Category Archives: Neurology

Prolactin

Secreted from the pituitary, but also a stress hormone (can be used to distinguish pseudo seizures from epileptic seizures). So can go up to 1000 in healthy people. Always worth repeating a high result at least 24hrs hours later, after a 20 minute rest.

Important because of prolactinomas, which can cause:

  • gynaecomastia
  • galactorrhoea
  • delayed puberty
  • space occupying lesion effects – headaches, visual field defects

Any lesion in the vicinity of the pituitary may also cause raised prolactin so not specific.

In children, high levels can be due to presence of macroprotein isoforms, which are not considered pathological – lab can check.

Arnold Chiari malformation

Thought to be congenital but often only picked up in adulthood when symptoms develop.

Type 1 most common, where cerebellar tonsils protrude into spinal canal, potentially putting pressure on brainstem, spinal cord and cause obstruction to flow of cerebrospinal fluid.

Can be found incidentally. Symptoms however include:

  • headache (especially occipital)
  • neck pain
  • numbness or paraesthesiae of fingers, arms, lower limbs
  • Coordination problems, dizziness

Can be complicated by upper spinal syringomyelia.

Rarely familial.

Fabry’s disease

Alpha-galactosidase defect, one of the lysosomal storage disorders, with accumulation in various tissues.

X-linked but females get disease, so not correct to call them carriers.

Classically, “pain attacks”, affecting the extremities. In the abdomen, can mimic appendicitis. Due to accumulation in nerves. Since nothing to really see on examination, easily misdiagnosed as functional.

Other features:

  • Renal impairment and failure.
  • Angiokeratomas – a more specific feature, but not always present, and seen in other lysosomal disorders.
  • Corneal changes
  • Cerebrovascular and cardiac problems

[Omim]

Cobalamin related metabolic disorders

Amino acid homocysteine is converted to methionine (“remethylated”) – cobalamin is involved in some of these processes, folate metabolism also important.

Various disorders.

Variety of presentations, at different ages:

  • Neurological (central and peripheral)
    • Feeding difficulties, apnoea in babies
    • Seizures
    • Subacute combined degeneration of spinal cord (peripheral neuropathy, ataxia, incontinence)
    • Acute and/or chronic encephalopathy – hypotonia, regression
    • Neuropsychiatric problems
  • vascular problems (stroke/embolism)
  • bone marrow (megaloblastic anaemia, cytopenia) – folate related
  • Atypical HUS
  • Glomerulopathy

Investigations

  • High homocysteine, usually
  • Vitamin B12 and folate, for differential
  • Methylmalonic acid (in urine)
  • Acylcarnitine
  • Methionine (usually goes low)

Treatment

Start intramuscular B12 (hydroxocobalamin) as soon as samples collected, to prevent end organ damage.

Betaine should be started if high homocysteine with low methionine found, helps push conversion to methionine.

Homocystinuria

Autosomal recessive condition of high homocysteine in blood and urine, causing similar neurological problems, thrombosis, Marfanoid appearance, downward subluxing lenses.

Needs low methionine diet. Betaine supplements help.

Mesial temporal sclerosis

= scarring in hippocampal area of temporal lobe. Commonly found on MRI in focal epilepsy (although focal EEG changes not always indicative of MRI abnormality, and other MRI lesions can account for temporal lobe epilepsy).

Often a history of febrile convulsions but unclear which comes first. Brain injury in early years from viral encephalitis or other cause often explains it.

Adjacent to language areas (assuming same side as language areas, which are usually on the left side in people who are right handed, but can be either side in people who are left handed) so seizures may affect speech. Also close to memory area so may not remember afterwards.

In people with drug resistant temporal lobe epilepsy, surgery can be useful.

Medication Overuse Headache

Well recognised condition where regular long term use of pain killers eg paracetamol leads to chronic headaches. Tends to be dull, particularly in the morning. And you might still get your migraine on top!

Of course, might be difficult to differentiate from chronic daily migraine (defined as more than 15 days in a month) or other headache that is not well controlled! It appears the majority of those with chronic migraine do not take or are not offered appropriate preventive medication.

