My E-Log Book - By Sakshi, Roll No.145, 8th Semester

This is my analysis and subsequent discussion of a very interesting case of
 "A 42-year-old woman with multiple health events since birth".

Here is the link to the original blog post by Dr. Avinash Kumar-
https://classworkdecjan.blogspot.com/2019/05/42-f-with-severe-regular-edema-with_17.html?m=1

Our main aim is to prioritise the patient's current concerns regarding her health and to give appropriate therapeutic solutions to help solve those problems.

 To be able to come to a definitive diagnosis, we need to primarily fill any gaps in the patient's history, perform a complete physical exam and use relevant investigations to aid in our diagnosis which will give us an anatomical localisation and an etiological diagnosis to our problem.

The diagnosis would then help us treat the patient more effectively and efficiently.

After going through the original blog post as sited above, I would like to list out the current order of the patient's perceived priority of her problems and proceed to share my inputs in the form of some questions :

1) To be able to hike and have a steady, reliable cognitive function.
2) Frequent falls to the left.
3) Left foot and left hand giving out.
4) Requiring large amounts of salt to not feel sick.
5) Swelling from emotional stress emotional stress, eating the wrong thing, exercise and smoke.

1. The patient wants to be able to hike and have steady reliable cognitive function. Could her cognitive dysfunction be related to having bipolar disorder, while being on the Autism Spectrum Disorder? Or could it be related to distress from her current health problems of being unable to walk properly (falling on her left) and her left foot and hand starting to give out? Or could it be both?

Although, the reason for her left foot and hand giving out could be related to AMPD1 deficiency which is characterized by muscle weakness (which she is already diagnosed with)

Suggestive Therapy : As we dig deeper into the cause, Cognitive Behavioural Therapy (CBT) can be beneficial in improving depressive symptoms, mania severity, and psychosocial functioning.
Reference:
Efficacy of cognitive-behavioral therapy in patients with bipolar disorder: A meta-analysis of randomized controlled trials.

2. Why is it that only her left side is affected? What does it infer? Does she have ataxia- pointing towards a cerebellar, sensory or vestibular etiology.

3. We need more history and have to perform a detailed neurological exam.

- Behavior or personality changes, dizziness, fatigue, headaches, low muscle tone, tremors, trouble walking, wide gait, changes in voice could point towards cerebellar ataxia.

- Decreased proprioception and dysdiadochokinesia could point towards sensory ataxia.

- Vertigo, Nystagmus, Tinnitus could point towards vestibular ataxia.

4. Do we have any radiological investigations such as an MRI or a CT scan to back this up?

5. What could be the possible cause of ataxia in this case?

One probable cause could be: (please read the May 2020 Update at the end of the blog first)

Neuro-Behçet’s disease (NBD) -

"-It is a serious complication, which affects up to 10% of patients and may cause parenchymal and non-parenchymal disease.
 -Parenchymal disease, which affects the cerebrum, brainstem, cerebellum and spinal cord, can result in intra-axial cranial neuropathy, pyramidal disease, focal and multifocal cerebral lesions, and various brainstem syndromes depending on the extent of neuraxial involvement.
- Non-parenchymal disease includes cerebral venous sinus thrombosis, intracranial hypertension and meningitis, which may be recurrent.
- However, the commonest neurological symptom is migraine, which is similar to non-BD migraine. 
- Radiological investigations, including magnetic resonance imaging (MRI), computerised tomography (CT), magnetic resonance angiography (MRA), computerised tomographic venography (CTV), magnetic resonance venography (MRV), cerebrospinal fluid studies and electroencephalogram, might be required in appropriate cases."
Reference:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297594/

Other differentials include- 

Amyotrophic lateral sclerosis (ALS) - 

"During ALS, upper and lower motor neurons undergo degeneration and thus fail to deliver coordination messages to muscles. This ultimately leads to progressively weakening muscle, muscle atrophy, and twitching. Eventually, the brain stops initiating and controlling voluntary muscle movements, and the ALS patients fail to do day-to-day activities such as eating, drinking, speaking, walking and even breathing.

ALS can occur due to several reasons including enzymatic imbalance, and one of them is deregulated function of G6PD. In patients with ALS, levels and activities of G6PD were low, and their erythrocytes were correlated with increased lipid peroxidation in these cells. "
Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150112/

Another probable cause is Cerebral Ischemia, which may be related to the neuroprotective role of the enzyme (G6PD), as well as the potential of G6PD in oxidative damage and the Reactive Oxygen Species (ROS) produced in Cerebral Ischemia, which is absent in this patient due to the deficiency of the enzyme G6PD

 Other possibilities could be vitamin B 6 toxicity, alcohol or drug intoxication, head trauma, stroke, some autoimmune disease like multiple sclerosis, celiac disease, etc.

