Peculiar Menstrual Psychosis in Adolescent | Child & Youth Mental Health Series

1. child & youth Mental Health Series Today’s topic: A Peculiar Presentation of Menstrual Psychosis in a Young Adolescent. Speakers: Dr. Anton Baksh MD FRCPC, Dr. Amy Robinson MD FRCPC Date

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7. Psychiatry Hx • “M” -14 yr female referred to UCC by Family MD & after CHEO ER visit 5 days prior • Family MD referral: • ER visit note: 4 day episode of anxiety- type Sx, difficulty sleeping, concentration, repeated vomiting, weight loss. Crisis noted disorganized speech with nonsensical answers. • Grade 9, intact family unit. Mother in education, dad in agriculture. One older sister.

8. Psychiatry Hx • Above was third episode in about a month or two • First episode over 1 month ago: sleep issues, anxiety, vomiting – duration 3-4 days • Second episode about 3 weeks before: similar Sx but slightly more intense along with difficulty maintaining ADLs without cueing and redirection

9. Psychiatry Hx • Latest episode • Started Tuesday previous week (7 days ago) at school. Pt complaints of feeling “lost”, decreased appetite, nausea with occasional vomiting, sleep trouble, agitated, disorganized speech and behavior. Possible auditory hallucinations. Looking fearful & needing to follow mother around everywhere in house. When questioned endorsed vague SI but M denied remembering this afterwards. • No other hyperactive or bizarre behaviors (at the time first I saw her, but this evolved) • Settling by Monday according to mother. I saw patient on Tuesday.

10. Psychiatry Hx: prior to onset of these episodes (premorbidly) • Doing ok, had good summer vacation, entered school with no major issues. No calls from the school with emotional or behavioral concerns. B student with slight decline in marks. • Interestingly, mom wondered about ADHD- “dreamy” child, distractible with problems with organization & completing tasks, but this has never been brought up by her teachers. • No Hx of aggressive or disruptive behavior in school or home.

11. Psychiatry Hx: prior to onset of these episodes (premorbidly) • Easygoing child. Able to make friends but a little shy. • Involved in soccer with participation in upcoming musical • Well behaved, follows household rules well within teenage norms • No concerns around drugs/EtOH • No concerns around conduct/delinquent behaviors • No relationships, not sexually active

12. Psychiatry Hx: prior to onset of these episodes (premorbidly) • No Hx of sustained depressive/dysphoric Sx. Happy with normal sleep & appetite prior to onset. Weight stable. • No Hx of GAD, OCD, panic attacks. • No prior safety concerns. No Hx NSSI. • Stressors: mild drama in classroom, no outright bullying, older sis away to university (close to her), some struggles with Math & French – course load decreased. No known Hx of abuse/trauma • No prior Psychiatric Hx

13. Past Medical HX • Was currently healthy. Past rash with Amoxil • Recurrent ear infections; as infant- got t-tubes • No Hx of seizures or concussions • Prn melatonin, no other meds. • M thinks her periods were regular (but not confirmed), Onset of menses age 12 or13. At the time I first saw her mom felt that there was no correlation with menses.

14. family Hx & developmental Hx • Mom has no MH issues. Mom has sister with LD and past Anorexia nervosa. Another sister of mom with Hx petit mal Sz. Mom has uncle with depression & distant cousin with schizophrenia. • No known MH issues on dad’s side, but has sister with dyslexia. • 18 yr sister healthy • Normal pregnancy, term baby. Easygoing infant • Slight language delay but attributed to recurrent ear infections, resolved with t-tubes • Did well at preschool. Transitioned to JK with no separation anxiety

15. HEREs where it gets interesting…Interview with patient & MSE • Tangential & would give answers fairly unrelated to questions I posed to her • “I’m really stressed out”, then spoke of a French test she was stressed out & worried about not pleasing her teacher. When asked if the test was last week (during her episode), unable to give clear answer. • Segued into feeling “angry” during last episode and “would listen to more music” • When asked about voices heard last episode, replied that “I snapped” & alluded to mild conflict with peer. In the end denied hallucinations. • When asked about triggers, tangentially talked about her grade 7 experience of being fearful of going off a higher diving board (for some reason was a topic on conversation on the drive here)

