Introduction

Biotin–thiamine-responsive basal ganglia disease (BTBGD) is a reversible neurodegenerative disorder that is widely underdiagnosed. Though found in a pan-ethnic distribution, it was first recognized as an inherited disorder among a cluster of Saudi Arabian families that presented with subacute encephalopathy, seizures, dystonia, dysarthria, dysphagia, supranuclear facial palsy, and external ophthalmoplegia [1]. Brain MRI consistently demonstrates cytotoxic and vasogenic edema affecting regions of cortex, subcortical white matter, basal ganglia, brainstem, and cerebellum [2]. Importantly, patients rapidly respond to biotin and thiamine administration, with resolution of neurological symptoms and long-term protection with maintenance treatment. Failure to expediently diagnose and initiate treatment results in severe and irreversible neurological disabilities, highlighting the necessity to understand the spectrum of clinicoradiological presentations, pertinent diagnostic testing, and appropriate treatment.

First described in 1998, BTBGD was initially named “biotin-responsive basal ganglia disease,” as biotin but not thiamine had been recognized as the critical metabolite to which patients responded. Two years later, the disorder was linked to inactivating mutations in SLCA19A3, the gene encoding the thiamine transporter THTR2 [3]. This raised questions about the biotin-responsive nature and the need for thiamine supplementation. Since that time, patients responsive to thiamine but not biotin have been identified and, along with radiographic similarities to Wernicke encephalopathy (a nutritional deficit in thiamine), it has been established that intracellular depletion of thiamine is the main pathophysiological mechanism. This has led to the renaming of the disorder as BTBGD.

A spectrum of clinical phenotypes is now recognized [4]. These phenotypes range from more severe cases in infancy to milder phenotypes in adulthood. The clinical heterogeneity is likely related to the age at onset and may be due to age-specific changes in energy metabolism during early development. Though variably effective among phenotypic subgroups, thiamine and biotin supplementation remains the standard of care, and expedient diagnosis remains paramount.

Clinicoradiographic Spectrum

The disease course in BTBGD falls into one of three major categories defined by the age at onset [4]: (1) an early-infantile syndrome; (2) classic childhood-onset BTBGD; and (3) an adult-onset Wernicke-like encephalopathy. Table 25.1 summarizes cases and phenotypes reported to date.

In early infancy, two distinct presentations of BTBGD are described: a Leigh-like syndrome and atypical infantile spasms [5, 6]. Collectively, BTBGD in early infancy has only been reported in ~30 patients. The Leigh-like syndrome in this age group presents with poor feeding, vomiting, acute encephalopathy, and severe lactic acidosis. Brain MRI shows elevated T2 signal and vasogenic edema involving the perirolandic area, bilateral putamen, and medial thalamic nuclei with MRS showing lactate peaks [2]. Several patients also displayed restricted diffusion in several areas of the cerebral cortex and white matter, corpus callosum, basal ganglia, thalamus, brainstem, and cerebellum. These lesions develop into rarefaction or cystic degeneration of the white matter and, finally, progressive cerebral, cerebellar, and brainstem atrophy. Biotin and thiamine supplementation appear to have a limited efficacy, although two reported infants showed favorable responses [2]. Another presentation of BTBGD in early infancy was reported in four Japanese patients (age range 2–11 months) who developed atypical infantile spasms with multifocal spike discharges on EEG without hypsarrhythmia [7]. Neuroimaging in all cases demonstrated bilateral T2 hyperintensities in the thalami and basal ganglia, with subsequent development of diffuse cerebral atrophy on follow-up imaging. All patients developed severe developmental delay and spastic quadriplegia. Biotin supplementation was attempted in one patient at 8 months after onset of symptoms and was without benefit, but the timing of treatment and additional supplementation of thiamine remain untested in this subpopulation.

The classic presentation of BTBGD occurs in later childhood and is characterized by subacute encephalopathy, epilepsy, external ophthalmoplegia, dysarthria, dysphagia, and dystonia that progresses to severe rigidity and spastic quadriparesis. Initial symptoms typically emerge in developmentally normal children who experience a progressive course punctuated by episodic deterioration. In acute crises of the classic form, brain MRI shows bilateral and symmetrical lesions in the basal ganglia, particularly the head of the caudate and putamen, in addition to cortical gray and subcortical white matter involvement (Figure 25.1). Though less frequently reported, the thalami and cerebellum can also be involved. The affected brain areas show a mix of cytotoxic and vasogenic edema, which is an important diagnostic clue. In the acute phase, a ribbon of cortical and some subcortical involvement is frequently seen but there is sparing of the central white matter. In the chronic phase, atrophy and necrosis of the basal ganglia are evident, with mineralization on follow-up imaging. Patients with classic BTBGD are typically responsive to biotin and thiamine supplementation with resolution of symptoms within days of treatment. The rapid initiation of treatment and lifelong supplementation can lead to favorable outcomes while delayed treatment after the onset of irreversible brain damage results in severe neurological disability or death.

Figure 25.1 Brain MRI findings in a 26-year-old adult with BTBGD. On (a) fluid-attenuated inversion recovery images, symmetrical hyperintense lesions are present in the lenticular nuclei (arrows), medial thalamus (arrow heads), and in numerous discrete areas of subcortical white matter and cortex. (b) T1-weighted imaging with contrast demonstrated a blush of contrast in the basal ganglia and medial thalamus, consistent with vascular tight junction dysregulation. (c) Apparent diffusion coefficient and (d) diffusion-weighted imaging show vasogenic edema in the basal ganglia. Diffusion restriction is not present indicating that the hyperintense signal on diffusion-weighted imaging is an artifact from T2 shine-through. (f) On MRS, a lactate doublet (asterisk) is present on a voxel placed over the basal ganglia.