To exclude, always have a day free of analgesia after any day where it has been used, and use a maximum of 3 days per week [Dr Abu-Arafeh’s advice].

Infantile spasms

Range of different shudders and twitches seen in babies and infants. Shudders and stereotypy can be dramatic, self stimulating behaviours, many kinds! Esp at 6-9/12, triggered by excitement but can also be boredom! So context important.  Can have a few together, but cluster would suggest epileptic.  Looks well. 

Differential is myoclonus, spasms (where at start may appear neurologically normal).

Infantile spasms can be mild and indistinguishable from myoclonus! So needs EEG to be sure, and even sleep EEG at that.  Many of these babies will need genetic and biochemical/metabolic input. Definition is 0.5-2secs.

Making diagnosis is urgent, as better initial control (in those without underlying aetiology) seem to have better developmental outcome). 

West syndrome – described by neurologist in his own son. May initially be developmentally normal, become less visually attentive.  Flexion of head and trunk, arms extend/flex, abduct/adduct (can be asymmetrical if underlying hemiplegia).  Briefly upset or dazed, may be grimace.  On waking or falling asleep. Various Youtube videos available.

Rarely metabolic (consider PKU, Menkes, molybendum cofactors along with others). More often structural esp tuberosclerosis (TS). Associated with Downs syndrome.  Do Woods lamp and genetics.

Investigations

EEG by definition is abnormal, but in early phase standard awake EEG may be normal.  Classical hypsarrhythmia in 50-70% = chaotic, high voltage.  But can be asymmetric.  If structural lesion, may be burst suppression (sudden high voltage then brief flattening) or focal features.

Treatment

UKISS study showed steroids superior to Vigabatrin unless TS, in which vigabatrin superior!  So urgent imaging and diagnosis important. ICISS (2016) show combination superior but needs longer follow up.  ACTH or prednisolone at prescriber’s discretion (ACTH is alternate day injection, expensive). 

Visual field loss with vigabatrin is seen in adults on long term treatment.  Side effects with both common, esp infection. 

Prognosis poor, even if spasms controlled, esp where underlying structural abnormality.

Sydenham’s chorea

One of the major criteria for Rheumatic fever but can sometimes be seen in isolation. See Jelly Jumps page.

Classically, involuntary, non-rhythmic movements, associated with emotional lability. Often misdiagnosed initially eg psychogenic [Mary King, ADC 2015]. Adults can get it rarely – tends to be relapse of childhood disease, female hormones seem to a trigger (eg pregnancy, oral or other contraceptives).

Chorea is a particular kind of movement – varies from smooth writhing (athetosis) to rapid, high amplitude jerks (ballism). Typical signs are repeated pouting of lips, milk maid sign (ask to squeeze fingers in hand), hyperextension of wrists, piano playing movements. Fine motor control usually lost, due to these extra movements. Gait disturbance common, can look like hip hop dancing! Ask to stick tongue out (unable to maintain – “motor impersistence”). Movements disappear in sleep. Can be hard to differentiate sometimes from stereotypies and tics, and of course these things are not uncommon so might co-exist.

Can be one side of the body predominantly (hemichorea). Underlying the involuntary movements is often a loss of tone, which may not become obvious until treatment started to suppress the chorea.

In severe cases, the loss of tone and weakness predominate (chorea paralyticum).

Variable severity. May just be some instability on walking, some difficulty with hand writing. Or unable to walk, talk, feed yourself.

Emotional lability well described, mild anxiety and poor attention less common – although developing a new disability without any cognitive impairment may explain some of it.

Pregnancy is associated with first onset but also relapse!

High risk of cardiac involvement, as type of rheumatic fever – 71% of cases in Turkish study, of which nearly half silent (no findings on clinical examination). Significant risk of long term morbidity, even if chorea never comes back, so always echo and give penicillin prophylaxis.