16. MSE (on initial assessment): • Alert and pleasant young lady who was quite cheerful during the interview and indeed she remained quite cheerful even when she was talking in the above in a tangential and disjointed fashion.  While her syntax was actually normal in terms of sentence structure (i.e., no word salad etc.), the answers to many questions posed to her did seem to have a very tenuous connection and were quite tangential.  She would also spontaneously come up with other comments and answers in a somewhat disjointed fashion.   • During this time, there was no psychomotor agitation noted.  Her eye contact was actually quite good.  While doing so, her affect remained quite bright and she had a smile on her face.  She was also able laugh at appropriate humorous comments.   • At the time of the assessment, M did not seem distracted by any particular hallucinatory phenomena.  She did not seem to exhibit any outright frank psychotic or delusional symptoms at the time of the assessment.  M denied any current suicidal or homicidal ideation.  Her attention and concentration were judged to be somewhat distractible.

17. Psychiatry Initial impression and plan • No firm Dx yet. No acute safety issues • Start Tx as a provisional anxiety D/O, but really, really needed to rule out organic causes. • Need time to see how this evolves or devolves. • Start low dose Celexa 10 mg/day. Start low dose Seroquel 25 mg hs for sleep regulation & may be slightly helpful for possible brewing psychosis. • Urgent EEG and MRI ordered • Flagged her chart to consider medical admission for observation and organic workup if presents to ER again with similar or worse episode

18. Next Psychiatry appt (20 days later) • Seen on a Monday. Separation anxiety started Saturday, anxious and dysregulated. • Poor sleep Sunday night. Fearful of coming to appointment but unable to say why. • Complaining of “I couldn’t poo today”, but no Hx of constipation. Nauseous, less interactive, monosyllabic responses, but more goal directed answers. No florid psychotic Sx at the time. • MRI normal. Continue meds & observation. • 2 days later due to deterioration was admitted to Medicine with similar Sx as before but greatly amplified agitation.

19. Medical intermission

20. Inpatient admission • Admitted after CHEO Emergency Department visit on December 12th • Admission Diagnosis: Rule out Encephalitis • Consultation by Neurology: • Recommended screening bloodwork, lumbar puncture • Discharged after 2 days to continue work-up as outpatient • Discharge Diagnosis: Behavioural changes NYD • Seen in post-hospital follow-up clinic by CHEO pediatrician, facilitated referral to community pediatrician and CHEO gynecology. • Two more Emergency Department visits (January 7th, February 2nd) – monthly pattern with menstrual association now more apparent, started on continuous OCP, for follow-up with DrBaksh and family MD • Eventual referral to Adolescent Medicine for further work-up of acute behavioural changes NYD, with possible link to her menstrual cycles

21. Medical work-up • Differential diagnosis of psychosis: • Neurologic • Systemic conditions with neuropsychiatric manifestations • Psychiatric

22. Medical work-up • Neurologic • Neurodegenerative disease • Space-occupying lesion (tumor, abscess) • Demyelinating disease • Immune-mediated encephalitis • Seizuredisorder

23. Medical work-up • Neurologic • Neurodegenerative disease • Space-occupying lesion (tumor, abscess) • Demyelinating disease • Immune-mediated encephalitis • Seizuredisorder Normal MRI

24. Medical work-up • Neurologic • Neurodegenerative disease • Space-occupying lesion (tumor, abscess) • Demyelinating disease • Immune-mediated encephalitis • Seizuredisorder • Lumbar puncture: • normal opening pressure, 12.25 (normal, <25 cm H2O) • Normal cell count • No oligoclonal bands (present in 85 - 95% of MS patients; autoimmune encephalitis) • Negative anti-NMDA receptor antibodies

