulceration
Digital gangrene
Visceral infarction
7.CNS
Peripheral neuropathy
Cord-compression
Entrapment neuropathies
Cognitive decline
8.EYE
Kerato cunjunctivitis sicca
Episcleritis
Scleritis

9. VARIOUS NEUROLOGICAL SYMPTOMS ARE
 Depression
 Sleep disturbances
 Fatigue
 Dementia
 All of these factors result in impairment of psychomotor
performance and adversely affect the quality of life.
COGNITIVE
DECLINE
FATIGUE
DEPRESSION
SLEEP
DISTURBANC
ES
DEMENTIA
 These symptoms are often termed as ‘brain fog’ commonly.

10. Symptoms of Cognitive Decline in RA
patients
Lack of mental clarity
Confusion
Forgetfulness
Inability to focus
Lethargy or ‘lack of energy’
Dementia (Alzheimer’s)

11. Various behavioural changes, during chronic illnesses are
referred to as sickness behaviours4.
 Various sickness Behavior in RA are:
 Fatigue
 Weight loss
 Fever
 Malaise
 Anorexia
 Depressed mood
 Reduced Motor activity
 Decreased social and personal interactions
 Loss of libido
The primary mechanisms through which these changes occur are
inflammatory molecular messengers in the central nervous
system (CNS) sentinel cells in the circumventricular organs and
transport across the blood–brain barrier (BBB)3.
NEUROLOGICAL SYMPTOMS cont….

12. WHAT IS BRAIN FOG ???

13. BRAIN FOG

16. Not all doctors who treat rheumatoid arthritis are convinced that brain
fog represents an important concern for their patients.

17. PATHOGENESIS
 The most important theory explaining the pathogenesis
The Cytokine Theory.
Cont…

18. SCHEME DEPICTING THE MECHANISM OF NEURO-
INFLAMMATION IN AUTOIMMUNE CONDITIONS

19. The systemic inflammation, characterized by increased
circulating levels of pro-inflammatory cytokines, has been
implicated in cognitive decline and dementia (i.e., Alzheimer’s
disease) in many studies7.
In patients with active RA, had a significantly higher ratio of
Choline to Creatine and a significantly lower ratio of N-
Acetylaspartate to Choline suggesting that the systemic
inflammation is associated with increased brain metabolism.
PATHOGENESIS CONT….

20.  Bartolini et al(5) observed that cognitive dysfunction was
common in RA patients, with prevalence rates ranging from 38%
( sustained attention and mental flexibility) to 71% (visuo-
spatial and planning functions).
 Hypoperfusion on brain single photon emission computed
tomography (SPECT) and increased white matter alterations on
magnetic resonance imaging were found.
Various studies so far….

21. Fig. 1.Typical cerebral SPECT scan of a patient with attentional, executive and
visuo-spatial disorders: note the hypoperfusion of the frontal (more
evident) and right parietal lobe

22. Shin SY et al (6) Cognitive function was assessed using a
battery of 12 standardized neuropsychological measures
yielding 16 indices. The proportion of persons who were
classified as cognitively impaired was 31%. The findings of
this study suggest that the burden of cognitive impairment
in RA is significant.
 Appenzeller et al (8) found cognitive impairment in 30%
of the RA cohort as compared to 8% of healthy controls.
Cont….

23. Bart J. Emmer et al9 studied the influence of inflammation
on cerebral metabolism in patients with rheumatoid
arthritis (RA) by means of proton magnetic resonance
spectroscopy (H-MRS).
They recruited 29 patients of RA and 25 healthy controls.
• Conclusion: Systemic inflammation in RA is associated with
metabolic changes in the brain.

24. The Latest Addition!!!!
 Schrepf et al; They showed that higher levels of
inflammation are associated with more positive connections
between multiple brain networks (functional and structural
MRI), which predicted fatigue, pain and cognitive dysfunction.
 Fifty four RA patients were studied
These patterns were remapped six months later and similar
patterns were observed .

25. Scatter plots showing the strength connectivity and levels of
erythrocyte sedimentation rate (ESR).

27. Neuroendocrine And Neurophysiological Effects
of Interleukin 6 in Rheumatoid Arthritis
Ernest H. S. Choy1 and Leonard H. Calabrese2
RA disease activity is associated with widespread inflammation, largely
mediated by the pro-inflammatory cytokine IL-6.

30. COGNITIVE DYSFUNCTION
ASSOCIATED WITH DMARDS
There are various theories explaining the possible mechanism
 Cognitive dysfunction may be due to folic acid depletion in CNS due
to use of methotrexate which is a folic acid antagonist.9
 DMARDs cause may exert a negative influence on learning and
memory by altering levels of certain neurotransmitters in the brain’s
hippocampus9.
 Some researchers also speculate that DMARD induced altrstion in
the GUT-BRAIN connections may also play a role.
 Almost all of the DMARDs, biologicals, corticosteroids, and
analgesics have at least some adverse effects on mental functioning
e.g. dizziness, drowsiness, headache, mood changes, anxiety etc.
which may have a significant impact on cognitive function13.

31. Why this relation is so important to study?
 Fatigue & depression, presence of chronic pain is also known to
adversely affect cognition; especially memory, mental flexibility and
attention.
This may possibly be due to the overlap between the brain
regions that involve both pain and cognition.
 Also patients have reported significant improvement in their fatigue
and related cognitive decline with biologic therapies, implying that
certain aspects of fatigue may be centrally driven and are mediated by
TNF or IL-6.
“These few studies have important implications in that, they highlight the potential burden of cognitive
impairment and its possible risk factors in persons with RA”

32. With controlling the inflammation
related to the Rheumatoid Arthritis, we
can limit the cognitive decline !!!!
Take Home Message

33. REFERENCES
1. Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W From inflammation to
sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9,
46–56 (2008).
2.Pradhan, A. D., Manson, J. E., Rifai, N., Buring, J. E. & Ridker, P. M. C-reactive protein, interleukin
6, and risk of developing type 2 diabetes mellitus. JAMA 286, 327–334 (2001).
3.Walker, Brian R.; Colledge, Nicki R.; Ralston, Stuart H.; Penman, Ian D., eds. (2014). Davidson's
principles and practice of medicine (22nd ed.). Churchill Livingstone/Elsevier.
4.Andrew Schrepf1, Chelsea M. Kaplan1 A multi-modal MRI study of the central response to
inflammation in rheumatoid arthritis.
5. Cognitive impairment in RA / M. Bartolini et al Clinical and Experimental Rheumatology 2002;
20491-497 .
6. Shin SY, Katz P, Wallhagen M, Julian L. Cognitive impairment in persons with rheumatoid
arthritis. Arthritis Care Res (Hoboken). 2012;64(8):1144-50.
7. Holmes C, Cunningham C, Zotova E, et al. Systemic inflammation and disease progression in
Alzheimer disease. Neurology. 2009;73(10):768-74.
8. Appenzeller S, Bertolo MB, Costallat LT. Cognitive impairment in rheumatoid arthritis. Methods
Find Exp Clin Pharmacol. 2004;26:339–43.
9. Emmer, Bart & Egon van der Bijl, A & W J Huizinga, Tom & C Breedveld, Ferdinand & C A
Steens, Stefan & Bosma, Gerlof & van Buchem, Mark & van der Grond, Jeroen. (2009). Brain
Involvement in Rheumatoid Arthritis A Magnetic Resonance Spectroscopy Study. Arthritis and
rheumatism. 60. 3190-5. 10.1002/art.24932.