Diagnosis

Essentially clinical, with supportive evidence of recent streptococcal infection (ASO titre, throat swab). But recognised that infection can be up to 6 months before, or too mild to really notice.

Other tests are directed at differential diagnosis – lumbar puncture, MRI brain etc. Putaminal enlargement described.

Although there is evidence of anti-neuronal antibodies directed against the basal ganglia (eg anti D2R, see Church 2003), these are not specific or sensitive (see Sugar 2003, same time as Church) so not used in clinical practice. “Cunningham panel” is private test, see PANDAS.

Management

There is a UFMG rating scale for SC, from Brazilian Universidade Federal de Minas Gerais (UFMG), for research purposes but only looks at motor function.

Occupational and physiotherapy useful for maintaining function and muscle tone.

Treatment with valproate is effective for controlling symptoms but doesn’t speed up recovery. Haloperidol used previously but prob more side effects. Case reports to support carbamazepine and levetiracetam.

One RCT supporting steroids from Paz, Brazil 2006, 22 cases of SC, remission reduced to 54 days from 119 days. Various other reports of use of oral or IV steroids from Israel, Italy [2012, 2017], Brazil [Cardoso 2005], immunoglobulin [Holland, 2016, South Africa 2016]. Some improvement can be seen within a few days of IV steroids. In Italy, prednisolone reduced average duration of symptoms from 9 weeks to 4 weeks, and these were severe cases [Fusco 2012]. South African group found less neuropsychiatric complications at 6 months with IVIG treatment (IVIG preferred due to fear of TB reactivation). [Review by Deans and Singer, 2017]

A course of penicillin is usually given at diagnosis, to definitively clear any remaining strep but no evidence this really achieves anything and active infection probably long gone. Penicillin prophylaxis, on the other hand, essential if you have other features of rheumatic fever. If isolated chorea, arguable whether cardiac risk justifies or not.

Recurrence

Recurrence seen in 16-40%. More likely if poor compliance with penicillin prophylaxis, of course. Sometimes associated with rise in ASO or other evidence of new streptococcal infection but certainly not always the case. No obvious clinical parameter that might predict those at risk of recurrence. More likely if failure to remit in initial 6 months, can recur with pregnancy.

Higher recurrence rates seen in longest follow up – can recur up to 10 years after the initial episode, so might be underestimated by series with shorter follow up.

Usually recurrence is just chorea, even if you had other features of rheumatic fever to being with. Just two reports of heart disease worsening after recurrence of chorea [Israel and Thailand]. The Thailand study also had 2 cases where carditis, which had improved after initial diagnosis, came back again. Some suggest that perhaps recurrent chorea is a different disease altogether. [Israel, Arch Neurol. 2004; Turkey, PMID 27209549]

Prognosis

10% reported long term tremor in one study (10 years follow up). Long term neuropsychiatric difficulties increasingly recognised (49 studies so far, {Michael Morton and Nadine Mushet 2016 PMID 25926089] esp Obsessive-compulsive disorder but also Attention-deficit-hyperactivity disorder, affective disorders, tic disorders, executive function disturbances, psychotic features, language impairment.

Heart involvement improves in about a third of cases (whether silent or not).[PMID 22734303]

Differential

  • PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections) – ICD criteria.
  • Tics, Tourettes, stereotypies
  • Benign hereditary chorea (BHC) – rare. In infants low muscle tone, chorea, lung infections, and respiratory distress. In older children, delayed motor and walking milestones, myoclonus, dystonia (esp upper limb), motor tics, and vocal tics. The chorea often improves with time, in some cases myoclonus persists or worsens. Some have learning and behaviour problems, thyroid problems and recurring chest infections. Caused by mutations in the NKX2-1 gene (autosomal dominant)
  • Bilateral striatal necrosis is a rare condition where similar symptoms but chronic and permanent. Various causes, has been seen in association with streptococcus. Has been described in a case of Sydenham’s where symptoms recurred and then persisted, so not clear whether coincidence or it wasn’t really Sydenham’s in the first place.

Patient/family support at Sydenham’s Chorea Association.