25. Medical work-up • Neurologic • Neurodegenerative disease • Space-occupying lesion (tumor, abscess) • Demyelinating disease • Immune-mediated encephalitis • Seizuredisorder Normal awake EEG, including activation procedures  (photic stimulation and hyperventilation)

26. Medical work-up • Systemic conditions with neuropsychiatric manifestations • Systemic lupus erythematosus • Hyperthyroidism/hypothyroidism (Hashimoto encephalopathy) • Wilson disease • Acute intermittent porphyria • Infections • Paraneoplasticencephalitis

27. Medical work-up • - Positive ANA - homogenous, 1:320 • - Low-titer ANA (≤ 1:320) can be found in approximately 15% to 20% of the healthy childhood population • - ESR, CRP normal • - Ferritin slightly high (65, normal 10 – 56; possible acute phase reactant?) • - CBC normal (no anemia, leukopenia, thrombocytopenia) • - Normal creatinine • Further rheumatologic work-up: • -  Negative anti-dsDNA antibodies • Negative anti-ENA antibodies • Normal Immunoglobulin levels • Normal Complement 4 level, slightly low C3 level • Systemic conditions with neuropsychiatric manifestations • Systemic lupus erythematosus • Hyperthyroidism/hypothyroidism (Hashimoto encephalopathy) • Wilson disease • Acute intermittent porphyria • Infections • Paraneoplasticencephalitis

28. Medical work-up • Systemic conditions with neuropsychiatric manifestations • Systemic lupus erythematosus • Hyperthyroidism/hypothyroidism (Hashimoto encephalopathy) • Wilson disease • Acute intermittent porphyria • Infections • Paraneoplasticencephalitis Normal TSH

29. Medical work-up • Systemic conditions with neuropsychiatric manifestations • Systemic lupus erythematosus • Hyperthyroidism/hypothyroidism (Hashimoto encephalopathy) • Wilson disease • Acute intermittent porphyria • Infections • Paraneoplasticencephalitis Normal serum ceruloplasmin, slightly low serum copper (10.6, normal 13.5 - 36.5 umol/L)

30. Medical work-up • Systemic conditions with neuropsychiatric manifestations • Systemic lupus erythematosus • Hyperthyroidism/hypothyroidism (Hashimoto encephalopathy) • Wilson disease • Acute intermittent porphyria • Infections • Paraneoplasticencephalitis • Urine porphyrin screen positive, although urine quantitative porphyrins negative • Urine ALA, PBG normal (confirmed tests sent during acute attack, as can be normal in between)

31. Medical work-up • Systemic conditions with neuropsychiatric manifestations • Systemic lupus erythematosus • Hyperthyroidism/hypothyroidism (Hashimoto encephalopathy) • Wilson disease • Acute intermittent porphyria • Infections • Paraneoplasticencephalitis - Negative EBV serologies (IgM, IgG)  - Normal anti-streptolysin O titers (520, normal <=640 IU/mL) [Pediatric acute-onset neuropsychiatric syndrome (PANS) or childhood acute neuropsychiatric symptoms (CANS)] - Negative HIV, syphilis screening

32. Medical work-up • Systemic conditions with neuropsychiatric manifestations • Systemic lupus erythematosus • Hyperthyroidism/hypothyroidism (Hashimoto encephalopathy) • Wilson disease • Acute intermittent porphyria • Infections • Paraneoplasticencephalitis • Ovarian teratomas have been linked to neuropsychiatric syndromes, most notably anti-NMDA receptor encephalitis (negative) • abdominal/pelvic ultrasound normal – no masses, no hepatic involvement (seen in porphyria), no serositis (seen in lupus)

33. Medical work-up • Differential diagnosis of psychosis: • Neurologic • Systemic conditions with neuropsychiatric manifestations • Psychiatric ?

