Category Archives: Neurology

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.

Of course, might be difficult to differentiate from chronic daily migraine or other headache that is not well controlled!

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. See Jelly Jumps page.

Classically, involuntary, non-rhythmic movements, associated with emotional lability. Often misdiagnosed initially eg psychogenic [PMID 26374756].

Movements disappear in sleep. Typical signs are lip protrusion, milk maid sign (ask to squeeze fingers in hand), extension of wrists, ask to stick tongue out (unable to maintain).

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, 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). Other tests directed at differential diagnosis – lumbar puncture, MRI brain.

Although there is evidence of anti-neuronal antibodies directed against the basal ganglia (eg anti D2R), these are not specific or sensitive and only used in research.

Management

There is a rating scale for SC, from the Universidade Federal de Minas Gerais (UFMG), for research purposes.

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.

Good evidence for immunosuppression eg oral or IV steroids from Italy [PMID 29287833 ], immunoglobulin [Holland, PMID 26837939, South Africa 25987537]. Some improvement can be seen within a few days of IV steroids. In Utah and Italy, prednisolone reduced average duration of symptoms from 9 weeks to 4 weeks, and these were severe cases [PMID 22197452]. South African group found less neuropsychiatric complications at 6 months with IVIG treatment.

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, as for rheumatic fever, on the other hand essential.

Recurrence

Recurrence seen in 16-30%. 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. More likely if failure to remit in initial 6 months, can recur with pregnancy. [Turkey, PMID 27209549]

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.

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]

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.

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)

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”.

Part of PANS, paediatric acute onset neuropsychiatric syndrome, 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.

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.

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.

PANDAS allowed to have choreiform movements but not “frank chorea”.  Subtle!?

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. 

Is 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.

2017 PANS/PANDAS guidelines (PANS/PANDAS Consortium) [J Child Adolesc Psychopharmacol. 2017;27(7):594–606 – open access] 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.

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

[Donald Gilbert, J Child Neurology 2019 https://doi-org.knowledge.idm.oclc.org/10.1177%2F0883073819848635]

Juvenile Myoclonic Epilepsy

Common form of childhood epilepsy. cf juvenile absence epilepsy.

One or more of:

  1. Myoclonic jerks on waking and first hour of day, esp if tired
  2. Absences (typical) in about half
  3. Tonic-clonic, on waking and first hour of day, esp if tired
  • Precipitated by alcohol, arousal!
  • Mid teens, hence alcohol/arousal…
  • 3-6 Hz spike and wave seen on EEG.
  • Often photosensitive (40%), unlike Juvenile absence epilepsy.
  • Very sensitive to valproate. Else lamotrigine, levetiracetam.
  • Usually life long, despite the name.

Juvenile absence epilepsy

Quite different from childhood absence epilepsy! Less nice.

  • Rare
  • Onset 9-12 years but occasionally younger.
  • Non-remitting, despite the name
  • Longer absences eg 45 seconds, more frequent
  • Automatisms (eg eye flickering, lip smacking), may be able to continue some automatic activities during absence
  • Occasional tonic clonic seizures, myoclonic jerks despite the name! But much less commonly seen than in juvenile myoclonic epilepsy (JME).
  • Not photosensitive cf JME.
  • Treat with valproate, ethosuximide (unless tonic clonic seizures), or lamotrigine.

Polymicrogyria

One of the most common malformations of cortical development.  

Bilateral perisylvian polymicrogyria (BPP) is the most common subtype , causes the congenital bilateral perisylvian syndrome:

  • oromotor dysfunction,
  • cognitive impairment,
  • epilepsy.

Many possible causes eg vascular or hypoxaemic insults (eg twin-to-twin transfusion syndrome) and congenital cytomegalovirus infection. Genetic causes also important – some syndromes eg 1p36.3 and 22q11.2 deletion syndromes. PIK3R2  gene defects are the most common genetic cause of BPP in patients with normal head size, and the second (to  PIK3CA ) most common cause of polymicrogyria associated with large head size. RTTN gene  also associated with isolated BPP.

[Lancet Neurology, The, 2015-12-01, Volume 14, Issue 12, Pages 1182-1195]