[Review article Oosterveer, NL Ped Neuro 2010]

Meningitis

=inflammation of the meninges. Clinically neck stiffness/pain, headache, photophobia. Almost always vomiting. Usually infective, so usually fever too. Can be viral, bacterial or tuberculosis.

This clinical picture gets confused with the diagnosis of meningococcal disease. Meningococcus (gram negative diplococcus, very distinctive under the microscope) commonly causes meningitis but tends to cause a relatively mild disease with good outcome. It can also cause sepsis that is rapid onset and often fatal, meningitis is rarely a feature of this disease (indeed, having meningitis at the same time is a good prognostic feature).

Diagnosis is by lumbar puncture. Bugs often seen under microscope, which will usually give organism too, else rapid antigen tests available. White cells will be high (often in thousands if bacterial), protein high (can be over 2 if bacterial). Neutrophil predominance suggests bacterial but this is not v reliable esp in babies. Low glucose v suggestive of bacterial.

Can be complicated by raised intracranial pressure and seizures.

Organisms

In neonates, mostly Group B streptococcus, else gram negative bacilli. Listeria can present with sepsis or meningitis in young infants (90% under 30 days).

In older infants and children, mostly meningococcal disease, else pneumococcal or haemophilus. All declining rapidly as a result of immunisation, currently conjugate Hib, PCV-13 and MenACWY plus 4CMenB.

Treatment

Antibiotics to kill bugs. Steroids to reduce damage.

Ceftriaxone is ideal, broad spectrum, good CSF penetration, once daily. But listeria resistant, and gets chelated by calcium so contraindicated if likely HDU/ICU care where calcium infusions often necessary. Also contraindicated in preterm infants under 41/40 corrected, and in neonates esp jaundice, acidosis, hypoalbuminaemia.

For listeria, amoxicillin or ampicillin for 21 days in total, plus gentamicin for at least the first 7 days.

Dexamethasone has been shown to reduce complications eg deafness. Regimen is 0.15 mg/kg (max 10 mg) qds x 4 days. Only given to children ≥ 3 months old. Ideally given before or with first dose antibiotics – NICE says within 12 hours, assuming positive LP viz frankly purulent CSF, or CSF WCC > 1000/μl, or raised CSF WCC and protein > 1 g/L, or bacteria on Gram stain. Steroids should not be used in developing countries.

TB meningitis is a whole different ball game. See NICE NG33 before administering steroids.

Complications

Hydrocephalus, epilepsy, deafness. Particularly seen with Pneumococcal disease.

Recent evidence highlights that meningitis in early childhood is associated with higher depressive and anxiety symptoms, psychological and behavioural problems, and increased risk of psychotic experiences. Not just that, higher risk of ADHD, and lower IQ on average. Follow up therefore very important for young babies, and probably appropriate to warn families.

PANDAS

=Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) – tics and obsessive-compulsive disorder that have an acute onset and relapsing course, related to streptococcal infection.

Swedo first reported 4 cases of acute onset/exacerbation (2 with evidence of strep), treated successfully with immunosuppression, in 1995. Term first suggested in 1998 by National Institute of Mental Health. Presumed to be causative of course, mediated by inflammation. Has ICD code (8E4A) and everything, but still in 2019 “substantial controversy regarding a role for inflammation in tics and OCD”.

Because many children with similar presentations did not have evidence of streptococcus, a broader category of PANS, paediatric acute onset neuropsychiatric syndrome, was created, which is agnostic to cause. But such a broad category, almost unhelpful.