34. Medical management • Complete work-up for organic causes of psychosis • Consultations with: • Neurology (as inpatient) • Metabolics (given initial positive screen for Porphyria) • Gynecology • Started on continuous oral contraceptive pills in Emergency Department, switched to Depo-Provera contraceptive injections for more consistent menstrual suppression • Continued monthly ‘behavioural episodes’ occuring in a predictable pattern every 26 - 27 days, just before monthly menses (luteal phase)

35. Pulsatile GnRH in hypothalamus stimulates pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH), which stimulates follicle growth in ovary. Menstrual cycle Dominant follicle secretes increasing amounts of estrogen, which causes endometrial lining to proliferate Increasing estrogen decreases LH and FSH levels until a certain level, when “LH surge” triggers ovulation Remaining follicular cells become corpus luteum, which secretes estrogen and progesterone, which stabilizes endometrium and prepares for fertilized ovum If no implantation, no human chorionic gonadotropin produced, corpus luteum involutes Menstrual cycle divided into 3 phases: Follicular (proliferative) Ovulation Luteal (secretory) Progesterone and estrogen levels fall, trigger for shedding of endometrial lining (menses) Gray SH. Menstrual disorders. Pediatrics in Review, 2013.

36. Pulsatile GnRH in hypothalamus stimulates pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH), which stimulates follicle growth in ovary Menstrual cycle Dominant follicle secretes increasing amounts of estrogen, which causes endometrial lining to proliferate • Episodes occurring in late luteal phase of menstrual cycle, coinciding with waning estrogen levels • ?role of estrogen withdrawal in psychosis (or other psychiatric symptoms) Increasing estrogen decreases LH and FSH levels until a certain level, when “LH surge” triggers ovulation Remaining follicular cells become corpus luteum, which secretes estrogen and progesterone, which stabilizes endometrium and prepares for fertilized ovum If no implantation, no human chorionic gonadotropin produced, corpus luteum involutes Menstrual cycle divided into 3 phases: Follicular (proliferative) Ovulation Luteal (secretory) Progesterone and estrogen levels fall, trigger for shedding of endometrial lining (menses) Gray SH. Menstrual disorders. Pediatrics in Review, 2013.

38. Next Psychiatry appt (42 days later) • Evidence of correlation with menses getting stronger. Mom noted episodes now occurring 27 days apart starting a couple of days before menses. OCP started. EEG normal • Cheerful young lady, “normal self’ according to mom. Nothing untoward on MSE • Need to continue to see how this evolves as well as continue outpatient Peds workup • Seroquel not felt to be making much difference, D/C’ed. Continue Celexa 10 mg/day

39. April 30 appointment • Was in a good space. Now on Depo injection. • Was due to have an episode the previous weekend by mom’s calculations but did well. • Continue management • ARRRGHHH:started with pre-episode sleep issues the day after, but episode briefer and attenuated. Discussion on trial of Seroquel XR discussed.

40. June 4 appointment • Timing of this appointment for 1 week after predicted next episode • Episode started with sleep disturbance May 28. Previous one was April 30. • Mom started Seroquel XR 50 mg hs. Helped disturbed sleep • Psychotic Sx not as florid, visual hallucinations less pronounced and scary • Todays appointment coming down from episode, tired and less reactive, but alert & oriented, may be element of mild sedation. • No menstrual bleeding. • Mom advised to stop Seroquel after tonight. Call office with feedback.