6. Why is she consuming so much Salt everyday?
Is she losing salt? But from where? She mentioned she doesn't sweat at all or very little.
I am unable to reason this out.


7. What can we do about the swelling?
We need to figure out the etiology of the swelling and treat accordingly, which I haven't been able to.

8. Does she have any history of skin allergies? angioedema? anaphylaxis?

Update -

Her Current problems as of May 2020 -
She was recently diagnosed with Behcet's Disease.

Behcet's Disease :

The International Criteria for Behçet’s disease (2006)8

Symptom	Score*
Genital aphthosis	Two points
Ocular lesions	Two points
Oral aphthosis	One point
Skin lesions	One point
Vascular lesions	One point
Pathergy	One point

*3 or more points satisfy criteria for Behçet’s disease

Overall, she is doing much better than last year. She does not have headaches, migrane aura or migrane anymore. She is able to sleep better.
1) Occasional hip and knee joint pain and cervical neck pain from a degenerative spine for which she prefers CBT over medication.
2) She still has swelling to stressors, but less severe overall.
3) Had Ulcers in mouth and vagina during her last flare.
4) She is using Nattokinase for atherothrombotic prevention
5) The patient may also have an underlying immunodeficiency syndrome which make her more prone to infections,which needs to be looked it.

___________________________________________

Discussion :

Efficacy of the various interventions she has been using -

-  Efficacy of supplementing exogenous D-ribose to improve muscle function in the mouse model of myositis :
"We treated normal and myositis mice with daily doses of D-ribose (4 mg/kg) over a 6-week time period and assessed its effects.
Treatment with D-ribose was found to have no statistically significant effects on body weight, grip strength, open field behavioral activity."
Reference:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681851/

-Effects of L-serine ingestion on human sleep (versus Placebo) :
"Subjective evaluation of sleep quality on waking was thus improved. In addition, objective evaluation using actigraphy showed that the “number of nighttime awakenings” tended to be decreased (p = 0.08). These findings suggest that intake of L-serine before going to bed may improve human sleep."
Reference:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155056/

- Here are some tables showing evidence based treatments of Behcet's disease using various pharmacological drugs and the indications for their use :

Reference:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992825/

My thoughts on possible changes to the treatment of Behcet's disease:
In our patient, since she cannot tolerate Cochicine due to having G6PD deficiency which poses a risk for Hemolytic crisis,
I recommend treatment with TUMOUR NECROSIS FACTOR INHIBITORS -
-Etanercept 25mg subcutaneous twice a week for 4 weeks could be given.

- or other possible treatment modalities are - Infliximab, Interferon alpha, Corticosteroids for flares.

The efficacies of the above therapies can be seen in the studies below:
- Anti-TNF therapy in the management of Behcet's disease:
" A 4- week randomized controlled trial of etanercept in patients with mucocutaneous manifestations reported that etanercept (25 mg twice/week, for 4 weeks) was effective in suppressing most mucocutaneous lesions. The drug had a clear effect on oral ulcers and nodular lesions, and the response was evident as early as the first week"
Reference :
https://academic.oup.com/rheumatology/article/46/5/736/2289806#35731379
-Another study where patients were treated with Infliximab and Adalimumab:
"Complete remission was defined by the disappearance of all neurological symptoms and by the improvement of radiological abnormalities at 12 months. Overall improvement following anti-TNF was evidenced in 16/17 (94.1%) patients including 6 (35.3%) complete response and 10 (58.8%) partial response."
Reference :
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907644/

- The Efficacy of Nattokinase :

"The purpose of this double-blind, placebo-controlled cross-over study was to comprehensively determine the effects of a single-dose of NK administration on coagulation/fibrinolysis profile in healthy young Japanese.
In conclusion, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously."

Reference:

https://www.nature.com/articles/srep11601

- I could not find any evidence that suggests Cimetidine for the treatment of swelling.

-Here is the sensitivity and specificity (Diagnostic Yield) of Next Generation Sequencing in Genetically Undiagnosed Patients with Primary Immunodeficiencies :
" Five studies described the sensitivity of the applied techniques, ranging from 83 to 100%, whereas specificity ranged from 45 to 99.9%. The percentage of patients who were genetically diagnosed ranged from 15 to 79%."

Reference:
https://link.springer.com/article/10.1007/s10875-019-00656-x