Finding evidence of previous streptococcal infection is not hard, nor uncommon. Tics and OCD are relatively common too. Although evidence of basal ganglia antibodies, these are non-specific. Lots of neurological problems have acute onset, not least epilepsy. 2020 US study found 91.4% of PANDAS cases had at least 1 of 4 neuronal antibodies, and most at least 2, cf 32% of normal controls. Levels dropped over time, as did symptoms. CaMKII (synaptic protein) activity higher too. [Frontiers in Psychiatry, 24 June 2020 – US study, including Swedo – compares PANDAS with Tourettes and OCD]

Neuropsychiatric problems are well recognised in and after Sydenhams chorea so it is not without basis (but other organ systems involved, and good evidence for inflammation). Encephalitis lethargica is an encephalitic illness with parkinsonism, dyskinesias, and psychiatric disturbance as dominant features. It is assumed to be autoimmune. NMDA-R encephalitis is an encephalitis with dramatic psychiatric disturbance, dyskinesias, cognitive alteration, and seizures, associated with autoantibodies against NMDA-R (originally described in relation to ovarian cancer).

Movement disorders are also described associated with systemic lupus erythematosus and antiphospholipid syndrome.

Diagnosis

PANS –

  • I. Abrupt, dramatic onset of obsessive-compulsive disorder or severely restricted food intake
  • II. Concurrent presence of additional neuropsychiatric symptoms, (with similarly severe and acute onset), from at least two of the following seven categories:
    • 1. Anxiety
    • 2. Emotional lability and/or depression
    • 3. Irritability, aggression, and/or severely oppositional behaviours
    • 4. Behavioural (developmental) regression
    • 5. Deterioration in school performance (related to attention-deficit/hyperactivity disorder [ADHD]-like symptoms, memory deficits, cognitive changes)
    • 6. Sensory or motor abnormalities
    • 7. Somatic signs and symptoms, including sleep disturbances, enuresis, or urinary frequency
  • III. Symptoms are not better explained by a known neurologic or medical disorder, such as Sydenham’s chorea.

So typically very ill, and usually referred urgently to psychiatric services. NB part III – PANS is a “diagnosis of exclusion”. [Swedo, 2012]

Family history is interesting – mental health issues including tic disorders often run in families, but so do autoimmune conditions, and Sydenham’s chorea.

Kiki Chang’s clinical evaluation guideline defines chorea-like movements seen in PANS as “piano playing movements of fingers when arms extended and eyes closed”, which is very specific. Also states this is only valid over age 8?! But then distinguishes this from “full chorea” (not specified), which should prompt search for a different diagnosis.

For PANDAS, specifies history of scarlatiniform rash, impetigo but also perianal/perivulval dermatitis. ASOT should show rise of at least 58% over 4-8 weeks, or else a single reading more than double the upper limit of normal.

Role of Cunningham panel stated as “useful ancillary information” for PANDAS, but unclear role in PANS.

[Chang 2015]

Treatment

Lack of controlled treatment trial with more than 50 patients.

2 studies looking at exacerbations and throat cultures in Acute onset and non acute onset, non relapsing tics/OCD.  V similar patterns of exacerbations and no obvious link to strep infection.

Controlled trials of antibiotics in PANDAS have not provided strong evidence. Large symptom improvements reported in placebo arm too, for example. No evidence for tonsillectomy. 2016 controlled trial of IVIG showed no benefit (n=35, doi: 10.1016/j.jaac.2016.06.017).

Groups often self selected so at risk of bias. No evidence for 4/52 azithromycin in PANS. 

2017 PANS/PANDAS guidelines (PANS/PANDAS Consortium) are not based on high impact journal research, mostly expert opinion.  The PANS/PANDAS approach may create, or validate, a parental expectation (from pre-visit internet searching) that these symptoms are to be feared because the brain is under inflammatory attack and may diminish expectations for spontaneous resolution. They may ultimately set the child up for multiple courses of antibiotics and/or immune modulatory treatments in response to natural waxing and waning of symptoms.

Is PANS/PANDAS diagnosis more acceptable than idiopathic psychiatric problem? Perverse incentives to diagnose, investigate and treat, of course.  Vaccines get blamed…

Useful perhaps that more research into inflammation getting done, even if putative triggers still unclear. Still v rare however to see high profile research in psychiatric conditions related to inflammation.

Just as interesting to research effect of parental anxiety and expectations on pattern of exacerbations and prognosis. 

[Donald Gilbert, J Child Neurology 2019]