41. Criteria of menstrual psychosis • 2005 paper by Brockington commonly quoted in a large number of subsequent articles on this topic • He defined menstrual psychosis as: • Acute onset on a background of normality • Brief duration with full recovery • Psychotic features • Circa-mensual (qmonthly) pattern in rhythm with menstrual cycle

42. Criteria • Brockington also suggested classification criteria based on timing within menstrual cycle: • Premenstrual psychosis: start in second half of cycle, stop abruptly with bleeding • Catamenial psychosis: begin with onset of menstrual flow • Paramenstrual psychosis: variable timing, but always in harmony with menstrual cycle • Mid-cycle psychosis: uncommon • Epochal menstrual psychosis: applies to bipolar psychosis lasting complete menstrual cycle with mood/affective flips linked to menstruation

43. Criteria • Clinical Sx in case reports compatible with Bipolar D/O so falls in spectrum of manic-depressive psychosis • Argued that psychotic features in monthly rhythm meshed with above Dx • Proportion go on to developing affective d/o, postpartum depression/psychosis • Brockington (2011) stated that in 80 confirmed cases, most had manic-depressive sx. • On the other hand: efficacy of antipsychotics and mood stabilizers questionable with better efficacy via hormonal Tx/interventions

44. Etiology of menstrual psychosis: #of theories • Psychodynamic: negative attitude & difficulty accepting being female = castration anxiety = disintegration of ego structure • Genetics: many case reports have first degree relatives with same or other psychosis related to female reproductive structure • Hormonal: no single hormonal mechanism ided, is felt to be due to a disturbance in the pituitary-ovarian axis. Also nonspecific association with Hypothalamic-Pituitary-Adrenal (HPA) axis

45. Etiology of menstrual psychosis: #of theories • Estrogen Hypothesis: triggered by sudden drop in estrogen after a sustained rise in susceptible females. Predicated on estrogen being protective for psychosis and reductions can precipitate or worsen psychosis • Estrogen known to have neuromodulatory effect on CNS dopamine, serotonin, noradrenergic and GABA pathways due to ability to cross blood-brain barrier • Interaction of serotonin/dopamine and estrogen/progesterone with other systems in the brain – implicates hypothalamic origin

46. Estrogen Hypothesis: evidence for this angle • Later age of psychotic disorder onset in females than males • Rising incidence of psychosis in females post-menopause (declining Est) • Greater severity symptoms in late onset psychosis in females than males • Period after childbirth = abrupt drop in Est & progesterone levels = 23X increased relative risk of affective psychotic episodes • Interventions associated with Est withdrawal can precipitate psychosis • Examples: termination of pregnancy, stopping estrogen medications, use of estrogen receptor blockers

47. epidemiology • Almost no data as most are case reports • Brockington (2011) mentions 80 cases with substantial evidence and 200 other possible cases • Most subsequent articles mention this number (if epidemiology mentioned at all)

48. Symptoms • Variable presentation of psychotic episodes between patients • Variable presentation of psychotic episodes within same patient • Paranoia, persecutory delusions, laughing at unknown stimuli, auditory & visual hallucinations • Confused, perplexed, frightened, tangential speech, nonsense answers, disorganized thinking • Depersonalization, insomnia, hyperactivity, emotional instability • ANS signs: flushing, appetite down, vomiting • Waxes and wanes • Like our teen, several cases presented with an initial Dx of an anxiety disorder before it evolved

49. Problem with DSM 5 • No specific Dx (or specifier) of menstrual psychosis • Karatepe et. al. (2010) argue that DSM & ICD take symptoms and signs into primary consideration rather than changes in cognitive/biological processes for diagnostic validity. • Makes it difficult to differentiate clinical conditions with similar signs and symptoms, but due to different processes.

50. Hmmm…food for thought, instead of a form of bipolar, is it a delirium? • DSM-5 diagnostic criteria for deliriumis as follows: • Disturbance of consciousness (ie, reduced clarity of awareness of the environment) occurs, with reduced ability to focus, sustain, or shift attention. • Change in cognition (eg, memory deficit, disorientation, language disturbance, perceptual disturbance) occurs that is not better accounted for by a preexisting, established, or evolving dementia. • The disturbance develops over a short period (usually hours to days) and tends to fluctuate during the course of the day. • Evidence from the history, physical examination, or laboratory findings is present that indicates the disturbance is caused by a direct physiologic consequence of a general medical condition, an intoxicating substance, medication use, or more than one cause.