Adult-onset disease has been reported in two Japanese males [8], who presented in their second decade of life with status epilepticus, diplopia, nystagmus, ptosis, ophthalmoplegia, and ataxia. MRI of the brain showed high-intensity FLAIR signal in the bilateral medial thalamus and periaqueductal gray region, similar to findings in Wernicke encephalopathy. A dramatic response to high-dose thiamine was reported in both patients.

Movement Disorders Associated with BTBGD

In the most common form of childhood BTBGD, the neurological symptomology is predominated by dystonia, a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. The movements are typically twisted, patterned, or tremulous in quality and may involve the extremities, neck, or facial muscles. The pattern of dystonia in BTBGD is often generalized, but segmental and focal presentations may also manifest. The onset of dystonia during acute decompensations is temporally associated with vasogenic edema of the basal ganglia. The persistence of these imaging changes in the acute period is predictive of the extent of ensuing atrophy and subsequent dystonia. If treatment is initiated early in the course of the disease, before irreversible damage of the basal ganglia has occured, dystonia usually resolves within days of biotin and/or thiamine treatment.

Ataxia may also be prominent in the initial acute presentation and has been reported in up to 70–80% of cases [4]. Interestingly, explicit involvement of the cerebellum is less frequently reported but has been identified as swelling of the cerebellar cortex during the acute presentation and subsequent development of atrophy. The mechanism underlying the radio-clinical dissociation seen in most patients, however, is uncertain but may relate to subtle injuries within the cerebellum not readily identified by standard imaging protocols. Alternatively, the involvement of the efferent cerebellar tracts in their course through the brainstem or targets in the thalamus may produce ataxia in patients, without overt cerebellar involvement. The appearance of vasogenic edema and responsiveness to biotin and/or thiamine are congruent with basal ganglia manifestations and consistent with a common pathomechanism.

Dysarthria is a motor speech disorder frequently reported in BTBGD. While not considered a movement disorder, it will often coincide with dystonia and may involve dystonia of the bulbar muscles. Some cases of BTBGD have been reported to progress to aphonia and aphagia [9]. It is unclear whether dysarthria is similarly responsive to biotin and thiamine treatment.

Eye movement abnormalities observed in BTBGD range from nystagmus to roving eye movements and ophthalmoplegia [5]. In older patients with a Wernicke-like encephalopathy, diplopia, ptosis, and ophthalmoplegia have been reported [8].

Differential Diagnosis

As the clinicoradiographic spectrum of disease varies across developmental period, so does the differential diagnosis. In early infancy, the presentation may mimic infantile spasms or Leigh syndrome. In the case of infantile spasms, a complete work-up with EEG and brain MRI should be pursued. A distinguishing feature of BTBGD in this time period may be the lack of hypsarrhythmia expected in typical cases of infantile spasms. Initiation of biotin and thiamine treatment should be started concurrent with adrenocorticotrophic hormone or other standard therapy for epileptic spasms, while brain imaging along with metabolic and genetic work-up are pursued.

Leigh syndrome, or subacute necrotizing encephalomyelopathy, is a neuropathological entity characterized by variable foci of spongiform degeneration in the basal ganglia, thalamus, brainstem, cerebellum, spinal cord, and optic nerves, with a clinical picture reflecting the anatomical location of the lesions. Children frequently present with poor feeding, vomiting, acute encephalopathy, and severe lactic acidosis. If the clinical presentation and brain imaging are suggestive of Leigh syndrome, biotin and thiamine treatment should be considered while confirmation of the genetic defect is awaited.

In childhood and adolescence, a patient presenting with acute or subacute dystonia raises an extensive differential diagnosis. Among the dystonia plus disorders, we generally first consider treatable diseases such as inherited defects of dopamine synthesis and Wilson disease. A trial of carbidopa/levodopa treatment or screening for abnormal serum copper or ceruloplasmin levels can distinguish these disorders from BTBGD. Ophthalmological evaluation for Kayser–Fleischer rings or other ocular abnormalities can also be helpful. Another category of disorders that symmetrically affects the basal ganglia is that of neurodegeneration with brain iron accumulation [10]. Generally these show low T2 signal, and not high T2 signal, in the caudate, putamen, and thalamus, which can be a helpful differentiator (see also Chapter 16).

If the appropriate clinical and radiographic picture emerges to suggest BTBGD, the differential diagnosis should center on mitochondrial disorders that can present at the age of the patient in question. Like BTBGD, mitochondrial disorders frequently present with a episodic fluctuation of symptoms [11] during which patients exhibit seizures, extrapyramidal signs, basal ganglia involvement on brain MRI, and the presence of lactate on MRS. In contrast to BTBGD, however, mitochondrial diseases more commonly display hearing and vision impairment.

Among the mitochondrial disorders, those that most closely mimic BTBGD include pyruvate dehydrogenase deficiency and disorders of mitochondrial DNA (mtDNA) depletion. Pyruvate dehydrogenase deficiency presents with developmental delay, seizures, choreoathetosis, dystonia, episodic ataxia, lactate accumulation, and basal ganglia damage. The age at presentation can vary from infancy through childhood. Disorders that cause mtDNA depletion, such as SUCLA2– and SUCLG1-associated syndromes, can show T2 hyperintensity in the caudate and putamen, and a lactate peak on MRS [12]. Problems in overall growth, vision, and hearing are commonly noted and are generally not seen in BTBGD.

Apart from the inherited disorders, the symmetrical involvement of the basal ganglia can be seen in intoxication syndromes such as intoxication with methanol, carbon monoxide, and cyanide. Diagnosis centers on a history concerning for intoxication.